ABCMdb

PMID: 15111507

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., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC8 p.Ala1369Ser 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 104 ABCC8 p.Ala1369Ser 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 105 ABCC8 p.Ala1369Ser 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 117 ABCC8 p.Ala1369Ser 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 118 ABCC8 p.Ala1369Ser 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 131 ABCC8 p.Ala1369Ser 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 132 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 164 ABCC8 p.Ala1369Ser 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 165 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 195 ABCC8 p.Ala1369Ser 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 196 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 202 ABCC8 p.Ala1369Ser 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 203 ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 205 ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 209 ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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 211 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser 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 ABCC8 p.Ala1369Ser 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