Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: Support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants

C. L. Avery, B. I. Freedman, A. T. Kraja, I. B. Borecki, M. B. Miller, J. S. Pankow, D. Arnett, C. E. Lewis, R. H. Myers, S. C. Hunt, K. E. North

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Aims/hypothesis: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). Subjects, materials and methods: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. Results: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. Conclusions/ interpretation: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.

Original languageEnglish
Pages (from-to)2329-2336
Number of pages8
Issue number10
StatePublished - Oct 2006

Bibliographical note

Funding Information:
Acknowledgements We acknowledge the support provided by NHLBI training grant HL007055. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The hypertension network is funded by cooperative agreements (U10) with NHLBI: HL54471, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515. We thank the HyperGEN study participants. We also acknowledge the HyperGEN Participating Institutions and Principal Staff (see ESM).


  • Genome scan
  • Genotype-by-sex interaction
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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