Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Genetic Risk Score Predicting Risk of Rheumatoid Arthritis Phenotypes and Age of Symptom Onset

Chibnik,  Lori B., Keenan,  Brendan T., Cui,  Jing, Plenge,  Robert M., Karlson,  Elizabeth W.

Purpose:

Cumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the cumulative impact of 22 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.

Method:

Blood was obtained from 32,826 women in the Nurses' Health Study (NHS) and 29,611 women in the Nurses' Health Study 2 (NHS2). An additional 33,040 NHS participants provided buccal cell samples. Incident RA and erosive changes were confirmed by medical record review for ACR criteria. We evaluated single nucleotide polymorphisms (SNPs) at 13 validated RA risk loci and 8 Human Leukocyte Antigen (HLA) alleles among 484 Caucasian RA cases and 481 age matched Caucasian controls from NHS and NHS2. We created a weighted genetic risk score for 22 alleles (wGRS). The weight for each risk allele was calculated as the log of the published odds ratio (OR) from GWAS analyses with replication or from a comprehensive meta-analysis. We examined wGRS as 7 ordinal groups based on the distribution in controls. We used logistic regression adjusting for age and pack-years of smoking (packs per day × years smoked) to assess the relationship between wGRS groups and the odds of developing seronegative RA (RF- and CCP-), seropositive RA (RF+ or CCP+), erosive RA and seropositive erosive RA phenotypes. A common control group was used for all phenotypes. Each group was compared to the median group. In separate case only analyses, we assessed the relationships between age of symptom onset and continuous wGRS using linear regression and between age of symptom onset and grouped wGRS using an ANOVA.

Results:

In 484 RA cases, 289 (60%) were seropositive, 146 (30%) had erosions and 95 (20%) were seropositive and had erosions at RA diagnosis. The mean age at RA onset was 55.7 ± 10.4. In the top wGRS risk group compared to the median group, we found an OR of 1.3 (95% CI = 0.7 – 2.3) for seronegative RA and an OR of 2.9 (95% CI = 1.8 – 4.6) for seropositive RA. The strongest relationships were in predicting erosive RA, with an OR of 3.6 (95% CI = 1.9 – 6.6) for erosive RA and an OR of 5.7 (95% CI = 2.8 – 12.0) for seropositive erosive RA for the highest wGRS group. No significant relationship was seen between continuous or grouped wGRS and age at symptom onset.

Conclusion:

We saw significant associations between a cumulative genetic risk score with 22 alleles and odds of seropositive, erosive and seropositive erosive RA. No associations were seen with age of symptom onset. Further studies are needed to assess the potential of the wGRS in predicting other phenotypes of RA.

 OR (95% CI)  
wGRS GroupSero- RASero+ RAErosive RASero+ Erosive RA
11.0 (0.5–2.1)0.5 (0.2–1.2)0.6 (0.2–1.8)0.7 (0.2–2.8)
20.7 (0.4–1.3)0.7 (0.4–1.2)1.0 (0.5–2.0)0.8 (0.3–2.2)
31.0 (0.6–1.7)0.7 (0.4–1.1)0.8 (0.4–1.6)0.5 (0.2–1.4)
41.0 (ref)1.0 (ref)1.0 (ref)1.0 (ref)
51.1 (0.6–1.9)1.7 (1.0–2.8)1.5 (0.8–3.1)1.5 (0.6–3.7)
61.7 (0.9–3.2)1.8 (1.0–3.2)2.1 (1.0–4.5)2.7 (1.1–6.5)
71.3 (0.7–2.3)2.9 (1.8–4.6)3.6 (1.9–6.6)5.7 (2.8–12.0)

To cite this abstract, please use the following information:
Chibnik, Lori B., Keenan, Brendan T., Cui, Jing, Plenge, Robert M., Karlson, Elizabeth W.; Genetic Risk Score Predicting Risk of Rheumatoid Arthritis Phenotypes and Age of Symptom Onset [abstract]. Arthritis Rheum 2009;60 Suppl 10 :745
DOI: 10.1002/art.25825

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