BACKGROUND AND AIM: The well-established link between body fat distribution and metabolic health has been suggested to act through an impact on the remodeling capacity of the adipose tissue. Remodeling of the adipose tissue has been shown to affect body fat distribution and might affect the ability to lose weight. We aimed to study the effect of weighted genetic risk scores (GRSs) on weight loss based on single-nucleotide polymorphisms (SNPs) associated with waist-hip-ratio adjusted for body mass index (WHRadjBMI).

METHOD: We included 707 participants (533 women and 174 men) from the NUGENOB multi-center 10 week diet intervention study with weekly weight measurements. We created 3 GRSs, one including all reported WHRadjBMI SNPs (GRStotal), one including only SNPs with genome wide significance in women or with significantly greater effect in women (GRSwomen), and one excluding SNPs in the GRSwomen (GRSmen). The data was analyzed in a mixed linear model framework.

RESULTS: The GRStotal and GRSwomen attenuated weight loss in women. The effect was strongest for the GRSwomen with an effect of 2.21 g/risk allele/day [95% CI (0.90;3.52), P=0.0009]. Adjustment for WHR, basal metabolic rate or diet compliance did not affect the result. The GRSs had no effect on weight loss in men. The VEGFA rs1358980-T strongly attenuated weight loss in both men and women [β 15.95 g/risk allele/ day, (3.16;26.74), P=0.013] and [β 15.95 g/risk allele/ day, (2.58;13.53), P=0.004], respectively).

CONCLUSION: Our findings suggest that genetic variants influencing body fat distribution attenuate weight loss in women independently on the effect on WHR. The stronger effect of the GRSwomen implies heterogenic effects of the WHRadjBMI variants on weight loss. A strong effect of rs1358980-T in the VEGFA locus suggests that angiogenesis plays a role, but this needs confirmation from functional studies.International Journal of Obesity accepted article preview online, 16 November 2017. doi:10.1038/ijo.2017.279.