Polymorphism in the Calsequestrin 1 (CASQ1) Gene on Chromosome 1q21 Is Associated With Type 2 Diabetes in the Old Order Amish

Abstract

Calsequestrin (CASQ)1 is involved in intracellular storage and release of calcium, a process that has been shown to mediate glucose transport in muscle. Its gene, CASQ1, is encoded on chromosome 1q21, a region that has been linked to type 2 diabetes in the Amish and several other populations. We screened all 11 exons, exon-intron junctions, and the proximal regulatory region of CASQ1 for mutations. We detected four novel single nucleotide polymorphisms (SNPs) (؊1470C3 T, ؊1456delG, ؊1366insG, and 593C3 T). Ten informative SNPs within CASQ1 were genotyped in Amish subjects with type 2 diabetes (n ‫؍‬ 145), impaired glucose tolerance (n ‫؍‬ 148), and normal glucose tolerance (n ‫؍‬ 358). Rs2275703 and rs617698 in introns 4 and 2 were significantly associated with type 2 diabetes (P ‫؍‬ 0.008 and 0.04, respectively); three other SNPs showed borderline evidence for association to type 2 diabetes (P ‫؍‬ 0.076 -0.093). Furthermore, in nondiabetic subjects (n ‫؍‬ 754), both rs2275703 and rs617698 were significantly associated with glucose area under the curve during an oral glucose tolerance test (P ‫؍‬ 0.035 and 0.013, respectively). Haplotype analysis suggested that no haplotype could explain these associations better than rs2275703. These findings, coupled with similar findings in Utah Caucasians, suggest that sequence variation in CASQ1 may influence risk of type 2 diabetes. Diabetes 53: [3292][3293][3294][3295][3296][3297][3298][3299] 2004

Evidence That Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) on 1q21 is a Type 2 Diabetes Susceptibility Gene in the Old Order Amish

“…Type 2 diabetes-associated SNPs in ARHGEF11 did not provide evidence for linkage to type 2 diabetes/IGT using the same family structures as in our original linkage analysis (2) (data not shown). These findings are consistent with the prevailing idea that there is more than one type 2 diabetes susceptibility gene on chromosome 1q21-q24 (21).…”

“…In an expanded set of 754 nondiabetic subjects (including 606 NGT and 148 IGT subjects), we also evaluated the effect of genotype on levels of quantitative traits (e.g., BMI, glucose level, and insulin level) by comparing mean trait levels across genotypes as previously described (21). We compared the likelihood of a model in which the trait values were allowed to vary by genotype (unconstrained model) to that in which the genotype effects were constrained to be zero using the likelihoods ratio test.…”

“…The OR was computed by comparing the odds of disease between subjects carrying one copy of the minor allele and subjects not carrying any copies of the minor allele. The association analyses were carried out using SOLAR as previously described (21).…”

Calsquestrin 1 (CASQ1) Gene Polymorphisms Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes in Northern European Caucasians

“…Hence, the observed associations are partially independent and not related exclusively to strong LD between closely spaced SNPs. This observation, along with data from Fu et al (19) from the AFDS, suggests that multiple CASQ1 SNPs may contribute to disease susceptibility. Like calpain 10 and many other recently described complex disease genes (20 -22), no associated variant alters the coding sequence and no single variant is likely to explain the association.…”

Type 2 Diabetes Susceptibility Genes on Chromosome 1q21–24

“…Each of the five genes is a strong T2D candidate: PKLR, a pyruvate kinase, is upregulated by glucose (Yamada & Noguchi, 1999) and is among the downstream targets of hepatic nuclear factor 1-α (Wang et al 2000;Shih et al 2001), which in turn causes early onset, autosomal dominant T2D when mutated. CASQ1 regulates muscle calcium, thereby affecting insulin action (Das et al 2004a;Fu et al 2004). APOA2 affects levels of free fatty acids that, in turn, affect glucose metabolism (Boden 2002).…”