Association of HFE genotypes with hemochromatosis-related phenotypes in the All of Us research program

Type 1 hereditary hemochromatosis (HH) can result in iron overload and liver disease if not detected and treated early. Most cases are found among people homozygous for HFE p.Cys282Tyr variants. Compound heterozygosity with the HFE p.His63Asp variant is associated with disease to a lesser degree. We sought to examine the association of HFE variation with HH-related phenotypes and assess the prevalence of testing and diagnosis of HH using All of Us data.

We used data from 133,978 participants with genetic information linked to medical records. For different HFE genotypes, we examined the prevalence of HH diagnosis codes and related biochemical and clinical phenotypes.

Among participants who were p.Cys282Tyr homozygotes, the prevalence of HH diagnosis codes was 22.6% among males and 15.6% among females. Serum transferrin-iron saturation measures were available only for 31.4% of males and 21.1% of females who were p.Cys282Tyr homozygotes. Liver disease, including cirrhosis or hepatocellular carcinoma, was present more among males who were p.Cys282Tyr homozygotes compared with males with no p.Cys282Tyr or p.His63Asp variants (15.5% vs 8.5%, P = .0001). Of the 71 participants who were p.Cys282Tyr homozygotes with indication of liver disease, 32 (45.1%) did not have a serum transferrin-iron saturation measure, and 37 (52.1%) did not have diagnosis codes for HH.

Limited serum transferrin-iron saturation measures or HH diagnosis codes among p.Cys282Tyr homozygotes, even those with liver disease, suggests potential undertesting and underdiagnosis of type 1 HH in clinical practice and a need for improved awareness, education, and testing around HH.