Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis.
OBJECTIVE
Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA.


METHODS
A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls).


RESULTS
Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA.


CONCLUSIONS
This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood.
Hinks
Anne
A
University of Manchester, Manchester, UK. Anne.Hinks@manchester.ac.uk
Barton
Anne
A
Shephard
Neil
N
Eyre
Steve
S
Bowes
John
J
Cargill
Michele
M
Wang
Eric
E
Ke
Xiayi
X
Kennedy
Giulia C
GC
John
Sally
S
Worthington
Jane
J
Thomson
Wendy
W
D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics*; D018122:B7-1 Antigen / Q000235:genetics; D002874:Chromosome Mapping; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods* / Q000592:standards*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis / Q000592:standards*; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D013489:Suppression, Genetic; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D018122:B7-1 Antigen; D006680:HLA Antigens; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human