American Journal of Epidemiology Advance Access originally published online on August 23, 2006
American Journal of Epidemiology 2006 164(9):862-872; doi:10.1093/aje/kwj287
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Original Contribution |
Identifying Genetic Susceptibilities to Diabetes-related Complications among Individuals at Low Risk of Complications: An Application of Tree-Structured Survival Analysis
1 Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
2 Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA
3 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA
Correspondence to Dr. Trevor J. Orchard, University of Pittsburgh, Diabetes and Lipid Research Building, 3512 Fifth Avenue, Pittsburgh, PA 15213 (e-mail: tjo{at}pitt.edu).
The authors hypothesized that genetic predisposition to diabetes complications would be more evident among low-risk individuals and aimed to identify genes related to developing complications (confirmed distal symmetric polyneuropathy, overt nephropathy, or coronary artery disease) in low-risk groups. Participants in the Pittsburgh, Pennsylvania, Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes, first seen in 1986–1988 (mean age, 28 years; diabetes duration, 19 years), were reexamined biennially for 10 years. For each complication, subgroups with the lowest disease risk were identified by using tree-structured survival analysis, and 15 candidate genes were compared between subjects with and without complications. In the group with the lowest incidence of confirmed distal symmetric polyneuropathy (n = 123), confirmed distal symmetric polyneuropathy risk increased fivefold for those with the eNOS GG genotype (p < 0.05). In the group with the lowest risk of overt nephropathy (n = 340), the ACE D polymorphism increased overt nephropathy risk twofold (p = 0.05), whereas a protective effect was observed for the LIPC CC genotype (p < 0.05). In the group with the lowest incidence of coronary artery disease (n = 331), the MTHFR CC genotype increased coronary artery disease risk threefold (p < 0.05). Tree-structured survival analysis may help identify genetic predispositions among individuals who, despite low risk, develop diabetes-related complications.
diabetes complications; diabetes mellitus; genetic predisposition to disease; statistics; survival analysis
Abbreviations: ACE, angiotensin-converting enzyme; eNOS, endothelial nitric oxide synthase; HDL, high density lipoprotein; LIPC, hepatic lipase; MTHFR, methylenetetrahydrofolate reductase; TSSA, tree-structured survival analysis
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