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. 2012 Jun 15;21(12):2825-35.
doi: 10.1093/hmg/dds099. Epub 2012 Mar 9.

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

Jose-Ezequiel Martin  1 , Jasper C Broen, F David Carmona, Maria Teruel, Carmen P Simeon, Madelon C Vonk, Ruben van 't Slot, Luis Rodriguez-Rodriguez, Esther Vicente, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A González-Gay, Francisco J García-Hernández, Paloma García de la Peña, Patricia Carreira; Spanish Scleroderma Group; Alexandre E Voskuyl, Annemie J Schuerwegh, Piet L C M van Riel, Alexander Kreuter, Torsten Witte, Gabriella Riemekasten, Paolo Airo, Raffaella Scorza, Claudio Lunardi, Nicolas Hunzelmann, Jörg H W Distler, Lorenzo Beretta, Jacob van Laar, Meng May Chee, Jane Worthington, Ariane Herrick, Christopher Denton, Filemon K Tan, Frank C Arnett, Shervin Assassi, Carmen Fonseca, Maureen D Mayes, Timothy R D J Radstake, Bobby P C Koeleman, Javier Martin
Collaborators, Affiliations

Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up

Jose-Ezequiel Martin et al. Hum Mol Genet. .

Abstract

Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.

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Figures

Figure 1.
Figure 1.
Schematic showing the overall process followed during the present study, along with the number of SNPs associated and considered in each step. lcSSc, limited cutaneous scleroderma; dcSSc, diffuse cutaneous scleroderma; ACA, anti-centromere autoantibody; ATA, anti-topoisomerase autoantibody.
Figure 2.
Figure 2.
The Manhattan plot of the GWAS and replication cohorts meta-analysis. Grey dots represent P-values of SNPs which are genotyped only in the GWAS cohorts in the previous study by Radstake et al. (8). Other color dots represent PMH values of the 720 SNPs which were in both the GWAS and the replication cohorts (Mantel–Haenszel meta-analysis). Gene names in black have been previously reported as genetic risk factors for SSc, while gene names in red are novel ones.
Figure 3.
Figure 3.
ORs and 95% CIs of each of the novel genetic association with SSc found in this study, in either the meta-analysis of all cohorts and each population separately.
See this image and copyright information in PMC

References

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