Hemochromatosis Genotypes and Risk of Iron Overload—A Meta-Analysis

Purpose

The incomplete phenotypic penetrance of high iron Fe genotypes in relation to hemochromatosis poses a practical problem in the interpretation of the genotyping results by clinicians. We carried out meta-analyses of the associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild-type, H63D/H63D, H63D/wild-type, versus wild-type/wild-type and iron overload, both provisional (elevated serum iron markers) and documented (elevated serum iron markers associated with evidence of iron excess based on liver biopsy and/or quantitative phlebotomy).

Methods

After reviewing 3572 article titles and evaluating 92 articles in detail, odds ratios were pooled from 43 study populations (9986 cases and 25,492 controls) using a random-effects model.

Results

Homozygosity for either variant or compound heterozygosity was associated with both provisional and documented iron overload. Single heterozygosity conferred no risk for elevated hepatic iron index and/or mobilizable iron by quantitative phlebotomy. In patients with clinical hereditary hemochromatosis, no evidence of provisional and documented iron overload with transferrin saturation (TS) values greater than 55% was evidenced for C282Y and H63D single heterozygotes whereas documented iron overload including TS of 45% to 50% was weakly associated with C282Y/wild-type genotype; H63D/H63D genotype was not associated with documented iron overload in patients with TS values of 45% to 50%.

Conclusions

The results, mainly from case-control studies, cannot necessarily be extrapolated to the general population.

Key Words: Genotype, Hemochromatosis, Iron Overload, Meta-Analysis, Odds Ratio, Phenotype

Selected Abbreviations and Acronyms: CI, confidence interval, C282Y, cysteine substitution for tyrosine in position 282 of the HFE protein, H63D, histidine substitution for aspartic acid in position 63 of the HFE protein, HFE, (high iron Fe) gene located on short arm of chromosome 6 at location 6p21.3, HH, hereditary hemochromatosis, HII, hepatic iron index, HIS, hepatic iron score, HWE, Hardy-Weinberg equilibrium, LIC, liver iron concentration, NA, not available, OR, odds ratio, P, elevated mobilizable iron by quantitative phlebotomy, SF, serum ferritin, sFe, serum iron concentration, TS, transferrin saturation, WT, wild-type