HFE p.S65C (rs1800730) in Europe: A Geographic Study

Background: HFE (homeostatic iron regulator) p.S65C (rs1800730) is associated with European ancestry, although there is no comprehensive geographic study of p.S65C in Europe. Methods: We tabulated published p.S65C genotypes in European population/control cohorts, depicted allele frequency ranges in a map, and computed correlations of p.S65C allele frequencies with latitudes and longitudes of cohort recruitment sites. Results: We identified 44 cohorts from 24 of the 44 countries of Europe. These 24 countries comprise ~62.9% of Europe’s population. There were 233,528 subjects, including 38 HFE p.S65C homozygotes (~1 in 6145 subjects) and 4347 p.S65C heterozygotes (~1 in 54 subjects). Genotypes in 42 cohorts (95.5%) were consistent with Hardy–Weinberg equilibrium. The median allele frequency was 0.0129 (range 0–0.0350). p.S65C was not reported in Bulgaria, although the allele frequency in non-Bulgarian cohorts did not differ significantly (0/200 vs. 4423/462,432, respectively; p = 0.2728). Allele frequency ranges (means) were 0–0.0100 (0.0087), 0.0101–0.0200 (0.0146), and ≥0.0201 (0.0253) in 7, 14, and 3 respective aggregate country cohorts (p < 0.0001, all mean comparisons). The seven countries with low-range frequencies extend from north to south (Estonia to Italy). The three countries with high-range frequencies are east of ~14.1° E (western-most border of Poland). Correlations of allele frequencies with latitudes and longitudes in 44 cohorts were not significant (p = 0.1745 and 0.6031, respectively). Conclusions: We conclude that the median HFE p.S65C allele frequency in Europe is 0.0129, allele frequencies differ between some countries, and there is no linear north-to-south or west-to-east allele frequency gradient.