ADAM17_i33708A>G polymorphism interacts with dietary n-6 polyunsaturated fatty acids to modulate obesity risk in the Genetics of Lipid Lowering Drugs and Diet Network study

Background and aims: The disintegrin and metalloproteinase ADAM17, also known as tumor necrosis factor alpha converting enzyme, is expressed in adipocytes. Importantly, elevated levels of ADAM17 expression have been linked to obesity and insulin resistance. Therefore, the aim of this study was to evaluate the association of six ADAM17 single nucleotide polymorphisms (SNPs) (m1254A > G, i14121C > A, i33708A > G, i48827A > C, i53440C > T, and i62781. G > T) with insulin-resistance phenotypes and obesity risk, and their potential interactions with dietary polyunsaturated fatty acids (PUFA). Methods and results: ADAM17 SNPs were genotyped in 936 subjects (448 men/488 women) who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Anthropometrical and biochemical measurements were determined by standard procedures. PUFA intake was estimated using a validated questionnaire. G allele carriers at the ADAM17_m1254A > G polymorphism exhibited significantly higher risk of obesity (P= 0.003), were shorter (P= 0.017), had higher insulin (P= 0.016), and lower HDL-C concentrations (P= 0.027) than AA subjects. For the ADAM17_i33708A > G SNP, homozygotes for the A allele displayed higher risk of obesity (P= 0.001), were heavier (P= 0.011), had higher BMI (P= 0.005), and higher waist measurements (P= 0.023) than GG subjects. A significant gene-diet interaction was found (P= 0.030), in which the deleterious association of the i33708A allele with obesity was observed in subjects with low intakes from (n-6) PUFA (P< 0.001), whereas no differences in obesity risk were seen among subjects with high (n-6) PUFA intake (P> 0.5). Conclusion: These findings support that ADAM17 (m1254A > G and i33708A > G) SNPs may contribute to obesity risk. For the ADAM17_i33708A > G SNP, this risk may be further modulated by (n-6) PUFA intake.