Complement component 3 polymorphisms interact with polyunsaturated fatty acids to modulate risk of metabolic syndrome12

Complement component 3 (C3) is a novel determinant of the metabolic syndrome (MetS). Gene-nutrient interactions with dietary fat may affect MetS risk. The objectives were to determine the relation between C3 polymorphisms and MetS and whether interaction with plasma polyunsaturated fatty acids (PUFAs), a biomarker of dietary PUFA, modulate this relation. C3 polymorphisms (rs11569562, rs2250656, rs1047286, rs2230199, rs8107911, rs344548, rs344550, rs2241393, rs7257062, rs163913, and rs2230204), biochemical measurements, and plasma fatty acids were measured in the LIPGENE–SUpplementation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study in MetS cases and matched controls (n = 1754). Two single nucleotide polymorphisms were associated with MetS. rs11569562 GG homozygotes had decreased MetS risk compared with minor A allele carriers [odds ratio (OR): 0.53; 95% CI: 0.35, 0.82; P = 0.009], which was augmented by high plasma PUFA status (OR: 0.32; 95% CI: 0.11, 0.93; P = 0.04). GG homozygotes had lower C3 concentrations than those in AA homozygotes (P = 0.03) and decreased risk of hypertriglyceridemia compared with A allele carriers (OR: 0.54; 95% CI: 0.34, 0.92; P = 0.02), which was further ameliorated by an increase in long-chain n–3 (omega-3) PUFAs (OR: 0.46; 95% CI: 0.22, 0.97; P = 0.04) or a decrease in n–6 PUFAs (OR: 0.32; CI: 0.16, 0.62; P = 0.002). rs2250656 AA homozygotes had increased MetS risk relative to minor G allele carriers (OR: 1.78; CI: 1.19, 2.70; P = 0.02), which was exacerbated by low n–6 PUFA status (OR: 2.20; CI: 1.09, 4.55; P = 0.03). Plasma PUFAs may modulate the susceptibility to MetS that is conferred by C3 polymorphisms, which suggests novel gene-nutrient interactions. This trial was registered at clinicaltrials.gov as NCT00272428.