Genetics of vasculitis

Carmona, F. David; Martín, Javier; González-Gay, Miguel Á.

doi:10.1097/bor.0000000000000124

Cited by 51 publications

(32 citation statements)

References 49 publications

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“…In the last years, the use of novel technologies has produced a substantial advance in the elucidation of the genetic component of LVV5. Large-scale genetic analyses have been recently published separately for both GCA and TAK using the Immunochip platform67.…”

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confidence: 99%

Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Carmona

Coit

Saruhan‐Direskeneli

et al. 2017

Sci Rep

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Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus.

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confidence: 99%

Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Carmona

Coit

Saruhan‐Direskeneli

et al. 2017

Sci Rep

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“…The etiology of vasculitis is not completely understood, but accumulating evidence demonstrates that genetic factors significantly contribute to disease susceptibility [3]. However, genetic factors alone may not be enough to explain the broad range of variations in vessel and organ involvement, demographics, pathology, and the heterogeneous clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

Epigenetics and Vasculitis: a Comprehensive Review

Renauer

Coit

Sawalha

2015

Clinic Rev Allerg Immunol

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Vasculitides represent a group of relatively rare systemic inflammatory diseases of the blood vessels. Despite recent progress in understanding the genetic basis and the underlying pathogenic mechanisms in vasculitis, the etiology and pathogenesis of vasculitis remain incompletely understood. Epigenetic dysregulation plays an important role in immune-mediated diseases, and the contribution of epigenetic aberrancies in vasculitis is increasingly being recognized. Histone modifications in the PR3 and MPO gene loci might be mechanistically involved in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Similarly, other studies revealed important epigenetic contribution to other vasculitides, including Kawasaki disease and IgA vasculitis. More recently, genome-wide epigenomic studies have been performed in several vasculitides. A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission. Genome-wide DNA methylation profiling characterized the inflammatory response in temporal artery tissue from patients with giant cell arteritis and showed increased activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling, prompting the suggestion that a specific calcineurin/NFAT inhibitor that is well tolerated and with the added beneficial anti-platelet activity, such as dipyridamole, might be of therapeutic potential in giant cell arteritis. While epigenetic studies in systemic vasculitis are still in their infancy, currently available data clearly indicate that investigating the epigenetic mechanisms underlying these diseases will help to better understand the pathogenesis of vasculitis and provide novel targets for the development of disease biomarkers and new therapies.

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“…Outside the HLA region, there have been many studies of candidate genes in BD, but many of them have conflicting results and were not replicated in independent studies [8]. In addition, different genome-wide association studies (GWAS) have been performed in BD, including two in Turkish, one in Iranian, and three in Asian (Japanese, Chinese and Korean) populations [9–14].…”

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confidence: 99%

Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

et al. 2016

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Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.

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Genetics of vasculitis

Cited by 51 publications

References 49 publications

Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Epigenetics and Vasculitis: a Comprehensive Review

Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

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