The RS855791 polymorphism of TMPRSS6 is not a genetic modifier of hereditary hemochromatosis

Hemochromatosis is associated with homozygosity for the C282Y polymorphism of the HFE gene in more than 80% of patients. In screening studies, the penetrance of this hemochromatosis-associated genotype was 10% to 33%, where environmental and genetic factors have been identified to modify disease expression. Several genome wide association studies have identified the common genetic variant rs855791 of TMPRSS6 polymorphism as a genetic determinant of iron status in healthy subjects. This variant was recently shown to modulate transcription of the iron hormone hepcidin in vitro and determine serum hepcidin levels in normal individuals. The aim of the present study was to investigate if the SNP rs855791 is a genetic modifier of serum iron paraemters in HFE hemochromatosis.

We determined rs855791 genotype by a validated TaqMan genotyping assay in 123 C282Y homozygotes, 76 C282Y/H63D compound heterozygotes and 80 controls (wildtypes, C282Y heterozygotes and H63D heterozygotes) who were referred for HFE genotyping. The genotyping results were then correlated with serum iron parameters.

Median ferritin concentration and transferrin saturation was 711µg/l and 76%, respectively, in C282Y homozygotes, 432µg/l and 47% in compound heterozygotes and 651µg/l and 45% in controls. TMPRSS6 rs855791 variants were not significantly more frequent in homozygotes (16%/43%/41% for AA/GA/GG) and compound heterozygotes (11%/49%/40% for AA/GA/GG) as compared to controls (14%/45%/41% for AA/GA/GG). When patients were grouped according to rs855791 genotype, no significant differences were found in mean ferritin, serum iron, transferrin and transferrin saturation. When patients were grouped according rs855791genotype in AA and GA versus GG genotype no significant differences in prevalence of iron overload defined as ferritin >300µg/l and transferrin saturation >45% was found: 34% vs. 50% in C292Y, 83% vs. 67% in compounds and 9% vs. 28% in controls.

The genetic variant rs855791 did not show any effect on iron parameters in C282Y homozygotes and C282Y/H63D compound heterozygotes. This suggests that in contrast to control subjects, the TMPRSS6 genotype is no determinant of serum iron parameters and that the possible effects of this SNP on hepcidin expression are overruled by the effects of the C282Y polymorphism of the HFE gene.