A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend P(comb): 1.45E-06 --> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential.
Chang
Monica
M
Celera, Alameda, California, United States of America.
Rowland
Charles M
CM
Garcia
Veronica E
VE
Schrodi
Steven J
SJ
Catanese
Joseph J
JJ
van der Helm-van Mil
Annette H M
AH
Ardlie
Kristin G
KG
Amos
Christopher I
CI
Criswell
Lindsey A
LA
Kastner
Daniel L
DL
Gregersen
Peter K
PK
Kurreeman
Fina A S
FA
Toes
Rene E M
RE
Huizinga
Tom W J
TW
Seldin
Michael F
MF
Begovich
Ann B
AB
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9; D021901:DNA, Intergenic / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D009426:Netherlands; D009656:North America; D009687:Nuclear Proteins / Q000235:genetics; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D012217:Rheumatoid Factor / Q000235:genetics; D012307:Risk Factors; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics; D014157:Transcription Factors; D044465:White People
D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D009687:Nuclear Proteins; C497703:PHF19 protein, human; D047990:TNF Receptor-Associated Factor 1; D014157:Transcription Factors; D012217:Rheumatoid Factor