We investigated HFE C282Y and H63D allele frequencies in three Dutch towns in the Netherlands, as well as their association with cardiovascular disease (CVD) mortal-ity. Study subjects were selected from participants of the Monitoring Project on Cardiovascular Disease Risk Factors in the Netherlands carried out in Amsterdam, Doetinchem and Maastricht among > 35000 subjects, 20-59 years of age. Mortality follow-up lasted 9 to 13 years. A random sample of the cohort (n = 1075) provided information on the total study population. The random sample and all CVD deaths (n = 301) were genotyped for the C282Y and H63D mutation. Adjusted hazard ratios (HR) for CVD mortality were calculated per genotype. C282Y allele frequencies differed significantly between the towns investigated (p = 0.017), whereas the allele frequencies of H63D were similar (p = 0.141) across towns. In Maastricht we found a C282Y allele frequency of 0.086 compared to 0.055 in Amsterdam and 0.054 in Doetinchem. C282Y and H63D heterozygosity did not predict fatal CVD in either men or women, whereas homozygosity for the H63D mutation increased fatal CVD in women (adjusted HR = 8.5; 95% CI = 2.3-31.1). The unexpected high C282Y allele frequency in Maastricht is in line with the recent evidence of a Celtic origin of citizens from the former southern Netherlands and with prehistorical population migrations revealed in the context of the international Genographic Project, a landmark study of prehistorical human migrations around the globe. We recommend that when designing national screening programmes and national registries for genetic disorders, potential regional prevalence differences should be taken into account.

HFE C282Y Maastricht H63D Genographic project Allele frequencies cardiovascular disease

genetics genotype Netherlands prospective study ferritin blood level proportional hazards model cardiovascular risk molecular epidemiology Human Migration Proportional Hazards Models alcohol consumption Cardiovascular Diseases follow up Prospective Studies human sex difference risk assessment middle aged school child Humans cardiovascular disease Adolescent male female risk factor Risk Factors gene Gene Frequency Article gene mutation adult major clinical study migration Histocompatibility Antigens Class I heterozygosity ferritin hemochromatosis H63D gene Membrane Proteins cardiovascular mortality HFE protein, human C282Y gene cohort analysis HLA antigen class 1 Case-Control Studies anthropometry disease association case control study Mutation population migration mortality membrane protein Child