In short, across this myriad of analyses, we found no evidence for association or overlap between GS or CD and ALS, and no evidence that initiation of a GFD in ALS patients would be beneficial

In short, across this myriad of analyses, we found no evidence for association or overlap between GS or CD and ALS, and no evidence that initiation of a GFD in ALS patients would be beneficial. TG6 has been relatively recently added to the list of gluten-related antibodies and, since then, has been described in patients with idiopathic cerebellar ataxia, myelopathy URAT1 inhibitor 1 secondary to malabsorption, autoimmune neuropathy and ALS [2,25,26]. 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. == Electronic supplementary material == The online version of this article (doi:10.1007/s00415-017-8400-8) contains supplementary material, which is available to authorized users. Keywords:Amyotrophic lateral sclerosis, Gluten, Epidemiology, Serology, Genome-wide association studies == Introduction == 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 then 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. CD has a clear genetic component (heritability ~80% [4]), 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]. In contrast, in ALS, which has a heritability of ~65% [6], GWAS revealed a total of 7 loci [7]. URAT1 inhibitor 1 Despite these distinct architectures, overlap between immune-regulated and neurological disease is not unheard of: CD can present with neurological symptoms [813], and frontotemporal dementia, which has several risk loci that overlap with those of ALS [14], shows an additional risk variant in the MHC [15]. If CD and ALS are causally related, one can expect a significant overlap in genetic architectures; methods to estimate this overlap are currently available [16,17]. The association between GS or CD and ALS may have implications for our understanding of a pathogenic mechanism, as well as for future ALS treatment options. In this study, therefore, we combined population-based casecontrol data on gluten-related antibodies with medical history and dietary information, and large-scale genetic data from GWAS on CD and ALS, to examine the evidence for the role of GS or CD in ALS etiology. == Methods == == Study population == All participants in the serological and questionnaire studies were included in the Prospective ALS study the Netherlands (PAN) between 1 January 2006 and 31 December 2015 [18]. Patients were diagnosed according to the revised El Escorial criteria [19]. The population-based design of the PAN study was ensured by inclusion of patients through multiple sources: neurologists, rehabilitation physicians, the Dutch neuromuscular Patient Association URAT1 inhibitor 1 and our ALS website. Age- (5 years) and gender-matched controls were included through the general practitioner of the participating patient. In the Netherlands, every resident Rabbit polyclonal to N Myc is registered at a general practitioner, which makes the sample representative of the general population. For genetic correlation analyses, we used data from a GWAS of ALS, which included 12,577 sporadic ALS cases and 23,475 unaffected controls, and a GWAS of CD, which included 4533 patients and 10,750 controls. Both studies comprised cohorts from Europe and the USA [7,20]. Separately, ALS cases and population-matched controls are being collected worldwide as part of Project MinE [21]. A subset of these samples is drawn from the neuromuscular clinic at URAT1 inhibitor 1 the University Medical Center Utrecht and controls are selected from the PAN study to match cases URAT1 inhibitor 1 by geography, age and gender. Data collected on the samples include disease status and genotyping on the Illumina 2.5M array. As part of the Project MinE, samples and variants have undergone quality control (detailed description in Online Resource 1) [7]. == Serological testing == In 359 population-based patients and 359 matched controls, we measured TG6 antibody concentrations using the ELISA IgA kit (Zedira, Darmstadt, Germany). TG6 positivity was calculated using the mean of the control group (17.33 U/mL) plus 2 standard deviations (2 19.59 U/mL), and was set at 56.51 U/mL. In a subset of 199 patients and 199 controls, antibodies to TG2 were measured using the ELiA Celikey IgA kit (Phadia AB, Uppsala, Sweden). Serum samples containing a TG2 antibody titer of more than 10.

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