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Background  The aim of this study was to investigate whether two variants of the TCF7L2 (rs7903146 and rs12255372) modify the association between nut consumption and the risk of metabolic syndrome (MetS). Additionally, the modifying effect of weight change during follow-up on these associations was investigated.    Material and methods  We prospectively studied 1423 participants of the Tehran Lipid and Glucose study aged 19–74 years who were followed-up for dietary assessment using a validated, semi-quantitative food frequency questionnaire. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for MetS events. Genotyping was performed by Human Omni Express-24-v1-0 chip.    Results  Over a median 8.9 years of follow-up, 415 new cases of MetS were documented. The median nut consumption was 20.0 g/week (Interquartile Range (IQR): 8.6–38.9 g/week). Regarding the rs7903146 genotype, in carriers of T allele (CT + TT), highest tertile of nut consumption was associated with a reduced risk of MetS after adjusting for confounders (HR: 0.67 (0.50–0.91)). Regarding the rs12255372 genotype, highest versus lowest tertile of nut consumption in participants with T allele (GT + TT) resulted in 34% reduction of MetS risk after adjustment for confounders (HR: 0.66 (0.49–0.69)). After stratification by weigh change (< 7% or ≥ 7% weight gain), in individuals with ≥ 7% weight gain, highest tertile of nut consumption was associated with reduced risk of MetS among the risk allele of rs7903146. In the risk allele of rs12255372, among individuals with < 7% weight gain, third tertile of nuts intake reduced the risk of MetS, after adjustment for confounders.    Conclusion  Higher consumption of nuts may reduces the risk of MetS in T-risk allele of the TCF7L2 rs7903146 and rs12255372 variants and weight change may modify this association.

TCF7L2 polymorphisms, nut consumption, and the risk of metabolic syndrome: a prospective population based study