Genome-wide association study of determinants of anti-cyclic citrullinated peptide antibody titer in adults with rheumatoid arthritis.
We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P < or = 3.5 x 10(-6)). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r(2) = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 x 10(-5)) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r(2) = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.
Cui
Jing
J
Division of Rheumatology, Immunology & Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. jcui3@partners.org
Taylor
Kimberly E
KE
Destefano
Anita L
AL
Criswell
Lindsey A
LA
Izmailova
Elena S
ES
Parker
Alex
A
Roubenoff
Ronenn
R
Plenge
Robert M
RM
Weinblatt
Michael E
ME
Shadick
Nancy A
NA
Karlson
Elizabeth W
EW
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000235:genetics* / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D000071797:Butyrophilins; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D000906:Antibodies; C408263:BTNL2 protein, human; D000071797:Butyrophilins; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide