Multiple common variants for celiac disease influencing immune gene expression

Dubois, P; Trynka, Gosia; Franke, Lude; Hunt, Karen A.; Romanos, Jihane; Curtotti, Alessandra; Zhernakova, Alexandra; Heap, Graham A.; Ádány, Róza; Aromaa, Arpo; Bardella, Maria Teresa; Berg, Leonard H van den; Bockett, Nicholas; Concha, Emilio G. de la; Dema, Bárbara; Fehrmann, Rudolf S.N.; Fernández‐Arquero, Miguel; Fiatal, Szilvia; Grandone, Elvira; Green, Peter M.; Groen, Harry J.M.; Gwilliam, Rhian; Houwen, Roderick H. J.; Hunt, Sarah; Kaukinen, Katri; Kelleher, Dermot; Korponay-Szabó, Ilma Rita; Kurppa, Kalle; MacMathúna, Padraic; Mäki, Markku; Mazzilli, Maria Cristina; McCann, Owen T.; Mearin, M. Luisa; Mein, Charles A.; Mirza, Muddassar M.; Mistry, Vanisha; Mora, Barbara; Morley, Katherine I.; Mulder, Chris J.; Murray, Joseph A.; Núñez, Concepción; Oosterom, Elvira; Ophoff, Roel A.; Polanco, Isabel; Peltonen, Leena; Platteel, Mathieu; Rybak, Anna; Salomaa, Veikko; Schweizer, Joachim J.; Sperandeo, Maria Pia; Tack, Greetje J.; Turner, Graham; Veldink, Jan H.; Verbeek, Wieke H.M.; Weersma, Rinse K.; Wolters, Victorien M.; Urcelay, Elena; Cukrowská, Božena; Greco, Luigi; Neuhausen, Susan L.; McManus, Ross; Barisani, Donatella; Deloukas, Panos; Barrett, Jeffrey C.; Saavalainen, Päivi; Wijmenga, Cisca; Heel, David A. van

doi:10.1038/ng.543

Cited by 912 publications

(875 citation statements)

References 46 publications

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“…Three loci did reach a suggestive level of significance ( P < 2.25 × 10 −5 ). Of particular interest is the chromosome 3 p21.31 region, which is known to be associated with multiple autoimmune diseases such as celiac disease, type 1 diabetes mellitus, and Behçet's disease and is suggestively associated in juvenile idiopathic arthritis (JIA) 35, 36, 37, 38. The strongest association in this region was with rs112088397, which tags a large haplotype block where many additional SNPs reached a suggestive level of significance and is the same risk haplotype as that reported in JIA (r 2 = 0.87) 35, 39.…”

Section: Discussionmentioning

confidence: 99%

Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Rothwell

Cooper

Lundberg

et al. 2017

Arthritis & Rheumatology

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ObjectiveInclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune‐related genes using the Immunochip.MethodsA total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA.ResultsThe HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10−33). HLA imputation identified 3 independent associations (with HLA–DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA–DRB1 molecule. No association with anti–cytosolic 5′‐nucleotidase 1A–positive status was found independent of HLA–DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non‐HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant.ConclusionThis is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide‐binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.

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Section: Discussionmentioning

confidence: 99%

Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Rothwell

Cooper

Lundberg

et al. 2017

Arthritis & Rheumatology

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“…11,23 In short, this dataset consists of 244 males and 193 females with a mean age of 62 years, who where recruited as controls in a study of gene expression in amyotrophic lateral sclerosis. These control subjects were selected for being in good general health and unaffected for neurological and neurodegenerative diseases; no separate screen for psychiatric disorders was performed for these subjects.…”

Section: Materials and Methods Eqtl Analysis In Controlsmentioning

confidence: 99%

“…Subtle effects of these SNPs on gene expression could be a functional mechanism by which they confer risk for development of schizophrenia. 10,11 Recently, it has been shown that true GWAS hits are enriched for expression QTLs (eQTLs). [11][12][13][14] Therefore, variations influencing gene expression are more likely to be contributing to the phenotype.…”

Section: Introductionmentioning

confidence: 99%

Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

et al. 2012

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and The PGC Schizophrenia (GWAS) Consortium 7There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 singlenucleotide polymorphisms (SNPs) with significance threshold at Po0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n¼437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n¼202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility.

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“…9 Recently, multiple genetic loci have been implicated in CD pathogenesis, but their impact on the development of the disease seems to be limited as compared to that of the HLA system. 10 T-cell-mediated immune response plays a crucial role in the pathogenesis of the disease. 11 There is strong evidence that the mucosal lesions of gluten-sensitive enteropathy are initiated within the lamina propria and are due to major histocompatibility complex class 2-expressing activated macrophages that present gliadin peptides to a/ b T-cell receptor CD4 1 lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Celiac disease: diagnostic criteria in progress

2011

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Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of 'borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the 'old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity.

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Multiple common variants for celiac disease influencing immune gene expression

Cited by 912 publications

References 46 publications

Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

Celiac disease: diagnostic criteria in progress

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