Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 non- screening Alabama hemochromatosis probands with HFE C282Y homozygosity Running head: Diabetes, family history, and hemochromatosis

Objective: We sought to identify predictors of diabetes diagnosed before hemochromatosis. Research Design and Methods: We studied these 16 variables in 159 non-screening hemochromatosis probands with HFE C282Y homozygosity: age; sex; body mass index (BMI); diabetes reports in first-degree family members (dichotomous); heavy ethanol consumption; cigarette smoking; elevated serum ALT/AST levels; non-alcoholic fatty liver; chronic viral hepatitis; cirrhosis; hand arthropathy; iron removed by phlebotomy; and positivity for HLA-A*01, B*08; A*03, B*07; and A*03, B*14 haplotypes. We performed univariable and multivariable analyses. Results: Twenty-three probands (14.5%) had diabetes; 19 were men. Each of the 23 probands had type 2 diabetes. Mean BMI was greater in probands with diabetes (31.7 ± 8.5 (SD) kg/m 2 vs. 27.6 ± 5.1 kg/m 2 ; p = 0.032). Reports of any first-degree family member with diabetes were more prevalent in probands with than in probands without diabetes (69.6% vs. 17.6%; p <0.0001). In probands with diabetes, the odds ratio (OR) of maternal diabetes was 6.7 ((95% CI 2.3, 19.7); p = 0.0005) and of sibling diabetes was 11.7 ((95% CI 3.0, 45.5); p = 0.0004). In a logistic regression model, predictors of diabetes at hemochromatosis diagnosis in 159 probands were diabetes reports in family members (OR 8.5 (95% CI 2.9, 24.8); p<0.0001) and BMI (OR 1.1 (1.0, 1.2); p=0.049). This model explained 26.0% of total deviance contributing to diabetes. Conclusions: In non-screening hemochromatosis probands with HFE C282Y homozygosity, a heritable factor(s) increases the risk of diabetes diagnosed before hemochromatosis. Page 2 of 30 Diabetes Care