Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians

Abstract

Objective: Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians.

Research design and methods: We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians.

Results: We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 x 10(-8), all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 x 10(-9)), which is in moderate linkage disequilibrium with rs1387153 (r(2) = 0.60) and rs10830963 (r(2) = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01-0.08) versus 0.05 (0.03-0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06-1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians.

Conclusions: Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.

FIG. 1.

Genomic context of melatonin receptor MTNR1B region showing pairwise LD between SNPs with minor allele frequency ≥0.05 directly genotyped in both Indian Asians (A) and European Caucasians (B) using Haploview's standard color scheme.

FIG. 1.

Genomic context of melatonin receptor MTNR1B region showing pairwise LD between SNPs with minor allele frequency ≥0.05 directly genotyped in both Indian Asians (A) and European Caucasians (B) using Haploview's standard color scheme.

FIG. 2.

Distribution of risk allele score (number of risk alleles at the MTNR1B, GCKR, GCK, and G6PC2 loci) among Indian Asians (blue squares) and European Caucasians (red circles) as well as the relationship of risk allele score to glucose levels in the two populations.