Hereditary Hemochromatosis (HFE) genotypes in heart failure: Relation to etiology and prognosis

Abstract

BackgroundIt is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the HFE gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of HFE genotypes.MethodsWe studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known HFE variants C282Y, H63D and S65C.ResultsThe genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of HFE variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).ConclusionHFE genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. HFE variants do not affect mortality in HF.

Hemojuvelin hemochromatosis receiving iron chelation therapy with deferasirox: improvement of liver disease activity, cardiac and hematological function

“…In addition, Møller et al. (13) reported that in patients with HFE H63D polymorphisms carriers, hemoglobin levels were higher compared with those of non‐carriers.…”

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2

“…The translation of molecular findings in LQTS patients into patient-specific clinical management decisions is difficult due to the low level of strict evidence, the complexity of the genetics, including the existence of genetic modifiers of phenotype [ 10 ]. Some of these problems may be alleviated if the use of patient-specific pluripotent stem cells turns out to give relevant information [ 69 ].…”

“…Here we report the disease-causing mutations identified in Danish LQTS families during the preceding 15 years. Furthermore, as the evidence base for considering mutations disease-causing is not always clear [ 10 ], and rare variants which are not associated with disease are found in controls [ 11 ], we report our reasoning for considering the variants found in this cohort disease-causing. Finally, we compare the distribution of mutations with that found in other population studies.…”

Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil

“…Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism with incomplete penetrance and variable expressivity (Møller et al, 2010;Santos et al, 2012;Leão et al, 2014). It is characterized by a progressive iron accumulation and abnormal deposition in several organs, such as the liver, heart, pancreas, joints, and skin, leading to cirrhosis, heart failure, diabetes, arthritis, hypogonadism, skin pigmentation and hepatocellular carcinoma (Møller et al, 2010;Neghina and Anghel, 2011;Salgia and Brown, 2015).…”

“…It is characterized by a progressive iron accumulation and abnormal deposition in several organs, such as the liver, heart, pancreas, joints, and skin, leading to cirrhosis, heart failure, diabetes, arthritis, hypogonadism, skin pigmentation and hepatocellular carcinoma (Møller et al, 2010;Neghina and Anghel, 2011;Salgia and Brown, 2015).…”