Further support for the association of GNPAT variant rs11558492 with severe iron overload in hemochromatosis
Authors: Céline Besson‐Fournier, Maria Martinez, Jean‐Pierre Vinel, Patricia Aguilar‐Martinez, Hélène Coppin, Marie‐Paule Roth
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold denote shared co‐first authorship. To the Editor: We read with great interest the article by McLaren et al.,1 who identified by whole‐exome sequencing a variant (rs11558492) in the GNPAT gene associated with severe iron overload in HFE C282Y homozygous men. Although genetic factors that can modify the disease phenotype in HFE hemochromatosis have long been sought, none of the polymorphisms in the genes involved in the regulation of iron metabolism has proved so far to be a major modifier.2 Therefore, the finding of an allelic variant present in 72.7% of HFE C282Y homozygotes with markedly increased iron stores and in none of the low expressors raised considerable interest3 but has not yet been confirmed in an independent set of patients.4 We genotyped rs11558492 in 284 unrelated HFE C282Y homozygous patients (174 males, 110 females) recruited in the south of France. Mean age (± standard deviation) at diagnosis was 46.2 (±12.0) years in males and 47.9 (±12.7) years in females. Median serum ferritin values (and interquartile range) before treatment were 1456 ng/mL (838‐2938) in males and 674 ng/mL (381‐1323) in females. Current or past alcohol consumption ≥20 g per day was reported by 16.7% of males and 10.9% of females. The additive effect of rs11558492 allele G on the logarithm of serum ferritin, assessed through a linear regression controlling for sex, age, and alcohol consumption, was not significant (β = ‐0.066, 95% confidence interval ‐0.321 to 0.188). We then followed the strategy of McLaren et al.1 and restricted our analysis to the 81 most severe males (ferritin >1000 ng/mL at diagnosis, >5 g iron removed the first year of phlebotomy treatment, and no current or past alcohol consumption >20 g per day). Seven were homozygous for the minor allele G, and 37 were heterozygous AG. The G allele frequency in these 81 males was 31.5%, which is higher (P = 0.0006) than the 20.6% reported in 4300 European Americans (Exome Variant Server). Therefore, although not directly associated with serum ferritin, rs11558492 allele G is significantly enriched in the subset of males with markedly increased iron stores. Most of our HFE C282Y homozygotes were diagnosed because they presented with abnormal iron indices or clinical symptoms. Our sample is thus biased against low/no expressors who could have been contrasted with the 81 males with severe iron overload, and not surprisingly, G allele frequency in the group of 93 unclassifiable males was 19.9%, a figure comparable to that in European Americans. Differences in selection criteria may explain part of the discrepancy between the studies of McLaren et al.1 and Bardou‐Jacquet et al.4 Indeed, it appears from Bardou‐Jacquet et al.'s Fig. 14 that, although considered severe, several of their 34 extreme patients did not reach the ferritin threshold of 1000 ng/mL, one of the selection criteria in McLaren et al.1 On the contrary, the median serum ferritin (2480) and interquartile range (1541‐4021) in our set of extreme patients were similar to those selected in McLaren et al.1 While our estimate of rs11558492 allele G frequency is lower than in the original report (31.5% versus 38.6%), our data confirm its enrichment in the subset of HFE C282Y homozygous males with a severe phenotype. Defining the precise role of GNPAT in the regulation of hepcidin will certainly prove interesting.