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

Division of Statistical Genetics (M.C.M., D.A.G.), Departments of Biostatistics (M.C.M., D.A.G.) and Psychiatry (D.A.G.), Columbia University, New York, New York 10032; National Disease Research Interchange (J.T.L., R.M., E.S.), Philadelphia, Pennsylvania 19103; Section of Medical Statistics and Epidemiology (M.C.M., C.M.), Department of Health Sciences, University of Pavia, 27100 Pavia, Italy; and New York State Psychiatric Institute (D.A.G.), New York, New York 10032

Address all correspondence and requests for reprints to: David A. Greenberg, 722 West 168th Street, Room 623, New York, New York 10032. E-mail: dag2005{at}columbia.edu.

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.