title: Association of familial and sporadic rheumatoid arthritis with a single corticotropin-releasing hormone genomic region (8q12.3) haplotype.
abstract: 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 x 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 x 10(-4)) and association (P = 5.5 x 10(-3)) for this haplotype with RA.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Guy's, King's and St. Thomas' School of Medicine, King's College, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Fife
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Sheila
authors.initials: S
authors.lastname: Fisher
authors.forename: Julia
authors.initials: J
authors.lastname: Newton
authors.forename: Kirsten
authors.initials: K
authors.lastname: McKay
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Chandrabala
authors.initials: C
authors.lastname: Shah
authors.forename: Andreas
authors.initials: A
authors.lastname: Polley
authors.forename: Andre
authors.initials: A
authors.lastname: Rosenthal
authors.forename: William
authors.initials: W
authors.lastname: Ollier
authors.forename: Cathryn
authors.initials: C
authors.lastname: Lewis
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: Jerry
authors.initials: J
authors.lastname: Lanchbury
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D005192:Family Health; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D020080:Tandem Repeat Sequences
chemical_list: D005819:Genetic Markers; D003346:Corticotropin-Releasing Hormone