Department of Chronic Diseases Epidemiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. caroline.van.rossum@rivm.nl OBJECTIVE: To investigate the association between DNA polymorphisms in several candidate genes for obesity and weight gain. Polymorphisms in these genes may contribute to weight gain through effects on energy intake, energy expenditure or adipogenesis. DESIGN AND METHODS: From two large cohorts in The Netherlands (total 17,500 adult men and women), we compared 286 subjects aged 20-40 y who gained an average of 12.8 kg (range 5.5-47 kg) during a mean follow-up of 6.8 y with 296 subjects who remained relatively constant over the same period with respect to occurrence of several polymorphisms in candidate genes of obesity and some lifestyle factors. Subjects who were dieting, were high alcohol consumers, were pregnant, changed their smoking status recently, or those who suffered from serious illnesses were excluded. Polymorphisms were determined in the LEPR-gene (LEPR Lys109Arg, LEPR Gln223Arg, LEPR Lys656Asn), in the UCP1 gene (A-G mutation at position-3826 5' region), in the UCP2 gene (Ala55Val, 45 bp Ins/Del), in the PPARG2 gene (Pro12Ala) and in the ADRB2 gene (Gly16Arg and Gln27Glu). RESULTS: With the exception of the Gly16Arg polymorphism in the ADRB2 gene in men (P = 0.04) and women (P = 0.05), and the Lys109Arg polymorphism in the LEPR gene in women, no statistically significant differences in the genotype and allele frequencies were observed between weight gainers and non-weight gainers. Weight gainers differed in some aspects of dietary habits and physical activity patterns: weight gainers consumed relatively more savory snacks and were less active during leisure time compared with non-weight gainers. CONCLUSION: Only variations in the ADRB2 gene and LEPR gene, may contribute to susceptibility to weight gain. None of the other studied genetic markers were clearly associated with weight gain. Further research is necessary to establish the role of ...