Abstract
To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case–control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely.
Highlights
Recent studies have proposed a potential link between celiac disease (CD) and ALS [1, 2], and suggest that sensitivity to gluten (GS) may occur in a subgroup of patients, who may benefit from a gluten-free diet (GFD) [2]
CD has a clear genetic component, and genome-wide association studies (GWAS) have revealed [40 common-variant loci associated with CD; the strongest associated with the human leukocyte antigen (HLA) genes, which lie in the major histocompatibility complex (MCH) [5]
No missing data in controls or in the serological cohort patient and zero controls. This patient was the only participant who tested positive for endomysial antibodies (EMA), and was one of the eleven patients with positive antibodies to transglutaminase 6 (TG6)
Summary
Recent studies have proposed a potential link between celiac disease (CD) and ALS [1, 2], and suggest that sensitivity to gluten (GS) may occur in a subgroup of patients, who may benefit from a gluten-free diet (GFD) [2]. The efficacy of GFD in seropositive patients is currently being investigated [3]. These epidemiological observations suggest that CD and ALS may share (genetic) susceptibility factors. In ALS, which has a heritability of *65% [6], GWAS revealed a total of 7 loci [7] Despite these distinct architectures, overlap between immune-regulated and neurological disease is not unheard of: CD can present with neurological symptoms [8,9,10,11,12,13], and frontotemporal dementia, which has several risk loci that overlap with those of ALS [14], shows an additional risk variant in the MHC [15]
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