Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies

Abstract

Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in the HFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFE in ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CY vs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.

HFE p.H63D polymorphism does not influence ALS phenotype and survival

“…Several articles have suggested that the p.H63D polymorphism of HFE represents a risk factor for ALS (Goodall et al, 2005, Restagno et al, 2007 and Sutedja et al, 2007), but others did not confirm this finding; 2 meta-analyses of literature arrived at opposite conclusions (Li et al, 2014 and van Rheenen et al, 2013). This discrepancy may arise from several reasons: first, some articles are based on small, underpowered series; second, in some studies controls are not matched by ethnic origin to cases.…”

Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants

“…On the contrary, the second and most recent one yielded a significant OR for C282Y polymorphism. More precisely, C282Y was significantly associated with decreased ALS risk, in a specific allele model (Y vs C: OR = 0.76, 95%CI = 0.62-0.92, p = 0.005) and also in the dominant model of this allele (YY + CY vs CC: OR = 0.75, 95%CI = 0.61-0.92, p = 0.006) (Li et al, 2014). Results from pooled-analysis suggested a positive association between ALS and H63D homozygotes, heterozygotes and mutation carriers.…”

Hepcidin: SNP-Like Polymorphisms Present in Iron Metabolism and Clinical Complications of Iron Accumulation and Deficiency

“…However, two meta-analysis studies indicate that these polymorphisms do not contribute to the development of these diseases [60,61]. The C282Y genotype is related to propensity for the development of hepatocarcinoma, amyotrophic lateral sclerosis, non-fatty liver disease and venous ulceration, even in patients who do not show signs and symptoms of haemochromatosis [62][63][64][65]. Lifestyle, epigenetic factors, diet, alcoholism contribute to the development of iron overload in patients presenting the HFE gene C282Y, H63D and S65C polymorphisms.…”