Quantifying risk modifiers of hereditary hemochromatosis using genomic and electronic health record data

Hereditary hemochromatosis is an autosomal recessive disorder of excessive iron accumulation. Early diagnosis enables treatment before organ damage. The C282Y variant in the HFE gene is the main cause, but its penetrance of only 20% limits its utility for population-wide screening. We aimed to identify and quantify novel genetic and non-genetic modifiers of C282Y-related disease from electronic healthcare records, and thereby partly explain its incomplete penetrance.

We carried out a cohort study on data from 420,543 individuals in the FinnGen project, for whom genotype information and healthcare records were available. We performed both standard and interaction genome-wide association study analyses for hemochromatosis and fitted statistical models including age, sex, 21 million genetic variants, preceding diagnoses, and blood donation history as predictors. Results were validated using data from the UK Biobank.

We identified three novel fine-mapped variants within 4 Mb of the HFE gene. Of these, variant rs181949568 in the CASC15 gene remained significant in the multivariable model (odds ratio 7.25, 95% CI 3.63-28.87, p = 1.96 × 10^-8). We found that donating blood at least twice a year is likely sufficient to reduce the risk of C282Y homozygotes (male risk 0.16, 80% CI 0.13-0.19) to that of C282Y-H63D compound heterozygotes (male risk 0.018, 80% CI 0.015-0.023). Additionally, the S65C variant protects against severe disease (incidence ratio 0.328, 95% CI 0.192-0.562).

We demonstrated that use of large-scale electronic health record data allows for precise quantification of individual-level risk, which we present as risk tables to support clinical practice. Furthermore, our findings suggest that hemochromatosis may be under-recognized in Finland.

Because the factors influencing the penetrance of the C282Y variant in hemochromatosis remain incompletely understood, a study leveraging newly available large-scale healthcare and genetic data is warranted. We present the findings of our study as an individual-level risk table designed for practicing clinicians, summarizing the combined effects of key variables most frequently observed in the dataset. Our results suggest that asymptomatic individuals who are homozygous for C282Y could significantly reduce their risk of developing hemochromatosis by donating blood just twice a year.