<b>Impact of Parental or First-Degree Family History of Diabetes on Diabetes Incidence and Progression during Long-term Follow-up in the Diabetes Prevention Program Outcomes Study</b>

<p dir="ltr">OBJECTIVE</p><p dir="ltr">To determine the effects of first-degree family history of diabetes on diabetes incidence in Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS) participants.</p><p dir="ltr">RESEARCH DESIGN AND METHODS</p><p dir="ltr">The DPP randomized adults with prediabetes to an intensive lifestyle intervention or metformin or placebo and followed them for incident diabetes. Upon study completion, 88% of eligible DPP participants re-enrolled in DPPOS for long-term follow-up. The present analysis includes all 3072 participants with family history information through DPPOS, with a median follow-up of 21 years (1975 had parental history {PH} [312 biparental, 947 maternal, 716 paternal]), 226 had only sibling history {SH}, and 871 denied any family history of diabetes {No-FH}). The primary outcome is incident diabetes based on American Diabetes Association criteria, adjusted for demographic and clinical variables, DPP randomization arm, and polygenic risk score (PRS). </p><p dir="ltr">RESULTS</p><p dir="ltr">The adjusted hazard ratio (HR) and 95% confidence interval [95% CI] were 1.21 [1.06, 1.38] for any family history, 1.19 [1.04, 1.35] for PH, and 1.15 [0.91, 1.44] for SH. Biparental history conferred greater hazard (1.44 [1.22, 1.69]) than maternal (1.22 [1.08, 1.38]) or paternal (1.22 [1.08, 1.39]) diabetes history alone. PRS explained 32% of the association of any family history with diabetes risk.</p><p dir="ltr">CONCLUSIONS</p><p dir="ltr">Parental history increased type 2 diabetes risk after controlling for DPP treatment groups. That effect was only partially explained by PRS, suggesting that rare gene variants, familial, and environmental factors may contribute to type 2 diabetes risk in people with prediabetes.</p>