Zimmermann E, Ängquist LH, Mirza SS, Zhao JH, Chasman DI, Fischer K, Qi Q, Smith AV, Thinggaard M, Jarczok MN, Nalls MA, Trompet S, Timpson NJ, Schmidt B, Jackson AU, Lyytikäinen LP, Verweij N, Mueller-Nurasyid M, Vikström M, Marques-Vidal P, Wong A, Meidtner K, Middelberg RP, Strawbridge RJ, Christiansen L, FTO-Mortality Collaborating Group , Kyvik KO, Hamsten A, Jääskeläinen T, Tjønneland A, Eriksson JG, Whitfield JB, Boeing H, Hardy R, Vollenweider P, Leander K, Peters A, van der Harst P, Kumari M, Lehtimäki T, Meirhaeghe A, Tuomilehto J, Jöckel KH, Ben-Shlomo Y, Sattar N, Baumeister SE, Smith GD, Casas JP, Houston DK, März W, Christensen K, Gudnason V, Hu FB, Metspalu A, Ridker PM, Wareham NJ, Loos RJF, Tiemeier H, Sonestedt E, Sørensen TIA
Obes Rev 16 (4) 327-340 [2015-04-00; online 2015-03-05]
Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.