Hemochromatosis genotypes have been associated with liver disease, diabetes mellitus, heart disease, arthritis, porphyria cutanea tarda, stroke, neurodegenerative disorders, cancer, and venous disease. We performed meta-analyses including 202 studies with 66,263 cases and 226,515 controls to examine associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild type, H63D/H63D, and H63D/wild type versus wild type/wild type and 9 overall endpoints and 22 endpoint subgroups. We also explored potential sources of heterogeneity. For liver disease, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.9 (99% confidence interval: 1.9-8.1) overall, 11 (3.7-34) for hepatocellular carcinoma, 4.1 (1.2-14) for hepatitis C, and 10 (2.1-53) for nonalcoholic steatohepatitis. For porphyria cutanea tarda, the odds ratios were 48 (24-95) for C282Y/C282Y, 8.1 (3.9-17) for C282Y/H63D, 3.6 (1.8-7.3) for C282Y/wild type, 3.0 (1.6-5.6) for H63D/H63D, and 1.7 (1.0-3.1) for H63D/wild type versus wild type/wild type. Finally, for amyotrophic lateral sclerosis, the odds ratio was 3.9 (1.2-13) for H63D/H63D versus wild type/wild type. These findings were consistent across individual studies. The hemochromatosis genotypes were not associated with risk for diabetes mellitus, heart disease, arthritis, stroke, cancer, or venous disease in the overall analyses; however, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.4 (1.1-11) for diabetes mellitus among North Europeans.
Conclusion: In aggregate, clinically ascertained cases who are homozygous for the C282Y mutation are associated with a 4-11-fold risk of liver disease, whereas all 5 hemochromatosis genotypes are associated with a 2-48-fold risk of porphyria cutanea tarda, and H63D/H63D is associated with a 4-fold risk of amyotrophic lateral sclerosis. These results, mainly from case-control studies, cannot necessarily be extrapolated to the general population.