Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

Zhernakova, Alexandra; Festen, Eleanora M.; Franke, Lude; Trynka, Gosia; Diemen, Cleo C. van; Monsuur, Alienke J.; Bevova, Marianna; Nijmeijer, Rian M.; Slot, Ruben van ‘t; Heijmans, Roel; Boezen, H. Marike; Heel, David A. van; Bodegraven, Adriaan A. van; Stokkers, Pieter; Wijmenga, Cisca; Crusius, J.B.A.; Weersma, Rinse K.

doi:10.1016/j.ajhg.2008.03.016

Cited by 230 publications

(207 citation statements)

References 56 publications

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“…Interestingly, SNP rs917997 of the IL18RAP gene, which was associated with disc signal intensity in the present study, was recently shown to be associated with inflammatory bowel disease in 3 independent Dutch cohorts (42). According to the HapMap data, allele A of the rs917997, which was associated with lower average disc signal intensity at the L1-L4 level in our study, perfectly tags the IL1RL1;IL18R1;IL18RAP;SLC9A4 haplotype, which was shown to be associated with both Crohn's disease and ulcerative colitis.…”

Section: Discussionmentioning

confidence: 91%

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Videman

Saarela

Kaprio

et al. 2009

Arthritis & Rheumatism

125

104

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Objective. To examine the allelic diversity of structural, inflammatory, and matrix-modifying gene candidates and their association with disc degeneration.Methods. Subjects were 588 men ages 35-70 years. We investigated associations of single-nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software. P values were derived from 1,000 permutations, and empirical P values for global significance also were applied.Results. Twelve of the 99 variants in 25 selected candidate genes provided evidence of association (P < 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631; P ‫؍‬ 0.001), COL1A1 (rs2075555; P ‫؍‬ 0.005), COL9A1 (rs696990; P ‫؍‬ 0.00008), and COL11A2 (rs2076311; P ‫؍‬ 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P ‫؍‬ 0.010) and COL9A1 (P ‫؍‬ 0.014), as well as variants in the COL11A1 gene (rs1463035 [P ‫؍‬ 0.004]; rs1337185 [P ‫؍‬ 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797; P ‫؍‬ 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P ‫؍‬ 0.027]; rs1420100 in IL18RAP [P ‫؍‬ 0.005]) were associated with disc signal intensity.Conclusion. Genetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition.Intervertebral disc degeneration is a suspected cause of common back pain (1), but both the etiology and pathogenesis of disc degeneration are poorly understood (2). A 1992 review of relevant scientific literature identified physical demands of occupational and leisure activities as primary risk factors, while the role of genetics was uncertain (3). However, results from later twin studies suggested that heredity plays a major role, accounting for an estimated 34-74% of variance in disc degeneration (4,5).

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Section: Discussionmentioning

confidence: 91%

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Videman

Saarela

Kaprio

et al. 2009

Arthritis & Rheumatism

125

104

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“…It remains to be seen whether the same will hold true for humans. Several loci appear to have opposite effects across related diseases Maier et al 2009), and could represent important checkpoints in the branching pathways that lead to the development of related but distinct diseases (Zhernakova et al 2008). A few GWAS-discovered loci are associated with multiple diseases not previously thought to be related.…”

Section: Gwas and Their Findings-implications For Genetic Architecturementioning

confidence: 99%

“…GWAS of related diseases often reveal an overlapping genetic basis, and the overlaps promise to shed light on disease mechanisms. Several so-called ''autoimmunity'' loci are associated with multiple autoimmune diseases, including the HLA genes of the MHC region, and other genes involved in both innate and adaptive immunity (Maier and Hafler 2008;Zhernakova et al 2008). Among cancers, the 8q24 ''gene desert'' region, has been found to harbor common variants associated with bladder, breast, colon, ovarian, and prostate cancers (reviewed in Ghoussaini et al 2008), whereas most other cancer GWAS discoveries are disease specific (reviewed in Easton and Eeles 2008).…”

Section: The Progress Of Gwas-medical Genetic Discoverymentioning

confidence: 99%

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

2011

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Enormous progress in mapping complex traits in humans has been made in the last 5 yr. There has been early success for prevalent diseases with complex phenotypes. These studies have demonstrated clearly that, while complex traits differ in their underlying genetic architectures, for many common disorders the predominant pattern is that of many loci, individually with small effects on phenotype. For some traits, loci of large effect have been identified. For almost all complex traits studied in humans, the sum of the identified genetic effects comprises only a portion, generally less than half, of the estimated trait heritability. A variety of hypotheses have been proposed to explain why this might be the case, including untested rare variants, and gene-gene and gene-environment interaction. Effort is currently being directed toward implementation of novel analytic approaches and testing rare variants for association with complex traits using imputed variants from the publicly available 1000 Genomes Project resequencing data and from direct resequencing of clinical samples. Through integration with annotations and functional genomic data as well as by in vitro and in vivo experimentation, mapping studies continue to characterize functional variants associated with complex traits and address fundamental issues such as epistasis and pleiotropy. This review focuses primarily on the ways in which genome-wide association studies (GWASs) have revolutionized the field of human quantitative genetics.M ANY phenotypes are quantitative in nature, and complex in etiology, with multiple environmental and genetic causes. The observation that complex traits cluster in relation to genetic relatedness suggests heritability, and advances in theoretical and experimental genetics, combined with analytical developments and high-throughput genomics, have provided an unprecedented view into the mode of inheritance and genetic architecture of complex traits.

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“…The caspase recuitment domain-containing protein 9 (CARD9) plays a role in chronic intestinal inflammation (2,3) and may be an important factor in colorectal cancer progression (4). Its presence in mice is essential for full myeloid activation as well as antifungal response through the immunoreceptor tyrosine-based activation motif (ITAM) domain-containing Dectin transmembrane receptors (5).…”

Section: Introductionmentioning

confidence: 99%

CARD9 Promotes Sex-Biased Colon Tumors in the APCmin Mouse Model

Leo

Tan

Bergmann

et al. 2015

Cancer Immunology Research

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Caspase recuitment domain-containing protein 9 (CARD9) functions in different inflammation pathways to elicit responses to microbial signals and is known to affect intestinal inflammation. Examining the APC min mouse model of intestinal tumorigenesis and using stringently controlled, sex-and age-matched pairs of CARD9-competent and CARD9-deficient mice, we have found that CARD9 has a restricted but strong effect on tumorigenesis in the large intestine. We have found that CARD9 reduces viability specifically in males and promotes tumorigenesis specifically in the large intestines of these male mice. To our knowledge, this is the first gene ablation in APC min mice that solely affects colon tumors in male subjects and, as such, may have significant clinical implications. Additional data suggest correlative disruption of plasma cytokine expression and immune infiltration of the tumors. We speculate that known sex-specific differences in human colorectal cancer may involve inflammation, particularly CARD9-dependent inflammation. Cancer Immunol Res; 3(7); 721-6. Ó2015 AACR.

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Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

Cited by 230 publications

References 56 publications

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

CARD9 Promotes Sex-Biased Colon Tumors in the APCmin Mouse Model

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