SIRT1 Genetic Variation Is Related to BMI and Risk of Obesity

OBJECTIVE-SIRT1 has pleiotropic metabolic functions. We investigated whether SIRT1 genetic variation is associated with obesity. RESEARCH DESIGN AND METHODS-In 6,251 elderly subjects from the prospective, population-based Rotterdam Study, three single nucleotide polymorphisms (SNPs) in the SIRT1 gene were studied in relation to BMI and risk of obesity (BMI >= 30 kg/m(2)) and prospectively with BMI change after 6.4 years of follow-up. We used cross-sectional data from 2,347 participants from the Erasmus Rucphen Family (ERF) study for replication. RESULTS-Minor alleles of rs7895833 (G = 20.2%) and rsl467568 (A = 36.8%) were associated with lower BMI in the Rotterdam Study (P = 0.02 and 0.04) and in the replication cohort ERF study (P = 0.03 and 0.008) and in both studies combined (P = 0.002 for both SNPs), with a 0.2-0.4 kg/m(2) decrease in BMI per allele copy. Carriers of these alleles had 13-18% decreased risk of obesity (for rs7895833 in the Rotterdam Study: odds ratio 0.79 [95% CI 0.67-0.94], P = 0.007; in the ERF study: 0.93 [0.73-1.19], P = 0.37; and in the studies combined 0.87 [0.77-0.97], P = 0.02; for rs1467568 in the Rotterdam Study: 0.80 [0.68-0.94], P = 0.007; in the ERF study: 0.85 [0.72-0.99], P = 0.04; and in the studies combined: 0.82 [0.73-0.92], P = 0.0009). In the Rotterdam Study, the two variants were also associated with a lower BMI increase during 6.4 years of follow-up (P = 0.01 and 0.08). CONCLUSIONS-Two common variants in SIRT1 are associated with lower BMI in two independent Dutch populations. Carriers of these variants have 13-18% decreased risk of obesity and gain less weight over time. The availability of SIRT1 stimulators makes these findings relevant in light of the growing obesity epidemic. Diabetes 58:2828-2834, 2009