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Background: To examine the association of increased plasma leptin concentration with prevalent stroke and coronary heart disease (CHD) and to examine the genetic contributions of leptin to this association in the Jackson Heart Study cohort., Methods: A cohort of 5170 participants aged 21-84 years who underwent Exam I during 2000-2004 was analysed. Odds ratios (OR) of prevalent stroke and CHD were calculated using a logistic regression model adjusted for age, smoking, hypertension and waist circumference (WC). Variance component analysis was used to partition the phenotypic variance of leptin into the polygenic and environmental components., Results: The prevalence of stroke and CHD was 4.04% and 5.85% in women, and 4.88% and 8.92% in men, respectively. Body mass index (BMI) and WC were highly correlated with leptin both in men and women. In multivariate analysis stratified by sex, leptin was significantly associated with stroke (OR = 1.97, 95% CI = 1.21-3.21) in women after adjustment for age, smoking, systolic blood pressure, BMI and WC (P = 0.0079). No significant association was observed in men. Heritability of sex-, age-adjusted log-transformed leptin for this cohort was 38.0% and 37.8% after further adjustment for WC and hypertension, respectively. In addition, a sibship effect was also found to be significant and explained 12.2% of the total variance of leptin (P = 0.007)., Conclusion: There is a significant association of leptin with stroke in women, which is partly influenced by the genetic factor. The findings suggest that leptinemia is an independent risk factor for stroke in African American women.