Article

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

Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
Human Molecular Genetics (impact factor: 7.64). 03/2012; 21(12):2825-35. DOI:10.1093/hmg/dds099 pp.2825-35
Source: PubMed

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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Keywords

768 polymorphisms
 
environmental components
 
first successful genome-wide association study
 
five independent cohorts
 
genetic component
 
genome-wide significance
 
GWAS
 
large replication study
 
loci PSD3
 
novel SSc genetic risk locus
 
odds ratio
 
ones
 
previous GWAS
 
PSD3
 
putative genetic risk factors
 
regions
 
replicated significant SNPs
 
replication cohorts
 
replication-GWAS cohorts
 
Systemic sclerosis