Familial aggregation of cardiometabolic traits and long-term cardiometabolic risk in offspring: a 15-year prospective analysis from the PREVEND cohort

Abstract

Family history is a well-established predictor of cardiometabolic risk; however, the independent prognostic contribution of sibling disease history, beyond parental history, remains to be elucidated. Using data from the prospective population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, we investigated the associations between family history of six common cardiometabolic disorders and incident cardiovascular disease (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF). Primary family history was categorized into three groups: no family history, parental history only, or any sibling history. To further disentangle the distinct familial contributions, parental history was additionally stratified as no parent affected, father only affected, mother only affected, or both parents affected. The sibling disease score was calculated from reported sibling disease history across six cardiometabolic conditions and categorized as 0, 1, or ≥ 2 entries. Fine-Gray competing-risk models were employed to estimate subdistribution hazard ratios (SHRs), with death accounted for as a competing event. Among 8,592 participants (mean age, 49.8 ± 12.7 years; 49.9% male), biparental history was independently associated with incident CVD (SHR, 1.48; 95% CI, 1.06–2.05), whereas maternal-only history (SHR, 1.50; 95% CI, 1.17–1.92) and biparental history (SHR, 1.67; 95% CI, 1.16–2.41) were significantly associated with incident DM. In contrast, no significant associations were observed for incident CKD or HF. Compared with no family history, any sibling history was associated with higher risks of incident CVD (SHR, 1.71; 95% CI, 1.33–2.20) and DM (SHR, 1.69; 95% CI, 1.18–2.43), independent of traditional cardiometabolic risk factors and social determinants of health. After additional adjustment for parental history, the sibling disease score remained significantly associated with incident CVD, with SHRs of 1.47 (95% CI, 1.11–1.95) for a sibling disease score of 1 and 2.36 (95% CI, 1.53–3.64) for a sibling disease score of ≥ 2. A significant dose–response relationship was observed for both CVD ( P for trend < 0.001) and DM ( P for trend = 0.035). The sibling disease history provides incremental prognostic value beyond parental history and is robustly associated with CVD, while it is attenuated with DM. These findings highlight the importance of incorporating sibling history into comprehensive cardiometabolic risk assessment.