ABCMdb

ABCC8 p.Ala1369Ser

ClinVar:	c.4105G>T , p.Ala1369Ser N , Likely benign
Predicted by SNAP2:	C: N (87%), D: N (97%), E: N (97%), F: N (72%), G: N (97%), H: N (97%), I: N (97%), K: N (97%), L: N (97%), M: N (97%), N: N (97%), P: N (97%), Q: N (97%), R: N (97%), S: N (87%), T: N (66%), V: N (53%), W: N (82%), Y: N (87%),
Predicted by PROVEAN:	C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Candidate gene association study in type 2 diabete... PLoS Biol. 2003 Oct;1(1):E20. Epub 2003 Oct 13. Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O'Rahilly S, Wareham NJ
Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.
PLoS Biol. 2003 Oct;1(1):E20. Epub 2003 Oct 13., [PMID:14551916]

Abstract [show]
Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

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79 In ABCC8, five SNPs were associated with disease status under multiple models; the strongest evidence for association with disease were with SNP79 and SNP81, respectively an intronic variant (OR 1.68, p ¼ 0.0043; see Table 2) and a missense variant A1369S (OR 1.68, p¼0.0048; see Table 2). Login to comment
85 O2 0.0258 KCNJ11 74 3pþ215 0.75 0.0299 0.76 0.0021 0.59 0.0027 76 A190 0.79 0.0127 0.62 0.0260 77 E23K 1.49 0.0333 ABCC8 79 IVS38þ54 1.25 0.0131 1.68 0.0043 81 A1369S 1.23 0.0256 1.68 0.0048 84 IVS18-36 3.43 0.0163 87 K649 3.90 0.0157 89 IVS11-74 2.82 0.0480 ABCC9 100 IVS13-76 1.99 0.0339 LIPC 114 IVS1þ49 0.76 0.0468 0.77 0.0291 PYY 123 IVS3þ68 1.47 0.0240 1.47 0.0157 INSR 131 IVS6þ43 1.48 0.0039 1.32 0.0119 SNP identifiers (SNPID), OR, significance level (p value), and genetic model are shown. p values for the additive effect are for the test for a linear trend across the genotypes, which were coded as 0 ¼ 11, 1 ¼ 12, 2 ¼ 22. Login to comment
114 Association of KCNJ11 and ABCC8 Variants with Type 2 Diabetes Status Adjusted for E23K Genotype Gene SNPID SNP Allele 2 Dominant (22 þ 12) Additive Effect Allele 2 Recessive (11 þ 12) OR p Value OR p Value OR p Value KCNJ11 74 UTR3þ215 0.78 0.0846 0.78 0.0256 0.65 0.0149 76 A190 0.79 0.0948 0.82 0.0765 0.67 0.0672 ABCC8 79 IVS38þ54 1.62 0.3644 2.09 0.0652 3.67 0.0536 81 A1369S 1.36 0.5461 1.68 0.1878 2.85 0.1339 84 IVS18-36 0.99 0.9392 1.05 0.7251 3.23 0.0401 87 K649 1.09 0.5562 1.16 0.2767 4.36 0.0214 89 IVS11-74 0.83 0.1934 0.91 0.4635 3.16 0.0445 SNP identifiers (SNPID), OR, significance level (p value), and genetic model are shown. p Values for the additive effect are for the test for a linear trend across the genotypes, which were coded as 0 ¼ 11, 1 ¼ 12, 2 ¼ 22. Login to comment
531 The A1369S variant in the gene ABCC8 should have been written S1369A.The alanine variant is associated with increased risk.This mistake affects Tables 2 and 4,the text of the article in the section entitled "ABCC8 and KCNJ11" on page 45,and the Supporting Information Tables S1 and S2. Login to comment

[hide] Relationship between E23K (an established type II ... Eur J Hum Genet. 2007 Jun;15(6):679-84. Epub 2007 Mar 7. Barber TM, Bennett AJ, Gloyn AL, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Taponen S, Weedon MN, Hartikainen AL, Wass JA, Jarvelin MR, Zeggini E, Franks S, McCarthy MI
Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels.
Eur J Hum Genet. 2007 Jun;15(6):679-84. Epub 2007 Mar 7., [PMID:17342155]

Abstract [show]
Polycystic ovary syndrome (PCOS) is strongly associated with hyperinsulinaemia and type II diabetes (T2D). Sequence variation within KCNJ11 (encoding Kir6.2, the beta-cell inwardly rectifying potassium channel) is implicated in the pathogenesis of neonatal diabetes, hyperinsulinaemia of infancy and multifactorial T2D. Comprehensive tagging studies have demonstrated that the KCNJ11 E23K variant (or ABCC8 A1369S in LD>0.9) is responsible for the known association between KCNJ11 and T2D. Given the phenotypic overlap between PCOS and T2D, we investigated whether E23K is involved in susceptibility to PCOS and related traits. Case-control analyses for the KCNJ11 E23K variant were performed in (a) 374 PCOS cases and 2574 controls of UK British/Irish origin, and (b) 550 women with PCOS symptoms and 1114 controls from a Finnish birth cohort. The relationship between E23K genotype and androgen levels (a key intermediate phenotype relevant to PCOS) in 1380 samples was studied. The UK case-control analysis revealed no association between E23K genotypes and PCOS status (P=0.49; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (P=0.19). Similarly, the Finnish case-control analysis showed no association between E23K genotypes and PCOS status (P=0.75; Cochran-Armitage test), and no significant relationship between E23K genotype and androgen measures in the samples for which these phenotypes were available (Finnish controls, P=0.25; Finnish cases, P=0.08). In conclusion, these data (involving >4600 subjects) provide no evidence that common variants of the KCNJ11 E23K polymorphism have a major influence on PCOS susceptibility, though modest effect sizes (OR<1.25) cannot be excluded.

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2 Comprehensive tagging studies have demonstrated that the KCNJ11 E23K variant (or ABCC8 A1369S in LD40.9) is responsible for the known association between KCNJ11 and T2D. Login to comment
15 Rare mutations in KCNJ1114 can lead to neonatal diabetes and hyperinsulinaemia of infancy (depending on the direction of their effect on channel function).15 Previous comprehensive tagging studies have demonstrated that common variation within the single exon of KCNJ11, in particular the E23K variant (which is in almost complete LD (40.9) with the A1369S variant within the neighbouring ABCC8 but with no other nonsynonymous variants in KCNJ11), is heavily implicated in susceptibility to multifactorial T2D.16 Furthermore, E23K is the polymorphism within KCNJ11 most likely to be aetiological for T2D, on both statistical and functional grounds.16-19 Given the strong metabolic, physiological and epidemiological overlap between PCOS and T2D (thereby obviating the need for retagging of KCNJ11 in PCOS), we set out to test the hypothesis that the E23K polymorphism might impact on PCOS risk, through case-control studies and analysis of androgen levels as a continuous phenotype relevant to PCOS. Login to comment

[hide] Type 2 diabetes-associated missense polymorphisms ... Diabetes. 2007 Feb;56(2):531-6. Florez JC, Jablonski KA, Kahn SE, Franks PW, Dabelea D, Hamman RF, Knowler WC, Nathan DM, Altshuler D
Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
Diabetes. 2007 Feb;56(2):531-6., [PMID:17259403]

Abstract [show]
The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over approximately 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.

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0 Brief Report Type 2 Diabetes-Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program Jose C. Florez,1,2,3,4 Kathleen A. Jablonski,5 Steven E. Kahn,6 Paul W. Franks,7,8 Dana Dabelea,9 Richard F. Hamman,9 William C. Knowler,8 David M. Nathan,2,3 and David Altshuler1,2,3,4,10 for the Diabetes Prevention Program Research Group* The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. Login to comment
6 Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. Login to comment
15 Interestingly, this variant is in strong linkage disequilibrium with the upstream missense single nucleotide polymorphism (SNP) A1369S in the adjacent gene ABCC8, which encodes the functionally related sulfonylurea receptor SUR1 (7,8,13); thus, in all examined populations, lysine carriers at KCNJ11 E23K almost invariably carry the alanine allele at ABCC8 A1369S, and it remains possible that either or both variants are actually required to mediate these effects. Login to comment
66 In this study, we addressed five distinct hypotheses, limiting subsequent analyses to their further refinement: 1) genotype at KCNJ11 E23K (or at ABCC8 A1369S, as both are highly correlated) influences diabetes incidence, 2) this genetic effect is modified by a lifestyle intervention or 3) by metformin treatment, 4) genotype at KCNJ11 E23K affects insulin secretion, and 5) genotype at KCNJ11 E23K does not affect insulin resistance. Login to comment
77 We found strong linkage disequilibrium between ABCC8 A1369S and the downstream variant KCNJ11 E23K in the five ethnic groups: Lewontin`s DЈ (25) and r2 were 0.97/0.93, 0.98/0.93, 0.99/ 0.95, 0.99/0.88, and 0.97/0.95 in U.S. Caucasians, African Americans, Hispanic Americans, Asian Americans, and American Indians, respectively. Login to comment
78 Thus, not surprisingly, our findings in carriers of the alanine allele at ABCC8 A1369S were essentially the same as those for lysine carriers at KCNJ11 E23K in all of the analyses reported below. Login to comment
106 TABLE 2 Baseline measures of insulin secretion and sensitivity according to KCNJ11 E23K and ABCC8 A1369S genotypes in the DPP KCNJ11 E23K E/E E/K K/K P value (E/E vs. E/K)* P value (E/E vs. K/K)* n 1,658 1,445 364 Ins index ͓(␮U/ml)/(mg/dl)͔ 1.07 (0.94) 1.04 (0.87) 0.97 (0.79) 0.046 0.003 ISI ͓(␮U/ml) ϫ (mmol/l)͔-1 0.161 (0.121) 0.162 (0.124) 0.169 (0.144) 0.98 0.76 Fasting insulin (␮U/ml) 24 (16) 24 (17) 23 (18) 0.85 0.73 ABCC8 A1369S S/S A/S A/A P value (S/S vs. A/S)* P value (S/S vs. A/A)* n 1,635 1,424 378 Ins index ͓(␮U/ml)/(mg/dl)͔ 1.07 (0.95) 1.03 (0.86) 0.97 (0.81) 0.02 Ͻ0.01 ISI ͓(␮U/ml) ϫ (mmol/l)͔-1 0.162 (0.121) 0.162 (0.123) 0.172 (0.145) 0.87 0.67 Fasting insulin (␮U/ml) 24 (17) 24 (17) 22 (17) 0.73 0.88 Data are median (interquartile range). Login to comment

[hide] Association study of candidate gene polymorphisms ... Arch Med Res. 2011 Aug;42(6):523-31. Epub 2011 Nov 1. Duran-Gonzalez J, Ortiz I, Gonzales E, Ruiz N, Ortiz M, Gonzalez A, Sanchez EK, Curet E, Fisher-Hoch S, Rentfro A, Qu H, Nair S
Association study of candidate gene polymorphisms and obesity in a young Mexican-American population from South Texas.
Arch Med Res. 2011 Aug;42(6):523-31. Epub 2011 Nov 1., [PMID:22056417]

Abstract [show]
BACKGROUND AND AIMS: Obesity is increasingly a health problem and a risk factor for diabetes in young Mexican-American populations. Genetic association studies in older, mostly non-Hispanic populations have reported that polymorphisms in the candidate genes HSD11B1, CRP, ADIPOQ, PPARG, ANKK1, ABCC8 and SERPINF1 are associated with obesity or diabetes. We analyzed the polymorphisms rs846910, rs1205, rs1501299, rs1801282, rs1800497, rs757110 and rs1136287 in these candidate genes, for association with obesity and metabolic traits in a young Mexican-American population from south Texas. METHODS: Genotyping of the seven common SNPs were performed by allelic discrimination assays in 448 unrelated Mexican Americans (median age = 16 years) from south Texas. chi(2) tests and regression analyses using additive models were used for genetic association analyses adjusting for covariates; p values were corrected for multiple testing by permutation analyses. RESULTS: rs1800497 (ANKK1) shows association with waist circumference (p = 0.009) and retains the association (p = 0.03) after permutation testing. Analysis of metabolic quantitative traits shows that rs846910 (HSD11B1) was associated with HOMA-IR (p = 0.04) and triglycerides (p = 0.03), and rs1205 (CRP) with HOMA-IR (p = 0.03) and fasting glucose levels (p = 0.007). However, the quantitative traits associations are not maintained after permutation analysis. None of the other SNPs in this study showed associations with obesity or metabolic traits in this young Mexican-American population. CONCLUSIONS: We report a potential association between rs1800497 (linked to changes in brain dopamine receptor levels) and central obesity in a young Mexican-American population.

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148 rs757110 (Ala1369Ser) in ABCC8 is associated with T2D in Caucasian populations (65). Login to comment
149 rs757110 (Ala1369Ser) in ABCC8 is associated with T2D in Caucasian populations (65). Login to comment

[hide] Understanding the genetic basis for adverse drug e... Pharmacotherapy. 2010 Feb;30(2):195-209. Bai JP, Lesko LJ, Burckart GJ
Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors.
Pharmacotherapy. 2010 Feb;30(2):195-209., [PMID:20099993]

Abstract [show]
The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.

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101 Blockade of the mutant KATP channel by sulfonylurea provides the genetic basis for understanding the efficacy of sulfonylurea agents in treating neonatal diabetes.51 In a diabetes prevention randomized clinical trial of 3548 patients at 27 centers, both KCNJ11 E23K (rs5219) and ABCC8 A1369S (rs757110) were statistically significantly associated with impaired glucose tolerance at baseline.52 The alanine carrier of ABCC8 A1369S seemed to carry the lysine allele of KCNJ11 E23K as well. Login to comment
102 Of interest, this study revealed that the lysine allele (or the alanine allele of ABCC8 A1369S) seemed to protect the development of diabetes at the year-1 assessment (p<0.01). Login to comment

[hide] Haplotype structure and genotype-phenotype correla... Diabetes. 2004 May;53(5):1360-8. Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D
Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.
Diabetes. 2004 May;53(5):1360-8., [PMID:15111507]

Abstract [show]
The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r(2) > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby beta-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor gamma, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.

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5 We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. Login to comment
105 We noted that in this initial haplotype characterization, SNP 63 (marking an Ser3Ala change at the 1,369 position in exon 33 of SUR1) is in near-perfect LD with SNP 65 marking Kir6.2 E23K (r2 ϭ 0.98), such that in our CEPH panel, virtually every chromosome containing the K allele in E23K also contains the A allele in A1369S. Login to comment
118 lation (r2 ϭ 1.0), suggesting that in at least these three samples, the effects of E23K and A1369S are likely to be genetically indistinguishable. Login to comment
132 The other two coding variants in this region (SUR1 A1369S and Kir6.2 L270V) showed a signal for association that is statistically indistinguishable from that of E23K. Login to comment
133 LD between SUR1 A1369S and Kir6.2 E23K was very strong (r2 Ͼ 0.9), and we again observed that Ͻ1% of haplotypes separate the two SNPs in this substantially larger sample. Login to comment
165 LD between A1369S and E23K is nearly complete (r2 ‫؍‬ 0.98), making it impossible to distinguish (based on population-based data) which polymorphism may be the causal variant. Login to comment
166 TABLE 2 Association of other Kir6.2 tag SNPs with type 2 diabetes SNP OR P 95% CI rs2074310 1.14 0.02 1.02-1.28 rs2067043 1.14 0.04 1.01-1.28 rs757110 (A1369S) 1.14 0.02 1.02-1.28 rs1800467 (L270V) 1.25 0.05 1.00-1.58 rs1557764 1.11 0.09 0.98-1.25 rs2354867 1.15 0.02 1.03-1.30 rs1073443 0.88 0.03 0.78-0.99 In addition to E23K, seven SNPs tag the haplotype block that includes KCNJ11. Login to comment
196 However, as noted by others (3,9), we have documented strong LD of the E23K variant in Kir6.2 with another coding variant in the adjacent SUR1 gene, A1369S in exon 33. Login to comment
197 Because in our samples virtually every chromosome containing the K allele in E23K also contains the A allele in A1369S, it is not yet possible to distinguish on genetic grounds which one of the two variants-or, for that matter, TABLE 4 Genotype-phenotype correlation of measures of insulin secretion and E23K Nondiabetic discordant siblings General Recessive Allele E (39) K (39) P* EE or EK (22) KK (22) P* Ins index 9.74 Ϯ 5.8 6.89 Ϯ 3.9 0.006† 9.64 Ϯ 6.1 7.45 Ϯ 4.4 NS Disp index 7.76 Ϯ 3.0 6.30 Ϯ 3.5 0.06† 7.69 Ϯ 3.1 7.00 Ϯ 4.0 NS Scandinavian control subjects Genotype EE (168) EK (353) KK (153) P EE/EK KK P Ins index 5.31 Ϯ 4.0 5.59 Ϯ 4.9 4.52 Ϯ 3.3 EE vs EK:NS 5.50 Ϯ 4.7 4.52 Ϯ 3.3 0.008‡ EE vs KK: 0.028† EK vs KK: 0.008‡ Disp index 6.32 Ϯ 3.8 5.91 Ϯ 3.6 5.59 Ϯ 3.7 EE vs EK: NS 6.04 Ϯ 3.6 5.47 Ϯ 3.8 NS EE vs KK: 0.08† EK vs KK: NS Data are means Ϯ SD. Login to comment
203 One genetic approach to establish this difference involves genotyping both polymorphisms in a much larger sample to achieve enough power to test the risk attributable to the haplotypes on which E23K and A1369S are separated. Login to comment
205 A second alternative is to genotype both polymorphisms in a population in which chromosomes recombinant for E23K and A1369S are present at a higher frequency. Login to comment
209 This report does not specify which isoform of ABCC8 was used at the 1,369 amino acid position in the cell-based model; it is interesting that A1369S lies near the second nucleotide binding fold of SUR1, which may affect its binding affinity and influence the results observed. Login to comment
211 Although it is not clear which A1369S variant was used in the functional studies above, the authors do find that the increase in the E23K mutant channel activity persists in truncated constructs that lack the ability to dimerize with the SUR1 molecule, albeit at much higher palmitoyl-CoA concentrations. Login to comment
212 It is intriguing to hypothesize that both E23K and A1369S could interact in cis and that additional functional studies involving both variants would be valuable to clarify their possible respective contributions. Login to comment
104 We noted that in this initial haplotype characterization, SNP 63 (marking an Ser3Ala change at the 1,369 position in exon 33 of SUR1) is in near-perfect LD with SNP 65 marking Kir6.2 E23K (r2 afd; 0.98), such that in our CEPH panel, virtually every chromosome containing the K allele in E23K also contains the A allele in A1369S. Login to comment
117 lation (r2 afd; 1.0), suggesting that in at least these three samples, the effects of E23K and A1369S are likely to be genetically indistinguishable. Login to comment
131 The other two coding variants in this region (SUR1 A1369S and Kir6.2 L270V) showed a signal for association that is statistically indistinguishable from that of E23K. Login to comment
164 LD between A1369S and E23K is nearly complete (r2 d1d; 0.98), making it impossible to distinguish (based on population-based data) which polymorphism may be the causal variant. Login to comment
195 However, as noted by others (3,9), we have documented strong LD of the E23K variant in Kir6.2 with another coding variant in the adjacent SUR1 gene, A1369S in exon 33. Login to comment
202 One genetic approach to establish this difference involves genotyping both polymorphisms in a much larger sample to achieve enough power to test the risk attributable to the haplotypes on which E23K and A1369S are separated. Login to comment
204 A second alternative is to genotype both polymorphisms in a population in which chromosomes recombinant for E23K and A1369S are present at a higher frequency. Login to comment
208 This report does not specify which isoform of ABCC8 was used at the 1,369 amino acid position in the cell-based model; it is interesting that A1369S lies near the second nucleotide binding fold of SUR1, which may affect its binding affinity and influence the results observed. Login to comment
210 Although it is not clear which A1369S variant was used in the functional studies above, the authors do find that the increase in the E23K mutant channel activity persists in truncated constructs that lack the ability to dimerize with the SUR1 molecule, albeit at much higher palmitoyl-CoA concentrations. Login to comment

[hide] Genetic variations in the pancreatic ATP-sensitive... Acta Diabetol. 2009 Mar;46(1):43-9. Epub 2008 Aug 29. Chistiakov DA, Potapov VA, Khodirev DC, Shamkhalova MS, Shestakova MV, Nosikov VV
Genetic variations in the pancreatic ATP-sensitive potassium channel, beta-cell dysfunction, and susceptibility to type 2 diabetes.
Acta Diabetol. 2009 Mar;46(1):43-9. Epub 2008 Aug 29., [PMID:18758683]

Abstract [show]
The KCNJ11 and ABCC8 genes encode the components of the pancreatic ATP-sensitive potassium (KATP) channel, which regulates insulin secretion by beta-cells and hence could be involved in the pathogenesis of type 2 diabetes (T2D). The KCNJ11 E23K and ABCC8 exon 31 variants have been studied in 127 Russian T2D patients and 117 controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The KCNJ11 E23 variant and the ABCC8 exon 31 allele A were associated with higher risk of T2D [Odds ratio (OR) of 1.53 (P=0.023) and 2.41 (P=1.95 x 10(-5))], respectively. Diabetic carriers of the ABCC8 G/G variant had reduced 2 h glucose compared to A/A+A/G (P=0.031). The G/G genotype of ABCC8 was also significantly associated with increased both fasting and 2 h serum insulin in diabetic and non-diabetic patients. A HOMA-beta value characterizing the beta-cell homeostasis was higher in the non-diabetic carriers homozygous for G/G (98.0+/-46.9) then for other genotypes (HOMA-beta = 85.6+/-45.5 for A/A+A/G, P=0.0015). The KCNJ11 E23K and ABCC8 exon 31 variants contribute to susceptibility to T2D diabetes, glucose intolerance and altered insulin secretion in a Russian population.

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107 It is possible that both E23K and A1369S could interact in underlying Table 4 Association of the A/G R1273R ABCC8 variant with glucose tolerance and b-cell function Characteristics T2D (n = 129) Control (n = 117) GG (n = 41) AA + AG (n = 88) P value GG (n = 71) AA + AG (n = 46) P value Fasting plasma glucose (mmol/l) 9.6 ± 1.8 10.5 ± 1.7 0.069 5.5 ± 0.6 6.0 ± 0.4 0.42 2 h plasma glucose (mmol/l) 12.0 ± 1.0 13.1 ± 1.3 0.031 6.4 ± 0.7 7.5 ± 0.8 0.052 Fasting serum insulin (mU/l) 14.1 ± 7.6 15.3 ± 7.7 0.027 9.8 ± 6.6 10.7 ± 5.9 0.032 2 h serum insulin (mU/l) 81.4 ± 34.9 88.0 ± 32.9 0.018 46.8 ± 19.7 53.4 ± 20.1 0.044 HOMA-b 46.2 ± 20.8 43.7 ± 22.9 0.095 98.0 ± 46.9 85.6 ± 45.5 0.0015 Table 5 Carriage of the ''double risk`` genotype (K/K of the E23K KCNJ11 and A/A of the R1273R ABCC8), glucose tolerance and b-cell function Characteristics T2D (n = 129) Control (n = 117) KK/AA (n = 12) Others (n = 117) P value KK/AA (n = 4) Others (n = 111) P value Fasting plasma glucose (mmol/l) 10.6 ± 2.1 9.6 ± 1.6 0.28 6.1 ± 0.7 5.7 ± 0.5 0.48 2 h plasma glucose (mmol/l) 11.9 ± 1.5 12.6 ± 1.1 0.33 7.7 ± 0.8 6.7 ± 0.7 0.13 Fasting serum insulin (mU/l) 16.2 ± 8.1 14.6 ± 7.6 0.022 10.5 ± 6.3 10.2 ± 6.2 0.65 2 h serum insulin (mU/l) 91.5 ± 36.6 82.9 ± 31.6 0.0085 54.8 ± 19.3 47.9 ± 20.0 0.096 HOMA-b 45.6 ± 21.3 47.9 ± 22.8 0.14 80.8 ± 44.2 92.8 ± 46.5 0.0011 susceptibility toT2D on the region 11p15.1. Login to comment
108 It is possible that both E23K and A1369S could interact in underlying Table 4 Association of the A/G R1273R ABCC8 variant with glucose tolerance and b-cell function Characteristics T2D (n = 129) Control (n = 117) GG (n = 41) AA + AG (n = 88) P value GG (n = 71) AA + AG (n = 46) P value Fasting plasma glucose (mmol/l) 9.6 &#b1; 1.8 10.5 &#b1; 1.7 0.069 5.5 &#b1; 0.6 6.0 &#b1; 0.4 0.42 2 h plasma glucose (mmol/l) 12.0 &#b1; 1.0 13.1 &#b1; 1.3 0.031 6.4 &#b1; 0.7 7.5 &#b1; 0.8 0.052 Fasting serum insulin (mU/l) 14.1 &#b1; 7.6 15.3 &#b1; 7.7 0.027 9.8 &#b1; 6.6 10.7 &#b1; 5.9 0.032 2 h serum insulin (mU/l) 81.4 &#b1; 34.9 88.0 &#b1; 32.9 0.018 46.8 &#b1; 19.7 53.4 &#b1; 20.1 0.044 HOMA-b 46.2 &#b1; 20.8 43.7 &#b1; 22.9 0.095 98.0 &#b1; 46.9 85.6 &#b1; 45.5 0.0015 Table 5 Carriage of the ''double risk`` genotype (K/K of the E23K KCNJ11 and A/A of the R1273R ABCC8), glucose tolerance and b-cell function Characteristics T2D (n = 129) Control (n = 117) KK/AA (n = 12) Others (n = 117) P value KK/AA (n = 4) Others (n = 111) P value Fasting plasma glucose (mmol/l) 10.6 &#b1; 2.1 9.6 &#b1; 1.6 0.28 6.1 &#b1; 0.7 5.7 &#b1; 0.5 0.48 2 h plasma glucose (mmol/l) 11.9 &#b1; 1.5 12.6 &#b1; 1.1 0.33 7.7 &#b1; 0.8 6.7 &#b1; 0.7 0.13 Fasting serum insulin (mU/l) 16.2 &#b1; 8.1 14.6 &#b1; 7.6 0.022 10.5 &#b1; 6.3 10.2 &#b1; 6.2 0.65 2 h serum insulin (mU/l) 91.5 &#b1; 36.6 82.9 &#b1; 31.6 0.0085 54.8 &#b1; 19.3 47.9 &#b1; 20.0 0.096 HOMA-b 45.6 &#b1; 21.3 47.9 &#b1; 22.8 0.14 80.8 &#b1; 44.2 92.8 &#b1; 46.5 0.0011 susceptibility toT2D on the region 11p15.1. Login to comment

[hide] Association of the Kir6.2 E23K variant with reduce... J Clin Endocrinol Metab. 2008 Dec;93(12):4979-83. Epub 2008 Sep 16. Palmer ND, Langefeld CD, Bryer-Ash M, Rotter JI, Taylor KD, Bowden DW
Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.
J Clin Endocrinol Metab. 2008 Dec;93(12):4979-83. Epub 2008 Sep 16., [PMID:18796522]

Abstract [show]
CONTEXT: ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis. OBJECTIVE: The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo. DESIGN AND SETTING: The Insulin Resistance Atherosclerosis Family Study (IRAS-FS) is a community-based study of Hispanic-Americans (San Antonio, TX, and San Luis Valley, CO) and African-Americans (Los Angeles, CA). PARTICIPANTS: A total of 1,040 Hispanic-Americans and 500 African-American individuals formed the basis of this study. MAIN OUTCOME MEASURE(S): The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and included insulin sensitivity (S(I)), acute insulin response, and disposition index. Results: In African-Americans, both variants were associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles (additive P = 0.00053). S(I), a measure of insulin sensitivity, was not associated. In Hispanic-Americans, there was no association with measures of glucose homeostasis. CONCLUSIONS: We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population.

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2 Objective: The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo. Login to comment
9 Conclusions: We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population. Login to comment
22 Specifically, the Kir6.2 E23K and SUR1 A1369S variants, which are highly correlated, have been reproducibly implicated in type 2 diabetes (T2D) susceptibility (9, 10). Login to comment
25 Thus, although the association of the E23K variant with T2D is widely accepted, the contribution of the SUR1 A1369S has not been delineated, and results of studies in human populations and model systems have not provided a consistent mechanism for T2D susceptibility. Login to comment
26 The purpose of this study was to evaluate the association of the Kir6.2 E23K and SUR1 A1369S variants with quantitative measures of glucose homeostasis in carefully phenotyped African-American and Hispanic-American subjects from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS). Login to comment
64 Discussion The goal of this study was to assess the impact of Kir6.2 E23K and SUR1 A1369S variants on quantitative measures of glucose homeostasis to determine their probable role in vivo. In African-Americans we observed significant association of the Kir6.2 E23K variant with AIR. Login to comment
90 Evaluation of the common nonsynonymous mutation (A1369S, rs757110) resulted in the same associations as observed with the E23K mutation due to the strong allelic association. Login to comment

[hide] ABCC8 polymorphism (Ser1369Ala): influence on seve... Pharmacogenomics. 2010 Dec;11(12):1743-50. Sato R, Watanabe H, Genma R, Takeuchi M, Maekawa M, Nakamura H
ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas.
Pharmacogenomics. 2010 Dec;11(12):1743-50., [PMID:21142918]

Abstract [show]
AIMS: Sulfonylureas are categorized according to their binding sites of the ATP-sensitive K+ channel (K(ATP) channel) complex in pancreatic beta-cells. The binding sites are classified as A, B and A + B site (both A and B sites), respectively. The Ser1369Ala variant in the sulfonylurea receptor gene ABCC8 which encodes a subunit of the K(ATP) channel complex has been demonstrated to be associated with the hypoglycemic effect of gliclazide, which binds to the A site. However, the hypoglycemic effect of the Ser1369Ala variant on treatment with A + B binding site sulfonylureas, such as glimepiride or glibenclamide, is still uncertain. MATERIALS & METHODS: In a case-control study, 32 patients with Type 2 diabetes admitted to hospital with severe hypoglycemia and 125 consecutive Type 2 diabetic outpatients without severe hypoglycemia were enrolled. We determined the genotypes of the ABCC8 polymorphism (Ser1369Ala) in the patients with or without severe hypoglycemia. All of the patients were taking glimepiride or glibenclamide. RESULTS: In the patients treated with glimepiride or glibenclamide, we found no significant differences in the distribution of the Ser1369Ala genotype between patients with or without severe hypoglycemia (p = 0.26). Moreover, the Ala1369 minor allele tended to be less frequent in the hypoglycemic group (31 vs 43%; OR: 1.65; 95% CI: 0.92-2.96; p = 0.09). CONCLUSION: Our findings suggest that the Ser1369Ala variant is not a major predictive factor of severe hypoglycemia due to glimepiride or glibenclamide, both of which bind to the A + B site. It is likely that severe hypoglycemia due to A + B binding site sulfonylureas will be mediated by other factors, and not the Ala1369 minor allele.

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260 19 Florez JC, Jablonski KA, Kahn SE et al.: Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the diabetes prevention program. Login to comment

[hide] Genome-wide association with diabetes-related trai... BMC Med Genet. 2007 Sep 19;8 Suppl 1:S16. Meigs JB, Manning AK, Fox CS, Florez JC, Liu C, Cupples LA, Dupuis J
Genome-wide association with diabetes-related traits in the Framingham Heart Study.
BMC Med Genet. 2007 Sep 19;8 Suppl 1:S16., [PMID:17903298]

Abstract [show]
BACKGROUND: Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants. METHODS: We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0-120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age2-adjusted residual trait values, and Cox survival models to test incident diabetes. RESULTS: We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r2 < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r2 = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits. CONCLUSION: Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. Framingham 100K data replicate the TCF7L2 association with diabetes.

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8 There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. Login to comment
92 We found 6 SNPs in or near ABCC8, but no SNPs in strong LD with ABCC8 A1369S (rs757110) or KCNJ11 E23K (rs5219), and thus could not replicate these associations. Login to comment

[hide] The sulfonylurea receptor, an atypical ATP-binding... Circ Res. 2008 Feb 1;102(2):164-76. Burke MA, Mutharasan RK, Ardehali H
The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel.
Circ Res. 2008 Feb 1;102(2):164-76., [PMID:18239147]

Abstract [show]
ATP-binding cassette (ABC) proteins are highly conserved and widely expressed throughout nature and found in all organisms, both prokaryotic and eukaryotic. They mediate myriad critical cellular processes, from nutrient import to toxin efflux using the energy derived from ATP hydrolysis. Most ABC proteins mediate transport of substances across lipid membranes. However, there are atypical ABC proteins that mediate other processes. These include, but are not limited to, DNA repair (bacterial MutS), ion transport (cystic fibrosis transmembrane receptor), and mRNA trafficking (yeast Elf1p). The sulfonylurea receptor (SUR) is another atypical ABC protein that regulates activity of the potassium ATP channel (K(ATP)). K(ATP) is widely expressed in nearly all tissues of higher organisms and couples cellular energy status to membrane potential. K(ATP) is particularly important in the regulation of insulin secretion from pancreatic beta-cells and in regulating action potential duration in muscle cells. SUR is indispensable for normal channel function, and mutations in genes encoding SURs increase the susceptibility to diabetes, myocardial infarction, and heart failure. Here, we review the structure and function of ABC proteins and discuss SUR, its regulation of the K(ATP) channel, and its role in cardiovascular disease.

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111 However, there is significant linkage disequilibrium between the KCNJ11 E23K polymorphism and a common polymorphism in ABCC8, A1369S.99 In fact, these 2 polymorphisms are almost always found together and seem to be protective of progression to diabetes in patients enrolled in the Diabetes Prevention Program. Login to comment

[hide] Effects of single nucleotide polymorphisms in K(AT... Arch Med Res. 2012 May;43(4):317-23. doi: 10.1016/j.arcmed.2012.06.001. Epub 2012 Jun 13. Gonen MS, Arikoglu H, Erkoc Kaya D, Ozdemir H, Ipekci SH, Arslan A, Kayis SA, Gogebakan B
Effects of single nucleotide polymorphisms in K(ATP) channel genes on type 2 diabetes in a Turkish population.
Arch Med Res. 2012 May;43(4):317-23. doi: 10.1016/j.arcmed.2012.06.001. Epub 2012 Jun 13., [PMID:22704848]

Abstract [show]
BACKGROUND AND AIMS: ATP-sensitive potassium (K(ATP)) channels of pancreatic beta-cells play a key role in glucose-stimulated insulin secretion mechanism. The Kir6.2 protein, forming the K(ATP) channel pore inwardly, and the SUR1 protein that surrounds it forming the outside part of the channel were encoded by ABCC8 and KCNJ11 genes, respectively. Recent studies reported that the single nucleotide polymorphisms (SNPs) established in these genes are associated with defects in insulin secretion and type 2 diabetes mellitus (T2DM). We aimed to investigate the allele profiles and the risk alleles of the ABCC8 and KCNJ11 genes and to highlight the associations with the disease in patients in Konya region of Turkey where T2DM is common. METHODS: In this study, 169 patients with T2DM and 119 healthy controls were included. A total of 29 SNPs in ABCC8 and KCNJ11 genes were screened by PCR-SSCP technique and sequenced. Biochemical parameters and genotype-phenotype relationships were analyzed using variance analysis. RESULTS: R1273R silent substitution in exon 31 and 16/-3t-->c substitution in noncoding region of exon 16 of ABCC8 gene showed a significant association (OR 4.8 [95% CI 2.41-9.77], p <0.001 and OR 3.5 [95% CI 1.64-7.40], p <0.001 under dominant and recessive models, respectively). We detected a significant association between E/K heterozygote genotype and reduced plasma insulin level in patients with T2DM (p <0.05). CONCLUSIONS: ABCC8 exons 16 and 31 variants increase susceptibility to T2DM and KCNJ11 E23K decreases insulin secretion in a Turkish population.

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32 Recent studies showed that specifically E23K variant of KCNJ11 and A1369S of ABCC8 play an important role in predisposition to T2DM (10e12). Login to comment
33 It has also been reported that the individual containing the K allele in E23K also contains the A allele in A1369S (10,11). Login to comment
91 The SNPs A1369S of ABCC8 gene had no association with T2DM ( p O0.05). Login to comment
104 In contrast, the SNP A1369S having a homozygote genotype for allele 2 under recessive model increased glucose level. Login to comment
116 c2 Test results for associations between SNPs in ABCC8 and KCNJ11 genes and risk of type 2 diabetes Rs id SNP Gene Genotype Case Control Additive Dominant Reccessive n (%) n (%) p p p C/C 100 (100) 109 (98.9) rs8192695 A110A ABCC8 C/T - 1 (1.1) O0.05a - - - - - C/C 68 (40.2) 50 (56.2) rs72559731 A116P ABCC8 C/T 101 (59.8) 39 (43.8) O0.05a - - - - - C/C 68 (40.5) 49 (47.1) 1799854 16 (3) ABCC8 C/T 88 (52.4) 33 (31.7) !0.05 O0.05 !0.05 T/T 12 (7.1) 22 (21.2) G/G 15 (11.1) 31 (37.8) rs1799859 R1273R ABCC8 G/A 110 (81.5) 39 (47.6) !0.05 !0.05 O0.05 A/A 10 (7.4) 12 (14.6) G/G 4 (3.4) 7 (6.8) rs757110 A1369S ABCC8 G/T 35 (29.9) 40 (38.8) O0.05 O0.05 O0.05 T/T 78 (66.7) 56 (54.4) A/A 139 (92.7) 106 (96.4) 437 - ABCC8 A/T 11 (7.3) 4 (3.6) O0.05a - - - - - G/G 52 (32.1) 31 (39.2) rs5219 E23K KCNJ11 G/A 110 (67.9) 48 (60.8) O0.05a - - - - - C/C 109 (71.7) 80 (70.8) rs5218 A190A KCNJ11 C/T 42 (27.6) 31 (27.4) O0.05 O0.05 O0.05 T/T 1 (0.7) 2 (1.8) C/C 144 (97.3) 96 (94.1) rs5216 L267L KCNJ11 C/G 4 (2.7) 6 (5.9) O0.05a - - - - - C/C 68 (45.6) 60 (51.7) rs1800467 L270V KCNJ11 C/G 54 (36.3) 44 (37.9) O0.05 O0.05 O0.05 G/G 27 (18.1) 12 (10.4) A/A 59 (44.4) 56 (50.0) rs5215 I337V KCNJ11 A/G 31 (23.3) 44 (39.3) 0.07 O0.05 O0.05 G/G 43 (32.3) 12 (10.7) a These SNPs had only two genotypes; therefore, 11 vs. 12 (or 12 vs. 22) presented as additive model. Login to comment
129 In previous studies, the missense A1369S variant in exon 33 of ABCC8 gene showed association with T2DM in several populations (10e12,44). Login to comment
132 Controversially, we found no association between the A1369S variant and T2DM in fasting glucose in our population. Login to comment

[hide] CYP2C9, KCNJ11 and ABCC8 polymorphisms and the res... Eur J Clin Pharmacol. 2014 Apr;70(4):421-8. doi: 10.1007/s00228-014-1641-x. Epub 2014 Jan 18. Klen J, Dolzan V, Janez A
CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients.
Eur J Clin Pharmacol. 2014 Apr;70(4):421-8. doi: 10.1007/s00228-014-1641-x. Epub 2014 Jan 18., [PMID:24442125]

Abstract [show]
PURPOSE: Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice. METHODS: Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n = 21) or in combination with metformin (n = 135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110. RESULTS: The average duration of diabetes in the study group was 10.6 +/- 7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0 +/- 0.9). In total, 76 hypoglycemia events were observed (mean 0.48 +/- 1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n = 103). Among them, carriers of two wild-type alleles suffered 0.36 +/- 0.98 events, while patients with one or two polymorphic alleles had 0.79 +/- 1.7 or 2.67 +/- 4.6 events, respectively (p = 0.014). CONCLUSIONS: Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.

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59 Validated TaqMan SNP genotyping assays were also used to genotype ABCC8 rs757110 (4105G>T, Ala1369Ser), KCNJ11 rs5219 (67A>G, Lys23Glu) and KCNJ11 rs5215 (748G>A, Val250Ile) (C_600632_20, C_11654065_10 and C_2991148_10, respectively; ABI, Foster City, CA, USA). Login to comment

[hide] ABCC8 genetic variants and risk of diabetes mellit... Gene. 2014 Jul 25;545(2):198-204. doi: 10.1016/j.gene.2014.04.040. Epub 2014 Apr 21. Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B
ABCC8 genetic variants and risk of diabetes mellitus.
Gene. 2014 Jul 25;545(2):198-204. doi: 10.1016/j.gene.2014.04.040. Epub 2014 Apr 21., [PMID:24768178]

Abstract [show]
Diabetes mellitus (DM) is a major health problem worldwide and it will rapidly increase. This disease is characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. DM has three types: T1DM, T2M and gestational DM (GDM), of them T2DM is more frequent. Multiple genes and their interactions are involved in insulin secretion pathway. Sulfonylurea receptor encoded by ABCC8 gene, together with inward-rectifier potassium ion channel (Kir6.2) regulates insulin secretion by ATP-sensitive K(+) (KATP) channel located in the plasma membranes. Disruption of these molecules by different mutations is responsible for risk of DM. Several single nucleotide polymorphisms (SNPs) of ABCC8 gene and their interaction are involved in pathogenicity of DM. This review summarizes the current evidence of contribution of ABC8 genetic variants to the development of DM.

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75 A substitution of G to T (GCC ࢐ TCC) changes amino acid from alanine at 1369 residue to serine (Ala1369Ser). Login to comment
129 Polymorphism Location MAF Allele Amino Acid Association Reference Chromosome Gene Diabetes Association 1 rs757110 17,375,052 Exon 0.26 G N T Ala1369Ser T2DM Yes 42,52,61,78,77 No 11, 12,18,22,34,64, 67, 105 2 rs1799854 17,405,279 Intron 0.41 G N A - T2DM Yes 11,12,34,41,67,90,95,101 No 3,18,32,42,52,56,62,73,85,91,92,103,105 GDM Yes 71 No 10 3 rs1799859 17,375,854 Exon 0.33 G N A Arg1273Arg T2DM Yes 11,12,34,40,54,74,96,102 No 18,67 T2DM/GDM Yes 98 4 rs1801261 17,393,440 Exon 0.01 C N T Thr759Thr T2DM Yes 84,92,105 No 3,91,101 T2DM/GDM No 98 5 rs2074308 17,409,155 Intron 0.14 C N T - T2DM Yes 78 No 18,52 6 rs2074312 17,378,365 Intron 0.29 G N A - T2DM No 42,52 7 rs1799858 17,406,504 Exon 0.15 G N A Lys649Lys T2DM Yes 18,78 T2DM/GDM No 98 8 rs2188966 17,456,460 5'-UTR 0.36 C N T - T2DM No 54,74 9 rs2237984 17,402,596 Intron 0.41 T N C - T2DM No 42,52 10 rs3758947 17,501,210 Intron 0.19 G N A - T2DM Yes 54 No 74 11 rs3758953 17,456,122 5'-UTR 0.49 A N G - T2DM Yes 54 No 74 12 rs4148646 17,371,765 Intron 0.28 C N G - T2DM Yes 78 No 52 13 rs1048099 17,453,091 Exon 0.44 T N A Pro69Pro T2DM No 18,52 14 rs1805036 17,390,859 Exon 0.10 C N T Leu829Leu T2DM/GDM No 98 15 rs2073583 17,383,911 Intron 0.22 G N C - T2DM No 52 16 rs2074311 17,378,435 Intron 0.31 A N G - T2DM No 18 17 rs2237976 17,433,091 Intron 0.43 T N G - T2DM No 52 18 rs2237981 17,417,474 Intron 0.43 T N C - T2DM No 42 19 rs2237991 17,396,804 Intron 0.36 A N G - T2DM No 52 20 rs2237992 17,387,508 Intron 0.21 A N G - T2DM No 52 21 rs2283257 17,446,020 Intron 0.12 C N T - T2DM No 52 22 rs2301703 17,441,546 Intron 0.47 G N A - T2DM No 52 23 rs4148628 17,392,768 Intron NI C N T - T2DM Yes 78 24 rs4148630 17,392,541 Intron 0.24 G N A - T2DM No 52 25 rs59852838 17,431,350 Exon 0.06 T N C Tyr356Cys T2DM Yes 44 26 rs72559731 17,448,289 Exon NI C N G Ala116Pro T2DM No 11 27 rs7947326 17,425,068 Intron 0.38 A N C - T2DM No 52 28 rs8192695 17,448,305 Exon 0.55 G N A Ala110Ala T2DM No 11 29 rs886293 17,418,795 Intron 0.32 A N G T2DM No 52 function. Login to comment

[hide] The insulin-sensitivity sulphonylurea receptor var... J Mol Endocrinol. 2014 Oct;53(2):295-301. doi: 10.1530/JME-14-0083. Epub 2014 Aug 20. Rolim AL, Lindsey SC, Kunii IS, Crispim F, Moises RC, Maciel RM, Dias-da-Silva MR
The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis.
J Mol Endocrinol. 2014 Oct;53(2):295-301. doi: 10.1530/JME-14-0083. Epub 2014 Aug 20., [PMID:25143473]

Abstract [show]
Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the beta-cell ATP-sensitive K(+) channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K(+)/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP.

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2 Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. Login to comment
3 We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). Login to comment
27 In this study, we explore the relationship between the ABCC8 gene variant Ala1369Ser and susceptibility to TPP. Login to comment
38 We searched for the ABCC8 gene variant Ala1369Ser (rs757110) using PCR-restriction fragment length polymorphism (PCR-RFLP) screening and subsequent direct sequencing analyses. Login to comment
39 The ABCC8 gene region encompassing the Ala1369Ser variant (rs757110) was amplified using the following primers: forward, 50 -GGG AAG AGT CCA AGG AGG AG-30 , and reverse, 50 -CAG GAG ACT GCG ATG TCT GA-30 . Login to comment
49 The association between the ABCC8 Ala1369Ser variant and the risk of TPP was estimated by the odds ratio (OR) and considering the 95% CIs, using the non-risk genotype (ACCAA) as a reference. Login to comment
59 The distribution of the Ala1369Ser (rs757110) genotype frequency was examined in TPP patients and TWP subjects; representative electropherogram sequences and restriction analyses are shown in Fig. 1. Login to comment
67 Discussion In this case-control study, we demonstrate for the first time, to our knowledge, that the frequency of the Ala1369 variant is significantly higher in TPP patients than in TWP patients, revealing an association between the insulin-sensitivity-related p.Ala1369Ser genetic variant of SUR1 and TPP. Login to comment
78 In this study, we screened exon 33-37, where most mutations causing hyperinsulinaemia exist and focused on the most important SUR1 variant that confers insulin sensitivity, which is largely known as the non-synonymous variant p.Ala1369Ser (Hamming et al. 2009, Villareal et al. 2009). Login to comment
79 Interestingly, the SUR1 p.Ala1369Ser variant appears to be in linkage disequilibrium (LD) with the p.Glu23Lys Figure 1 Sequencing and genotyping results of the p.Ala1369Ser variant (rs757110). Login to comment
86 (B) Representative electropherogram sequences of the SUR1 p.Ala1369Ser variant detected in patients corresponding to lanes 3, 5 and 7. Login to comment
92 These authors also demonstrated that the SUR1 p.Ala1369Ser variant may be responsible for T2D risk by decreasing the ATP sensitivity of the KATP channel (Hamming et al. 2009). Login to comment
105 Table 2 Genetic association analysis of the SUR1 p.Ala1369Ser variant observed in the TPP and control groups. Login to comment
106 The allele (C/A) and genotype (AA, CC, AC and CC or AC) for the p.Ala1369Ser (rs757110) in thyrotoxic periodic paralysis (TPP) patients, thyrotoxic without paralysis (TWP) control patients and the population genetics control (1000 Genomes Project/1KGP) are listed with frequencies, odds ratio (OR), CI of 95% and P value for comparisons when available. Login to comment

[hide] Screening for Mutations in ABCC8 and KCNJ11 Genes ... Genes (Basel). 2015 Apr 13;6(2):206-15. doi: 10.3390/genes6020206. Adi A, Abbas BB, Hamed MA, Tassan NA, Bakheet D
Screening for Mutations in ABCC8 and KCNJ11 Genes in Saudi Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) Patients.
Genes (Basel). 2015 Apr 13;6(2):206-15. doi: 10.3390/genes6020206., [PMID:25871929]

Abstract [show]
The autosomal recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is associated with mutations in either ABCC8 or KCNJ11 genes. In the present study, we describe the clinical features and results of genetic analysis of 13 Saudi Arabian patients with PHHI. Clinically, most patients presented with infantile seizures and/or developmental delay, with a subset of patients who were also found to have abnormal brain imaging and electrophysiological studies. Interestingly no coding pathogenic mutations were identified in these two genes by direct sequencing. However, two splice variants were identified in ABCC8 gene in two patients, and a large deletion of exons 1-22 of the ABCC8 gene was identified in three patients. Our data shows that large deletions in ABCC8 gene are the common genetic mechanism in the Saudi population.

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97 Nucleotide Position Codon Number rs Number c.207 T > C P69P rs1048099 c.1812 C > T H562H No rs number c.3819 G > A R1273R rs1799859 c.4231 G > T A1369S No rs number c.4717 G > A V1573V No rs number Table 3. Login to comment

[hide] ABCC8 R1420H Loss-of-Function Variant in a Southwe... Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5. Baier LJ, Muller YL, Remedi MS, Traurig M, Piaggi P, Wiessner G, Huang K, Stacy A, Kobes S, Krakoff J, Bennett PH, Nelson RG, Knowler WC, Hanson RL, Nichols CG, Bogardus C
ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.
Diabetes. 2015 Dec;64(12):4322-32. doi: 10.2337/db15-0459. Epub 2015 Aug 5., [PMID:26246406]

Abstract [show]
Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the beta-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

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69 Three of the missense variants (2 in KCNJ11 that encode V337I and E23K and 1 in ABCC8 that encodes A1369S) are common with mAFs of 0.380.39 and are in high linkage disequilibrium (r2 $0.98) (Supplementary Fig. 2). Login to comment
79 When analyzed in all available DNA samples, the 3 common missense variants, V337I, E23K, and A1369S, again showed no association with type 2 diabetes, birth weight, or adult BMI (Table 2), and these variants were not associated with insulin secretion among the 298 subjects with normal glucose tolerance (Supplementary Table 3). Login to comment
120 The R1420H variant also does not appear to occur at a detectable frequency in Table 2-Association of KCNJ11 and ABCC8 variants with type 2 diabetes, birth weight, and adult maximum BMI in American Indians from the Gila River Indian Community Diabetes (N = 7,710) Birth Weight (N = 2,377) Adult BMI* (N = 5,918) Gene Variant Freqߤ OR (95% CI) minor allele Pߥ B minor allele (g) P&#a7; B minor allele (log e ) P|| KCNJ11 rs5215 V337I 0.39 1.03 (0.94-1.12) 0.54 221.2 0.16 20.0001 0.98 KCNJ11 rs5219 E23K 0.39 1.04 (0.95-1.13) 0.43 218.4 0.22 0.002 0.72 ABCC8 chr11:17414594T.C K1565E 0.01 0.88 (0.56-1.36) 0.56 44.9 0.52 20.051 0.01 ABCC8 chr11:17417205C.T R1420H 0.017 2.02 (1.45-2.82) 3.6 3 10 25 169.1 1.5 3 10 23 20.049 2.5 3 10 23 ABCC8 rs757110 A1369S 0.38 1.03 (0.94-1.12) 0.56 215.5 0.35 0.002 0.60 ABCC8 chr11:17418781C.T G1316Q&#b6; 0.0001 1.04 (0.32-3.38) 0.94 - - 0.037 0.40 ABCC8 chr11:17435016G.T M801I 0.03 1.29 (0.98-1.71) 0.07 272.9 0.08 0.009 0.53 ABCC8 chr11:17449457T.A D691E&#b6; 0.001 0.42 (0.07-2.70) 0.36 - - 20.162 4.1 3 10 23 ABCC8 chr11:17485070G.A S165L 0.01 1.59 (1.07-2.35) 0.02 71.0 0.32 0.078 1.8 3 10 24 OR (95% CI) per copy of the minor allele. Login to comment