1.
Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses.
van Dam, RM, Hoebee, B, Seidell, JC, Schaap, MM, de Bruin, TW, Feskens, EJ
Diabetic medicine : a journal of the British Diabetic Association. 2005;(5):590-8
Abstract
AIMS: To evaluate the relation between common variants in the ATP-sensitive K+ channel genes and glucose intolerance. METHODS We conducted a meta-analysis of reported association studies in Caucasian populations for common variants in the ABCC8 (exons 16 and 18) and the KCNJ11 (E23K) gene and examined sources of heterogeneity in the results. The meta-analysis was based on 7768-10216 subjects (depending on the gene variant), and included two new population-based studies in the Netherlands with 725 cases and 742 controls. RESULTS For the KCNJ11 variant, the summary odds ratio (OR) for glucose intolerance was 1.12 (1.01-1.23, P=0.03) for the EK genotype and 1.44 (1.17-1.78, P=0.0007) for the KK genotype, as compared with the EE genotype. For the ABCC8 exon 16 variant, the OR was 1.06 (0.94-1.19, P=0.34) for ct and 0.93 (0.71-1.20, P=0.56) for tt, as compared with the cc genotype. For ABCC8 exon 18, the OR was 1.20 (0.97-1.49, P=0.10) for CT/TT, as compared with the CC genotype. Studies of the ABCC8 variants that were published first or had smaller sample sizes (for the exon 18 variant) showed stronger associations, which may indicate publication bias. For the ABCC8 exon 18 and the KCNJ11 variant, associations were stronger for studies of clinical diabetes than newly detected glucose intolerance. The population attributable risk for clinical Type 2 diabetes was 6.2% for the KCNJ11 KK genotype and 10.1% for the KCNJ11 EK and KK genotype combined. CONCLUSIONS The common KCNJ11 E23K gene variant, but not the ABCC8 exon 16 or exon 18 variant, was consistently associated with Type 2 diabetes.
2.
Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.
Florez, JC, Burtt, N, de Bakker, PI, Almgren, P, Tuomi, T, Holmkvist, J, Gaudet, D, Hudson, TJ, Schaffner, SF, Daly, MJ, et al
Diabetes. 2004;(5):1360-8
Abstract
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.
3.
CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: a meta-analysis of association studies.
Glatt, SJ, Faraone, SV, Tsuang, MT
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2003;(1):14-20
Abstract
Schizophrenia and bipolar disorder both show some evidence for genetic anticipation. In addition, significant expansion of anonymous CAG repeats throughout the genome has been detected in both of these disorders. The gene KCNN3, which codes for a small/intermediate conductance, calcium-regulated potassium channel, contains a highly polymorphic CAG-repeat array in exon 1. Initial evidence for association of both schizophrenia and bipolar disorder with increased CAG-repeat length of KCNN3 has not been consistently replicated. In the present study, we performed several meta-analyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders. Each group of studies was analyzed under two models, including a test for direct association with repeat length, and a test for association with dichotomized repeat-length groups. No evidence for a linear relationship between disease risk and repeat length was observed, as all pooled odds ratios approximated 1.0. Results of dichotomized allele-group analyses were more variable, especially for schizophrenia, where case-control studies found a significant association with longer repeats but family-based studies implicated shorter alleles. The results of these meta-analyses demonstrate that the risks for both schizophrenia and bipolar disorder are largely, if not entirely, independent of CAG-repeat length in exon 1 of KCNN3. This study cannot exclude the possibility that some aspect of this polymorphism, such as repeat-length disparity in heterozygotes, influences risk for these disorders. Further, it remains unknown if this polymorphism, or one in linkage disequilibrium with it, contributes to some distinct feature of the disorder, such as symptom severity or anticipation.