Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF- B signalling

Trynka, Gosia; Zhernakova, Alexandra; Romanos, Jihane; Franke, Lude; Hunt, Karen A.; Turner, Graham; Bruinenberg, Marcel; Heap, Graham A.; Platteel, Mathieu; Ryan, Anthony W.; Kovel, Carolien G.F. de; Holmes, G. K. T.; Howdle, P D; Walters, Julian R.F.; Sanders, David S.; Mulder, Chris J.; Mearin, M. L.; Verbeek, Wieke H.M.; Trimble, Valerie; Stevens, Fiona; Kelleher, Dermot; Barisani, Donatella; Bardella, Maria Teresa; McManus, Ross; Heel, David A. van; Wijmenga, Cisca

doi:10.1136/gut.2008.169052

Cited by 175 publications

(133 citation statements)

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“…8 The region of interest spans B102 to 122 Mb and is clearly distinct from the HLA region as well as from the previously identified TNFAIP3 and TAGAP celiac susceptibility genes. 9,10 An independent study by Einarsdottir et al (unpublished) of susceptibility genes for celiac disease in Finnish and Hungarian families also showed linkage to 6q16-22, to a region overlapping with the linkage found in the Dutch population. Taken together, these results indicate the possibility of a genetic factor within the chromosome 6q21-22 region that is involved in susceptibility to celiac disease in multiple populations.…”

Section: Introductionmentioning

confidence: 99%

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

et al. 2011

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International audienceCeliac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed finemapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The twelve most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (p=0.0032, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (p=3.6*10-5, OR 0.76). Rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbours multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility

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Section: Introductionmentioning

confidence: 99%

Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

et al. 2011

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“…This study tested for association to approximately 310,000 single-nucleotide polymorphisms (SNPs) and identified a single risk locus in an LD block harboring IL2-IL21. Two follow up studies on the same sample (Hunt et al 2008;Trynka et al 2009) identified an additional nine non-HLA loci. A later CD GWAS by Dubois and colleagues (2010) included over 4,500 CD cases and over 11,000 controls from four populations (Finland, Italy, the Netherlands, the UK).…”

Section: Presentation Pathophysiology and Genetics Of CDmentioning

confidence: 99%

Celiac Disease as a Model for the Evolution of Multifactorial Disease in Humans

Sams

Hawks

2014

Human Biology

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Abstract. Celiac disease (CD) is a multifactorial chronic inflammatory conditionthat results in injury of the mucosal lining of the small intestine upon ingestion of wheat gluten and related proteins from barley and rye. Although the exact mechanisms leading to CD are not fully understood, the genetic basis of CD has been relatively well characterized. In this review we briefly review the history of discovery, clinical presentation, pathophysiology, and current understanding of the genetics underlying CD risk. Then, we discuss what is known about the current distribution and evolutionary history of genes underlying CD risk in light of other evolutionary models of disease. Specifically, we conclude that the set of loci underlying CD risk did not cohesively evolve as a response to a single past selection event such as the development of agriculture. Rather, deterministic and stochastic evolutionary processes have both contributed to the present distribution of variation in CD risk loci. Selection has shaped some components of this network, but this selection appears to have occurred at different points in the past.Other parts of the CD risk network have likely arisen due to stochastic processes such as genetic drift. Celiac disease (CD) is a multifactorial chronic inflammatory condition that resultsin injury of the mucosal lining of the small intestine. The earliest descriptions of a condition with symptoms like CD date back to the first and second century writings of the Greek physician Arataeus (Simoons 1981;Losowsky 2008). The first modern description of CD is attributed to English physician Samuel Jones Gee, who was familiar with the writings of Arataeus. In 1888 (Dowd and Walker-Smith 1974;Simoons 1981;Losowsky 2008) Gee described the 'coeliac affection' as a condition of chronic indigestion associated with diarrhea, wasting, and weakness and common in people of all ages. Gee's report was the first to hypothesize dietary factors as a primary cause of the condition (Dowd and Walker-Smith 1974), and during the early twentieth century some workers noted the value of a starch free diet for prevention of CD (Haas 1924). Dicke and colleagues (1950, 1953) observed the detrimental effect of wheat flour (but not wheat starch) on CD patients experimentally confirming a role for diet as a driver of CD. Shortly thereafter, Anderson and colleagues (Anderson et al. 1952;Alvey et al. 1957) confirmed the effect of wheat on CD and identified wheat gluten as the primary culprit.CD appears to be an evolutionary paradox. Only since the 1950s have clinicians recognized that a gluten-free diet is an effective treatment (Barker and Liu 2008). Before that time, diagnosed and undiagnosed CD reduced the health and fitness of sufferers, with juvenile cases leading to malnutrition or death, and adult cases causing wasting, lack of adequate nutrition, greater susceptibility to infection, and direct reductions in fertility (Corrao et al. 2001;Soni and Badawy 2010). Despite these apparent costs, CD is common today (>1%) in several popul...

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“…(SLE), rheumatoid arthritis, psoriasis, and celiac disease (24)(25)(26)(27)(28)(29). While only one missense coding allele has been identified thus far (in SLE), the wellestablished antiinflammatory functions of A20 in mice suggest that hypomorphic function or expression of A20 may contribute to the pathophysiology of these human conditions (24).…”

Section: A20 In Lymphocytesmentioning

confidence: 99%