title: Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.
abstract: BACKGROUND
  Cumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.
  
  
  RESULTS
  We evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II. We created a weighted genetic risk score (GRS) and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking) to assess the relationship between GRS group and odds of developing seronegative (RF- and CCP-), seropositive (RF+ or CCP+), erosive, and seropositive, erosive RA phenotypes. In separate case only analyses, we assessed the relationships between GRS and age of symptom onset. In 542 RA cases, 317 (58%) were seropositive, 163 (30%) had erosions and 105 (19%) were seropositive with erosions. Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8-2.1) for seronegative RA, 3.0 (95% CI = 1.9-4.7) for seropositive RA, 3.2 (95% CI = 1.8-5.6) for erosive RA, and 7.6 (95% CI = 3.6-16.3) for seropositive, erosive RA. No significant relationship was seen between GRS and age of onset.
  
  
  CONCLUSIONS
  Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America. lchibnik@rics.bwh.harvard.edu
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Liao
authors.forename: Karen H
authors.initials: KH
authors.lastname: Costenbader
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006262:Health / Q000706:statistics & numerical data; D006801:Humans; D008875:Middle Aged; D009726:Nurses / Q000706:statistics & numerical data; D016017:Odds Ratio; D010641:Phenotype; D012372:ROC Curve; D012307:Risk Factors; D014481:United States / Q000453:epidemiology