TY - JOUR
T1 - Association of familial and sporadic rheumatoid arthritis with a single corticotropin-releasing hormone genomic region (8q12.3) haplotype
AU - Fife, Mark
AU - Steer, Sophia
AU - Fisher, Sheila
AU - Newton, Julia
AU - McKay, Kirsten
AU - Worthington, Jane
AU - Shah, Chandrabala
AU - Polley, Andreas
AU - Rosenthal, Andre
AU - Ollier, William
AU - Lewis, Cathryn
AU - Wordsworth, Paul
AU - Lanchbury, Jerry
PY - 2002
Y1 - 2002
N2 - Objective. Rheumatoid arthritis (RA) is a common disabling autoimmune disease with a complex genetic component. We have previously described linkage of a region of chromosome 8q12.3 with RA and association of the microsatellite marker CRHRA1 with RA in 295 affected sibling-pair families. In the current study we aimed to physically link the RA-associated marker with the corticotropin-releasing hormone (CRH) candidate gene, and to examine the genomic region for additional short tandem repeat (STR) genetic markers in order to clarify the association with RA. Methods. We examined the association of 2 STR markers with disease in the original 295 multicase families and in a cohort of 131 simplex families to refine our understanding of this genetic region in disease susceptibility in sporadic and familial RA. Genomic library screening and sequencing were used to generate physical sequences in the CRH genomic region. Bioinformatic analysis of the sequence flanking the CRH structural gene was used to screen for additional STRs and other genetic features. Genotyping was carried out using a standard fluorescence approach. Estimations of haplotype frequencies were performed to assess linkage disequilibrium. The transmission disequilibrium test was performed using TRANSMIT. Results. Physical cloning and sequencing analyses identified the genomic region linking the CRHRA1 marker and the CRH structural locus. Moreover, we identified a further STR, CRHRA2, which was in strong linkage disequilibrium with CRHRA1 (P = 4.0 × 10-14). A haplotype, CRHRA1*10;CRHRA2*14, was preferentially carried by unaffected parents at a frequency of 8.6% compared with the expected frequency of 3.1%. This haplotype was overtransmitted in the multiply affected families (P = 0.0077) and, similarly, in the simplex families (P = 0.024). Combined analysis of both family cohorts confirmed significant evidence for linkage (P = 4.9 × 10-4) and association (P = 5.5 × 10-3) for this haplotype with RA. Conclusion. In demonstrating significant linkage disequilibrium between these 2 markers, we have refined the disease-associated region to a single haplotype and confirmed the significance of this region in our understanding of the genetics of RA.
AB - Objective. Rheumatoid arthritis (RA) is a common disabling autoimmune disease with a complex genetic component. We have previously described linkage of a region of chromosome 8q12.3 with RA and association of the microsatellite marker CRHRA1 with RA in 295 affected sibling-pair families. In the current study we aimed to physically link the RA-associated marker with the corticotropin-releasing hormone (CRH) candidate gene, and to examine the genomic region for additional short tandem repeat (STR) genetic markers in order to clarify the association with RA. Methods. We examined the association of 2 STR markers with disease in the original 295 multicase families and in a cohort of 131 simplex families to refine our understanding of this genetic region in disease susceptibility in sporadic and familial RA. Genomic library screening and sequencing were used to generate physical sequences in the CRH genomic region. Bioinformatic analysis of the sequence flanking the CRH structural gene was used to screen for additional STRs and other genetic features. Genotyping was carried out using a standard fluorescence approach. Estimations of haplotype frequencies were performed to assess linkage disequilibrium. The transmission disequilibrium test was performed using TRANSMIT. Results. Physical cloning and sequencing analyses identified the genomic region linking the CRHRA1 marker and the CRH structural locus. Moreover, we identified a further STR, CRHRA2, which was in strong linkage disequilibrium with CRHRA1 (P = 4.0 × 10-14). A haplotype, CRHRA1*10;CRHRA2*14, was preferentially carried by unaffected parents at a frequency of 8.6% compared with the expected frequency of 3.1%. This haplotype was overtransmitted in the multiply affected families (P = 0.0077) and, similarly, in the simplex families (P = 0.024). Combined analysis of both family cohorts confirmed significant evidence for linkage (P = 4.9 × 10-4) and association (P = 5.5 × 10-3) for this haplotype with RA. Conclusion. In demonstrating significant linkage disequilibrium between these 2 markers, we have refined the disease-associated region to a single haplotype and confirmed the significance of this region in our understanding of the genetics of RA.
UR - http://www.scopus.com/inward/record.url?scp=0036161902&partnerID=8YFLogxK
U2 - 10.1002/1529-0131(200201)46:1<75::AID-ART10034>3.0.CO;2-3
DO - 10.1002/1529-0131(200201)46:1<75::AID-ART10034>3.0.CO;2-3
M3 - Article
C2 - 11817611
AN - SCOPUS:0036161902
SN - 0004-3591
VL - 46
SP - 75
EP - 82
JO - Arthritis and Rheumatism
JF - Arthritis and Rheumatism
IS - 1
ER -