|Lai, Chao Qiang|
Submitted to: Nutrition Metabolism and Cardiovascular Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2009
Publication Date: 12/1/2010
Citation: Junyent, M., Arnett, D.A., Tsai, M.Y., Kabagambe, E.K., Straka, R.J., Province, M., An, P., Smith, C., Borecki, I., Parnell, L.D., Lai, C., Lee, Y., Ordovas, J.M. 2010. ADAM17_i33780A>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. Nutrition Metabolism and Cardiovascular Disease. 20(101):698-705. Interpretive Summary: ADAM17, a protein that cleaves some select proteins to release an active peptide, is expressed in fat cells and increased expression has been linked to obesity and insulin resistance. We assayed six different genetic variants of the ADAM17 gene for influence on insulin-resistance phenotypes and obesity risk in humans, as well as if such influence is modified by the amount and type of fat in the diet. The genetic variants were analyzed in 936 White Americans for whom anthropometrical and biochemical measurements were determined by standard procedures and dietary fat intake was estimated using a validated questionnaire. A genetic variant in the region of ADAM17 controlling its activity showed correlation with obesity, where presence of the less common variant associated with higher insulin levels, lower height, and lower HDL-cholesterol levels. Similarly, a second variant of ADAM17 associated with obesity via body mass index and waist circumference. However, the association of this second variant with measures of obesity was modified by the amount of (n-6) poly-unsaturated fat (PUFA) in the diet. This association was observed only when the (n-6) PUFA intake was below average. These findings support that two particular genetic variants of ADAM17 may contribute to development of obesity and this risk may be further modulated by (n-6) PUFA intake.
Technical Abstract: The disintegrin and metalloproteinase ADAM17, also known as tumor necrosis factor alpha converting enzyme, is expressed in adipocytes, and elevated levels of expression have been linked to obesity and insulin resistance. This study evaluated the association of six ADAM17 single nucleotide polymorphisms (SNPs) (m1254A>G, i14121C>A, i33708A>G, i48827A>C, i53440C>T, and i62781G>T) with insulin-resistance phenotypes and obesity risk, and their potential interactions with dietary polyunsaturated fatty acids (PUFA). 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. ADAM17_m1254A>G polymorphism was significantly associated with obesity (P=0.003), mainly driven by the association of the G allele with higher insulin (P=0.016), and lower height (P=0.017) and HDL-C concentrations (P=0.027) compared with AA subjects. ADAM17_i33708A>G polymorphism was also associated with obesity (P=0.001), mainly driven by the association of the A allele with higher BMI (P=0.005) and waist (P=0.023) compared with GG subjects. A marginal significant association was found for ADAM17_i53440C>T SNP, by which TT subjects displayed higher risk of obesity. Further analyses supported a significant protective effect against obesity of the haplotype A-G-C (P=0.003). The deleterious association of the i33708A allele with obesity was observed in subjects with low dietary intakes from (n-6) PUFA (P<0.001), leading to a significant gene-diet interaction (P=0.030). These findings support that the m1254A>G and i33708A>G polymorphisms may contribute to development of obesity and this risk may be further modulated by PUFA intake.