by Lori B. Chibnik, Brendan T. Keenan, Jing Cui, Katherine P. Liao, Karen H. Costenbader, Robert M. Plenge, Elizabeth W. Karlson
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. Methods/Principal Findings
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/Significance
Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.