SIRT1 Genetic Variation Is Related to BMI and Risk of

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 rs1467568 (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