Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy

Gorlova, Olga Y.; Martín, Jacqueline M.; Rueda, Blanca; Koeleman, B.; Jin, Ying; Teruel, María; Diaz-Gallo, Lina-Marcela; Broen, Jca; Vonk, Madelon C.; Simeon, C.P.; Alizadeh, Behrooz Z.; Coenen, Marieke J. H.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Riel, Plcm van; Vanthuyne, Marie; Slot, Ruben van ‘t; Ophoff, Roel A.; Hunzelmann, N.; Fonollosa, V.; Ortego-Centeno, Norbérto; Ma, Genshan; García–Hernández, Francisco J.; González-Escribano, M F; Airo, Paolo; Laar, Jacob M van; Worthington, Jane; Hesselstrand, Roger; Smith, Vanessa; Keyser, Filip De; Houssiau, F.; Chee, Meng May; Madhok, Rajan; Shiels, Paul G.; Westhovens, René; Kreuter, Alexander; Baere, Elfride De; Witte, Torsten; Padyukov, Leonid; Nordin, Annika; Scorza, R; Lunardi, Claudio; Lie, Benedicte A.; Hoffmann-Vold, A. M.; Peña, Paloma García de la; Carreira, P; Varga, John; Hinchcliff, Monique; Lee, A T; Gourh, Pravitt; Amos, Christopher I.; Riemekasten, Gabriela; Herrick, A.; Beretta, Lorenzo; Fonseca, Carmen; Denton, CP; Gregersen, Peter K.; Agarwal, Sandeep K.; Assassi, Shervin; Tan, Filemon K.; Arnett, Frank C.; Radstake, T.R.D.J.; Mayes, Maureen D.; Martin, Jose-Ezequiel

doi:10.1186/1479-5876-8-s1-o1

Cited by 18 publications

(25 citation statements)

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“…In our initial approach we found a signal in the PSORS1C1 gene that was comparable to the one described in the previous work;10 however, a comprehensive analysis showed that the PSORS1C1 association is dependent from the HLA-DPB1*13 : 01, HLA-DQA1*05 : 01 and HLA-DRB1*11 : 04 alleles (especially the HLA-DQA1*0501). These HLA loci have previously been described as ATA positivity risk factors,5 7 which is consistent with the lack of association in the ACA-positive subgroup. Altogether, our data do not confirm PSORS1C1 as an independent player in the SSc genetic susceptibility network.…”

Section: Discussionsupporting

confidence: 88%

“…The authors performed a dependence analysis controlling for the described association in the HLA-DQB1 gene and reported the independence of both loci. Nevertheless, HLA-DQB1 has been specifically related with the ACA-positive subset of patients,5 7 and both in our data and in the previous study no association of PSORS1C1 with ACA positivity has been shown 10. Therefore, a deeper analysis of this locus was needed, and we performed for the first time conditional logistic regression including all the independent signals in the HLA region.…”

Section: Discussioncontrasting

confidence: 45%

“…Moreover, the association was maintained in all the subgroups (including the ACA-negative and ATA-negative subsets) except for the ACA-positive patients. Considering that the association of the HLA region with SSc is influenced primary by the autoantibody profile of the patients,5 7 we aimed to test for an uncovered influence of the HLA genes. We thus carried out a step-wise logistic regression conditional analysis of the analysed PSORS1C1 variant with all the independent signals from the most significant to the lowest observed p values in the HLA region.…”

Section: Resultsmentioning

confidence: 99%

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Confirmation ofTNIP1but notRHOBandPSORS1C1as systemic sclerosis risk factors in a large independent replication study

Bossini‐Castillo¹,

Martin²,

Broen

et al. 2012

Ann Rheum Dis

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Introduction A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. Methods 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. Results Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 pMH=1.94×10−4, OR 1.19; rs4958881 pMH=3.26×10−5, OR 1.19; rs3792783 pMH=2.16×10−4, OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. Conclusions These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 45%

Section: Resultsmentioning

confidence: 99%

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Confirmation ofTNIP1but notRHOBandPSORS1C1as systemic sclerosis risk factors in a large independent replication study

Bossini‐Castillo¹,

Martin²,

Broen

et al. 2012

Ann Rheum Dis

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“…Recent genome-wide association studies in European Caucasian populations further strengthened the evidence for the strong immune genetic component of SSc and have identified new risk loci 5 6 21. On the contrary, inconsistent data have been reported by different studies that investigated the potential contribution of fibrosis-related genes to the SSc genetic background 4.…”

Section: Discussionmentioning

confidence: 99%

Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis

et al. 2012

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“…In the case of multiple sclerosis, the higher concordance rates include 7.5 years of median follow-up of the unaffected twins differences. It should be noted, however, that genomic susceptibility remains a crucial element in determining disease susceptibility, as well illustrated by the recent data from GWAS in SLE [101][102][103][104], systemic sclerosis (SSc) [105,106], and other autoimmune diseases [107][108][109][110] in which a geoepidemiological gradient applies. As an example, a significant increase in the prevalence of SLE cases was reported in a neighborhood exposed to oil field waste, with possible synergistic effects of pollutants, including pristine, mercury and phytane, mercury, and other exposures [44].…”

Section: From Geoepidemiology To Pollution In Slementioning

confidence: 99%

The Therapeutic Potential of Epigenetics in Autoimmune Diseases

Santis

Selmi

2011

Clinic Rev Allerg Immunol

109

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A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

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Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy

Cited by 18 publications

References 0 publications

Confirmation ofTNIP1but notRHOBandPSORS1C1as systemic sclerosis risk factors in a large independent replication study

Confirmation ofTNIP1but notRHOBandPSORS1C1as systemic sclerosis risk factors in a large independent replication study

Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis

The Therapeutic Potential of Epigenetics in Autoimmune Diseases

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