No association of TNFRSF1B variants with type 2 diabetes in Indians of Indo-European origin

The initial phase evaluated association of seven SNPs viz. rs652625, rs496888, rs6697733, rs945439, rs235249, rs17883432 and rs17884213 with type 2 diabetes in 2,115 participants (1,073 type 2 diabetes patients and 1,042 control subjects). Further, we conducted replication analysis of three associated SNPs in 2,085 subjects (1,047 type 2 diabetes patients and 1,038 control subjects).We observed nominal association of rs945439, rs235249 and rs17884213 with type 2 diabetes (P < 0.05) in the initial phase. Haplotype CC of rs945439 and rs235249 conferred increased susceptibility for type 2 diabetes [OR = 1.19 (95%CI 1.03-1.37), P = 0.019/Pperm = 0.076] whereas, TG haplotype of rs235249 and rs17884213 provided protection against type 2 diabetes [OR = 0.83 (95%CI 0.72-0.95, P = 7.2 × 10-3/Pperm = 0.019]. We also observed suggestive association of rs496888 with plasma hsCRP levels [P = 0.042]. However, the association of rs945439, rs235249 and rs17884213 with type 2 diabetes was not replicated in the second study population. Meta-analysis of the two studies also failed to detect any association with type 2 diabetes.Our two-stage association analysis suggests that TNFRSF1B variants are not the determinants of genetic risk of type 2 diabetes in North Indians.Low-grade systemic inflammation plays a crucial role in the manifestation of type 2 diabetes [1]. Activation of TNF-TNFR axis in response to elevated Tumor Necrosis Factor α (TNFα) levels, a pro-inflammatory cytokine, can be speculated to contribute to the causation of type 2 diabetes. TNFα which is involved in varied processes such as inflammatory, immune and metabolic events, is over-expressed in adipose and muscle tissues of obese and type 2 diabetic subjects [2-4]. The metabolic activities of TNFα are mainly mediated through TNFR2 (type 2 receptor for TNFα), providing the inflammation-metabolic interface in type 2 diabetes.Enhanced TNFR2 expression and soluble TNFR2 (sTNFR2) levels have been observed in obesity, insu