The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population.
BACKGROUND
Mutations in HFE, a gene defect that can disrupt iron metabolism, have been implicated in increasing the risk of developing amyotrophic lateral sclerosis (ALS).


OBJECTIVE
To further establish the association between ALS and HFE mutations by investigating whether HFE mutations are associated with an increased risk of developing ALS in a population in The Netherlands and by pooling our results with those from previous studies.


METHODS
Retrospective study.


METHODS
Tertiary referral center for neuromuscular disorders.


METHODS
Genotyping for 2 common HFE mutations was performed in 289 patients with ALS and 5886 population-based controls in The Netherlands between January 1, 2000, and December 31, 2004.


METHODS
Development of ALS and clinical phenotype were compared among the different HFE genotypes, adjusting for known prognostic factors such as age at onset and sex.


RESULTS
Homozygosity for H63D was associated with an increased risk of developing ALS (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.1). After pooling our results with those from previous studies, a positive association between H63D homozygotes (OR, 2.7; 95% CI, 1.7-4.4), heterozygotes (OR, 1.5; 95% CI, 1.0-2.1), and mutation carriers (OR, 1.7; 95% CI, 1.1-2.5) was found. Within the patient group, heterozygosity for the H63D mutation was associated with a higher age at onset.


CONCLUSIONS
These findings suggest that H63D mutations in HFE play a role in the pathogenesis of ALS in various populations. This association might involve a later-onset subset of ALS.
Sutedja
Nadia A
NA
Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
Sinke
Richard J
RJ
Van Vught
Paul W J
PW
Van der Linden
Michiel W
MW
Wokke
John H J
JH
Van Duijn
Cornelia M
CM
Njajou
Omer T
OT
Van der Schouw
Yvonne T
YT
Veldink
Jan H
JH
Van den Berg
Leonard H
LH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D001216:Asparagine / Q000235:genetics*; D016001:Confidence Intervals; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000071020:Hemochromatosis Protein; D006639:Histidine / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D012189:Retrospective Studies
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D006639:Histidine; D001216:Asparagine