Submitted April 24, 2003
Accepted July 28, 2003
Mixture distribution analysis of phenotypic markers reflecting HFE gene mutations
Christine E McLaren*, Kuo-Tung Li, Chad P Garner, Ernest Beutler, and Victor R Gordeuk
Epidemiology Division, University of California School of Medicine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA
Scripps Research Institute, La Jolla, CA, USA
Department of Medicine, Division of Hematology/Oncology, Howard University, Washington, DC, USA
* Corresponding author; email: cmclaren{at}uci.edu.
The goal of this study is to determine if statistical modeling of population data for a phenotypic marker can reflect a major locus genetic defect. Identification of mutations in the HFE gene makes it possible to assess the association between transferrin saturtion (TS) subpopulations and HFE mutations. Data were analyzed from 27,895 Caucasians who attended a health appraisal clinic and had TS and common mutations of HFE determined. Mixture distribution modeling of TS was performed and the proportion of HFE mutations in TS subpopulations assessed on a probability basis. Three subpopulations of TS were identified consistent with Hardy-Weinberg conditions for major locus effects. For men, 72% of the subpopulation with the highest mean TS were individuals with HFE gene mutations, primarily homozygotes or compound heterozygotes. Seventy-three percent of the subpopulation with a moderate mean TS were also individuals with HFE gene mutations, predominantly simple heterozygotes, and 67% of the subpopulation with the lowest mean TS were homozygous wild type. Similar results were observed for women. These results suggest that statistical modeling of population clinical laboratory test data can reveal the influence of a major locus genetic defect and perhaps can be applied to other aspects of body metabolism than iron.
