Obesity-dependent association of TNF-LTA locus with type 2 diabetes in North Indians.

Six common genetic variants (rs2229094, rs1041981, rs1800630, rs1800629, rs361525, and rs1800610) in the TNF-LTA locus encoding the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-alpha have been shown to be associated with various metabolic traits including susceptibility to type 2 diabetes, metabolic syndrome, insulin resistance, and increased body mass index (BMI) in Caucasians from different geographic locations and have yielded mixed results. We tested for the association of these variants with type 2 diabetes in North Indians by studying 2,115 participants comprising of 1,073 type 2 diabetes patients and 1,042 controls. We report the association of a promoter region variant of TNF: rs1800630 and non-synonymous LTA variant: rs2229094 with type 2 diabetes [OR = 0.83 (95% CI 0.72-0.95), P = 0.005 and OR = 0.86 (95% CI 0.75-0.98), P = 0.02, respectively]. Although these associations were BMI-dependent, no interactive effect of BMI and variants on type 2 diabetes was detectable. Further, the haplotype carrying all the six major alleles conferred susceptibility to type 2 diabetes [OR = 1.23 (95% CI 1.06-1.42), P = 0.005; P (permuted) = 0.02], with the effect much enhanced in non-obese subjects [OR = 1.45 (95% CI 1.19-1.78), P = 2 x 10(-4): P (permuted) = 3 x 10(-4)]. The minor allele of rs2229094 was associated with lower hsCRP, BMI, and waist circumference (WC), while the minor allele of rs1800630 showed association with lower BMI and WC (all P < 0.01). This is the first report demonstrating association of rs1800630 and rs2229094 with type 2 diabetes in any population, suggesting an important role of the TNF-LTA locus in type 2 diabetes in North Indians.