Identifying genetic susceptibilities to diabetes-related complications among individuals at low risk of complications: An application of tree-structured survival analysis

Am J Epidemiol. 2006 Nov 1;164(9):862-72. doi: 10.1093/aje/kwj287. Epub 2006 Aug 23.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Diabetes Complications / epidemiology
  • Diabetes Complications / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Lipase / genetics*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Nitric Oxide Synthase Type III / genetics*
  • Peptidyl-Dipeptidase A / genetics*
  • Polymorphism, Genetic
  • Risk
  • Survival Analysis


  • LIPC protein, human
  • Nitric Oxide Synthase Type III
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Lipase
  • Peptidyl-Dipeptidase A