Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes

Abstract

To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10,870 cases and 73,735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR=0.90, 95% CI=0.86-0.93; P=3.7x10(-8)). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P<0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance.

Figure 1.

Plot of the −log₁₀P-values for the combined analysis for NHS and HPFS GWA trend tests. Each point represents an SNP from the 683 509 SNPs remaining after quality control filters and overlapped between the two study samples. Different bands are used to differentiate SNPs on consecutive autosomal and X chromosomes.

Figure 2.

Association signals at 2q24 locus: (A) association signals from the combined analysis for NHS and HPFS GWA trend tests, across a 500 kb region centering on rs1020731. The vertical axis representing the −log₁₀P-values from the Armitage trend test. SNP rs1020731 is shown in blue and rs7953730 is shown in red, labeled with discovery stage P-values. Estimated recombination rates from HapMap are plotted to reflect the local LD structure. Genes were extracted from the HapMap Genome Browser; (B) LD in the CEU HapMap population. Disequilibrium coefficient values for HapMap Phase II data (v. 22) were generated with Haploview.

Figure 3.

The relative expression levels of (A) RBMS1 and (B) ITGB6 genes in human tissues. The expression levels were determined by RT–PCR analysis.

Figure 4.

(A) RBMS1 is induced by pro-inflammatory stimulants in the macrophages. Bone marrow-derived wild-type mouse macrophages were incubated with or without interferon-γ (IFN-γ) (10 ng/ml) overnight followed by lipopolysaccharide (LPS) treatment (10 ng/ml) for 24 h. The experiments were done in triplicate. *P < 0.05; (B) RBMS1 expression profiles in the liver, white adipose tissue (WAT) and muscle of fasted, regular chow-fed and high fat-diet-fed (HFD, 2 months) mice.