This prospective cohort study in Japanese workers examined the relationship between the -1438A/G polymorphism in the 5-hydroxytryptamine receptor 2A gene and the development of positive findings for various life-style-related disorders. This study over the 5-year period, 1997-2002, included observations of several disorders in cohorts ranging between 560-1023 for males and 477-735 for females who had negative findings for each disorder at baseline. The criteria for development of the disorders were: hypertension, systolic blood pressure ≥140 mmHg or dia-stolic blood pressure ≥90 mmHg or taking antihypertensive medication; overweight, body mass index (BMI) ≥25 kg/m2; obesity, BMI ≥30 kg/m2; new onset of cerebral stroke; metabolic abnormalities, glycosylated hemoglobin A1c >6.0%, total cholesterol ≥240 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, uric acid >7.0 mg/dl, γ-glutamyl transpeptidase ≥60 IU/l in males and ≥30 IU/l in females. Pooled logistic regression analyses were performed using the -1438A/G genotype and other potential factors as covariates. The odds ratios to AA genotype were significant for uric acid (GG, 0.52; AG, 0.59), obesity (AG, 0.24) in males and for high-density lipoprotein cholesterol (GG, 0.11; AG, 0.36), γ-glutamyl transpeptidase (GG, 0.53; AG, 0.62) and total cholesterol (GG, 1.84) in females. The present study is the first prospective cohort investigation to demonstrate that the -1438G allele has a protective effect against the development of a range of cardiovascular and metabolic disorders. This study indicates that the -1438A/G polymorphism is an independent factor for various disorders in the general Japanese population and suggests that targeting of this polymorphism may be beneficial for preventing these disorders in Japan.

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