The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men

Abstract

<h4>Background</h4>Hereditary hemochromatosis resulting either from homozygosity for the C282Y polymorphism of the HFE gene, or compound heterozygosity for C282Y and H63D, manifests with liver disease and hypogonadism. However, it is unclear whether men who are heterozygotes for C282Y or H63D exhibit subtle abnormalities of sex hormone status.<h4>Aims</h4>To evaluate whether heterozygosity for either of the HFE gene polymorphisms C282Y or H63D is associated with circulating testosterone and SHBG in men.<h4>Subjects and methods</h4>We performed a cross-sectional analysis of 388 community-dwelling men. Men were genotyped for C282Y and H63D. Sera were analysed for testosterone and SHBG, and insulin resistance was estimated using a homeostatic model (HOMA2-IR).<h4>Results</h4>Mean age of men in the cohort was 56.9 yr. Men who were heterozygous for the C282Y polymorphism in the HFE gene had higher SHBG levels than men who did not carry this polymorphism (mean ± SE, 38.2 ± 1.64 vs 32.8 ± 0.71 nmol/l, p=0.006). Total and free testosterone levels did not differ in the two groups. In multivariate analysis adjusting for potential confounders including age, waist circumference, testosterone, and HOMA2-IR, C282Y heterozygosity remained associated with SHBG levels (p<0.001).<h4>Conclusion</h4>The C282Y polymorphism is associated with SHBG levels in men who do not manifest iron overload. Further studies are needed to clarify potential mechanisms and determine the clinical relevance of this finding.