Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India.
J Mol Med (Berl). 2010 May;88(5):515-22. doi: 10.1007/s00109-010-0594-5. Epub 2010 Feb 23.
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.
六个常见的遗传变异（rs2229094、rs1041981、rs1800630、rs1800629、rs361525 和 rs1800610）位于编码促炎细胞因子肿瘤坏死因子-α（TNF-α）和淋巴毒素-α的 TNF-LTA 基因座中，这些变异与各种代谢特征有关，包括易患 2 型糖尿病、代谢综合征、胰岛素抵抗和体重指数（BMI）增加在来自不同地理位置的白种人中，结果喜忧参半。我们通过研究包括 1073 名 2 型糖尿病患者和 1042 名对照在内的 2115 名参与者，检测了这些变体与北印度人的 2 型糖尿病之间的关联。我们报告了 TNF 的启动子区域变异 rs1800630 和非同义 LTA 变异 rs2229094 与 2 型糖尿病的关联[OR=0.83（95%CI0.72-0.95），P=0.005 和 OR=0.86（95%CI0.75-0.98），P=0.02]。尽管这些关联依赖于 BMI，但在 2 型糖尿病中未检测到 BMI 和变体的交互作用。此外，携带所有六个主要等位基因的单体型易患 2 型糖尿病[OR=1.23（95%CI1.06-1.42），P=0.005；P（随机）=0.02]，在非肥胖受试者中，这种效应更为明显[OR=1.45（95%CI1.19-1.78），P=2x10（-4）：P（随机）=3x10（-4）]。rs2229094 的次要等位基因与 hsCRP、BMI 和腰围（WC）降低有关，而 rs1800630 的次要等位基因与 BMI 和 WC 降低有关（均 P<0.01）。这是首次在任何人群中报告 rs1800630 和 rs2229094 与 2 型糖尿病相关的研究，表明 TNF-LTA 基因座在北印度人中的 2 型糖尿病中起重要作用。
