A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

Abstract

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…SNPs rs391300 and rs4523957 in the SRR gene were associated with T2DM in a Han Chinese GWA study. SNPs rs391300 and rs4523957 were in tight LD with each other (r 2 = 0.942 in HapMap HCB) [102]. The nearby SNP rs216193 also showed significant association; this SNP resides 3.8 kb upstream from SRR.…”

“…The nearby SNP rs216193 also showed significant association; this SNP resides 3.8 kb upstream from SRR. SNP rs216193 was in tight LD with rs391300 (r 2 = 0.942 in HapMap HCB) [102].…”

“…A GWA study in Chinese population identified two genes, PTPRD and SRR, which were not previously described to be involved in diabetes or glucose metabolism [102]. PTPRD is the protein tyrosine phosphatase receptor type D gene and widely expressed in skeletal muscle, pancreas, and brain which belong to the receptor type IIA (R2A) subfamily of protein tyrosine phosphatases (PTPs).…”

“…D-serine (co-agonist) and the neurotransmitter glutamate bind to the Nmethyl Daspartate (NMDA) receptors and trigger excitatory neurotransmission in the brain [102,112,113]. NMDA receptor activation requires binding of glutamate and D-serine, which plays a neuromodulatory role in NMDA receptor transmission, synaptic plasticity, cell migration, and neurotoxicity [62].…”

The New Perspectives on Genetic Studies of Type 2 Diabetes and Thyroid Diseases

“…KCNQ1 was thought to be an Asian-specific susceptibility gene for T2D when it was firstly detected by GWAS in Japanese [27,33] and followed by multiple replication studies in other Asian populations [30,38,46]. The previously reported GWAS performed in Europeans and Caucasians did not identify KCNQ1 until the large-scale combining genome-wide association data from European descent reported a second independent signal of KCNQ1, rs231362 [50], which is different from the previously reported ones among Asian populations (rs2237892 [33], rs2237895 [38], rs2237897[27], rs163182 [46]). The MAF of rs231362 in Caucasians is 0.52, which is much higher than 0.08 for rs2237892 and 0.05 for rs2237897.…”