Familial Risk Factors for Microvascular Complications and Differential Male-Female Risk in a Large Cohort of American Families with Type 1 Diabetes

Context: Type 1 diabetes (T1D) complications are responsible for much of the disease morbidity. Evidence suggests that familial factors exert an influence on susceptibility to complications. Objectives: We investigated familial risk factors and gender differences for retinopathy, nephropathy, and neuropathy. Design and Setting: This study was a case-control design nested on a cohort of T1D families. We collected data (questionnaire, medical records) starting in 1988. Follow-up has been ongoing since 2004. Patients: There were 8114 T1D patients among 6707 families. All patients had T1D onset age younger than 30 yr and required insulin treatment. Patients who remained without a complication after more than 15 yr of diabetes were considered to be without that complication for our analyses. Results: A complication in a sibling increased the risk for that complication among probands: odds ratio 9.9 (P ! 0.001) for retinopathy, 6.2 for nephropathy (P ! 0.001), and 2.2 for neuropathy (P ! 0.05). Compared with male probands, a female T1D proband had 1.7-fold higher retinopathy risk (P!0.001) and 2-fold higher neuropathy risk (P ! 0.001). T1D cases with onset between ages 5 and 14 yr had an increased complications risk compared with subjects diagnosed either at a very young age or after puberty. The presence of one complication significantly increased the risk for others. If a parent had type 2 diabetes, the risk for nephropathy increased (odds ratio 1.9, P ! 0.01, but T1D in a parent did not increase the risk). Conclusions: We confirmed that familial factors influence T1D microvascular pathologies, suggesting a shared genetic basis for complications, perhaps independent of T1D susceptibility. We also found an unexpected increased female risk for complications.