Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk

PLoS One. 2018 Feb 14;13(2):e0192696. doi: 10.1371/journal.pone.0192696. eCollection 2018.

Abstract

There is a growing body of evidence suggesting that type 1 diabetes (T1D) is a genetically heterogeneous disease. However, the extent of this heterogeneity, and what observations may distinguish different forms, is unclear. One indicator may be T1D-related microvascular complications (MVCs), which are familial, but occur in some families, and not others. We tested the hypothesis that T1D plus MVC is genetically distinct from T1D without MCV. We studied 415 families (2,462 individuals, 896 with T1D) using genome-wide linkage analysis, comparing families with and without MVC. We also tested for interaction between identified loci and alleles at the HLA-DRB1 locus. We found significant linkage scores at 1p36.12, 1q32.1, 8q21.3, 12p11.21 and 22q11.21. In all regions except 1p36.12, linkage scores differed between MVC-based phenotype groups, suggesting that families with MVCs express different genetic influences than those without. Our linkage results also suggested gene-gene interaction between the above putative loci and the HLA region; HLA-based strata produced significantly increased linkage scores in some strata, but not others within a phenotype group. We conclude that families with type 1 diabetes plus MVCs are genetically different from those with diabetes alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping
  • Diabetes Complications / genetics*
  • Diabetes Mellitus, Type 1 / genetics*
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Humans

Grant support

This study was funded by the Pennsylvania Department of Health’s Commonwealth Universal Research Enhancement Program (http://www.health.pa.gov/MyRecords/Health-Research/CURE/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.