To investigate whether Leu72Met polymorphism of the preproghrelin gene is associated with overweight/obesity in middle-aged and older Japanese.Cross-sectional analysis.A total of 2238 community-dwelling middle-aged and older Japanese people (age: 40-79 years) who participated in the first wave of examinations in the National Institute for Longevity Sciences - Longitudinal Study of Aging from April 1998 to March 2000.The Leu72Met polymorphism of prepoghrelin gene, anthropometric variables including body weight, body mass index (BMI), waist circumference, waist-to-hip ratio and whole-fat mass and biochemical variables including serum lipid levels, fasting plasma glucose, insulin and homeostasis model assessment for insulin resistance.The frequencies of the Leu72Leu, Leu72Met and Met72Met alleles were 63.4, 32.7 and 4.0%, respectively. No differences in the genotype distributions of the Leu72Met polymorphism were found between genders or age groups, and no significant associations were observed between polymorphism and anthropometric variables in women and older men. However, middle-aged men who were 72Met allele carriers showed a higher body weight change from body weight at 18 years of age, as well as a higher waist circumference and a tendency to a higher waist-hip-ratio than noncarriers. Although there were no significant differences in the genotype distribution according to BMI in women and older men, a significantly higher frequency of the 72Met allele was found in the higher BMI group (BMI> or =25 kg/m(2)) of middle-aged men than in the normal-weight group. No significant associations were observed between polymorphism and serum lipid, glucose or insulin levels.These results suggest that the 72Met allele of the preproghrelin gene is a contributing factor for midlife weight change in men.