GNPAT Variant associated with severe iron overload in HFE hemochromatosis
Authors: Edouard Bardou‐Jacquet, Marie de Tayrac, Jean Mosser, Yves Deugnier
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. To the Editor: By using exome sequencing in highly selected patients and in vitro experiments, the elegant study by McLaren et al. demonstrated the rs11558492 polymorphism in the GNPAT gene as a major factor of phenotypic expression in HFE hemochromatosis.1 As stated by the investigators, it is necessary to confirm a prognostic role for GNPAT p.D519G in a large sample of C282Y homozygotes. In the recent genome‐wide association study that we conducted in unselected C282Y homozygotes with HFE hemochromatosis, the rs11558492 was part of the polymorphisms studied and, surprisingly, was not found as a significant genetic modifier.2 We went back to our data and specifically studied markers of iron burden according to the genotype distribution of rs11558492 in the whole population, including females (n = 474), and in two subgroups consisting (1) of all males (n = 274) and (2) males selected using strictly similar criteria to those from McLaren et al. (no past or current alcohol consumption ≥20g/day; n = 36). Ancestry was genetically examined and all patients were identified as Europeans and particularly as coming from Western Europe.2 Allele frequencies of GNPAT p.D519G were homogeneous across both the whole population and subcohorts 1 and 2 (26.6%, 26.3%, and 25% respectively; Fisher's test, P = 0.974). They were similar with those from the 35 patients of McLaren et al. (24.3%; P = 0.78) and from the British in England and Scotland population of the 1000Genome (24.7%; P = 1.00). However, they were greater than that of European Americans from the Exome Variant Server database (20.6%; P < 0.001). Using regression models adjusted for age and sex for the whole population and age for males subgroups 1 and 2, we assessed the association between GNPAT rs11558492 genotypes, iron burden, and severe fibrosis defined as Metavir stages 3 and 4. Linear regression failed to show any significant association with serum ferritin (P = 0.847, 0.232, and 0.166, respectively) or amount of iron removed (P = 0.827, 0.21, and 0.688, respectively). Logistic regression did not find any significant association with severe fibrosis in any of these groups (P = 0.579, 0.15, and 0.943, respectively). Iron burden, according to serum ferritin or amount of iron removed, was similar in hetero‐ or homozygous patients for rs11558492, irrespectively of the population studied (Fig. 1).Figure 1: Mean ferritin at diagnosis (A) and amount of iron removed (B) levels in the different GNPAT rs11558492 genotype categories. A/G and G/G genotypic categories are pooled and standard deviations are reported as vertical bars.Finally, we cannot extend, in our population, the results of McLaren et al. because our data show that GNPAT p.D519G is not associated with iron burden or fibrosis in an unselected French population of C282Y homozygotes. More studies with diverse populations are needed to shed light on these discrepancies.