Heritability of Iron Status Phenotype in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study

Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western European descent. HH, defined using biochemical criteria, occurs in 0.2%–0.5% of US whites. Some HH patients absorb excessive dietary iron and develop consequent liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, and hypogonadotrophic hypogonadism. Most whites with HH have common mutations (C282Y and H63D) in HFE; this gene encodes HFE, which regulates iron absorption by modulating hepatic expression of hepcidin. The spectrum of HH phenotypes is broad, and mutations in known iron-related genes do not account for most phenotype variability. Thus, it is assumed that HH phenotypes are affected by other genetic and environmental factors. Gender and age are two important factors known to affect HH phenotypes. Putative genetic factors may influence dietary choices or modulate iron absorption or loss via mechanisms presently undefined. The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. We examined familial aggregation and genetic contributions to iron- and HH-related phenotypes in the HEIRS Family Study and hypothesized that both genetic and environmental factors influence serum iron measures after adjustment for gender, age, HFE C282Y and H63D genotype, and other clinical and demographic characteristics. Heritability (h²), defined as the proportion of total variation due to variability in genetic values, measures the fraction of variation between individuals in a population attributable to additive effects of their genotypes. We estimated heritability of TS, SF, and unbound iron-binding capacity (UIBC) in participants from the HEIRS Family Study (N=180 families, mean size 5.5). Eligible probands (aged >24 y) had both TS and SF values above gender-specific thresholds (TS>50% and SF >300 μg/L in men; TS >45% and SF >200 μg/L in women), or were C282Y homozygotes. Family members, 19 years of age or older, were eligible. There were 77% Caucasians, 3% African Americans, 8% Hispanics, and 10% Asians; average age (SD) was 49 (16) y; 56% were female. The distribution of HFE genotypes was 22% C282Y/C282Y, 7% C282Y/H63D, 2% H63D/H63D, 34% C282Y/+, 8% H63D/+, and 26% +/+. A variance component approach using SOLAR software estimated residual heritability, adjusting for age, gender, their interaction (age × gender), race/ethnicity, and HFE genotype (model 1). In another model, study site, body mass index, menopausal status, phlebotomy treatment, hepatitis, average daily intake of alcohol, and level of C-reactive protein were added to the core set of covariates (model 2). Log transformation of serum ferritin was performed prior to analysis. In model 1 (N=938 individuals), h² was 0.40 (SE 0.060) for UIBC, 0.26 (0.055) for log SF, and 0.25 (0.056) for TS; P < 0.0001 for each test of h²=0. Age, gender, race/ethnicity, and HFE genotype accounted for 38%, 38%, and 36% of the variability in UIBC, log SF, and TS, respectively. In model 2, based on complete data from N=828 individuals, adjusted for the full set of covariates, h² was 0.31 (0.067) for UIBC, 0.26 (0.067) for log SF, and 0.16 (0.061) for TS; P < 0.0013 for each. The proportion of variance due to age, gender, HFE gene and all measured environmental factors was 0.43 for UIBC, 0.44 for log SF, and 0.41 for TS. We conclude that quantitative serum iron measures in HEIRS Family Study participants have significant heritability components, even after accounting for effects of HFE C282Y and H63D genotypes. This suggests that other genetic variants contribute to the variability in TS, SF, and UIBC, and indicates the need for gene discovery studies to provide insight into clinical disorders in which morbidity and mortality are affected by perturbations of iron metabolism.