ABCMdb

ABCC8 p.Ala1369Ser

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Publications

PMID: 14551916 [PubMed] Barroso I et al: "Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action."

No. Sentence Comment

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

PMID: 17342155 [PubMed] Barber TM et al: "Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels."

No. Sentence Comment

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

PMID: 17259403 [PubMed] Florez JC 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."

No. Sentence Comment

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

PMID: 22056417 [PubMed] Duran-Gonzalez J et al: "Association study of candidate gene polymorphisms and obesity in a young Mexican-American population from South Texas."

No. Sentence Comment

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

PMID: 20099993 [PubMed] Bai JP et al: "Understanding the genetic basis for adverse drug effects: the calcineurin inhibitors."

No. Sentence Comment

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

PMID: 15111507 [PubMed] Florez JC et al: "Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region."

No. Sentence Comment

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

PMID: 18758683 [PubMed] Chistiakov DA et al: "Genetic variations in the pancreatic ATP-sensitive potassium channel, beta-cell dysfunction, and susceptibility to type 2 diabetes."

No. Sentence Comment

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

PMID: 18796522 [PubMed] Palmer ND et al: "Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans."

No. Sentence Comment

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

PMID: 21142918 [PubMed] Sato R et al: "ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas."

No. Sentence Comment

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

PMID: 17903298 [PubMed] Meigs JB et al: "Genome-wide association with diabetes-related traits in the Framingham Heart Study."

No. Sentence Comment

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

PMID: 18239147 [PubMed] Burke MA et al: "The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel."

No. Sentence Comment

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

PMID: 22704848 [PubMed] Gonen MS et al: "Effects of single nucleotide polymorphisms in K(ATP) channel genes on type 2 diabetes in a Turkish population."

No. Sentence Comment

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

PMID: 24442125 [PubMed] Klen J et al: "CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients."

No. Sentence Comment

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

PMID: 24768178 [PubMed] Haghverdizadeh P et al: "ABCC8 genetic variants and risk of diabetes mellitus."

No. Sentence Comment

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

PMID: 25143473 [PubMed] Rolim AL et al: "The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis."

No. Sentence Comment

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

PMID: 25871929 [PubMed] Adi A et al: "Screening for Mutations in ABCC8 and KCNJ11 Genes in Saudi Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) Patients."

No. Sentence Comment

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

PMID: 26246406 [PubMed] Baier LJ et al: "ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes."

No. Sentence Comment

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