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

M Li,X.L Qi,L Wang,Z.Y Tang,W Wang

doi:10.1590/1414-431x20133296

M Li, X.L Qi + Show 3 more

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https://doi.org/10.1590/1414-431x20133296

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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.

Highlights

The HFE gene, so named because of its dominant role in iron homeostasis and preventing hemochromatosis [1], is located on the short arm of chromosome 6 at location 6p21.3 [2]
HFE testing for the two main mutations (H63D and C282Y) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values [4], which have been implicated in neurodegenerative diseases [5]
Three articles were excluded: one because the allele frequencies in control subjects deviated from HWE [2], another because it had no usable data [21], and the third because it was written in Chinese

Summary

Introduction

The HFE gene, so named because of its dominant role in iron homeostasis and preventing hemochromatosis (i.e., iron overload in the blood) [1], is located on the short arm of chromosome 6 at location 6p21.3 [2]. Mutations of HFE have been associated with iron overload. Loss of iron homeostasis in the brain may lead to oxidative stress and inflammation [3]. HFE testing for the two main mutations (H63D and C282Y) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values [4], which have been implicated in neurodegenerative diseases [5]. As the most common adult-onset neurodegenerative disease, amyotrophic lateral sclerosis (ALS) is characterized by degeneration of lower and upper motor neurons in the brain and spinal cord.

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