Background/Purpose: The identification of high risk groups is crucial for RA prevention strategies. Individuals with family history (FH) of autoimmunity are at increased risk for RA. Genetic markers have been associated with RA and genetic risk scores (GRS) have incorporated these markers for RA risk. We aimed to identify groups at increased risk of RA using FH and GRS.

Methods: We investigated the association between FH and GRS and risk of RA in a nested case-control study in the Nurses’ Health Study (NHS) and replicated in the Epidemiological Investigation of RA (EIRA). RA cases in NHS were validated by chart review and matched to controls. In EIRA, RA cases at diagnosis were matched to controls. All cases satisfied the 1987 ACR criteria for RA classification and were Caucasian. FH data were obtained from questionnaires (FH of RA or lupus for NHS) and registries (FH of RA for EIRA). Serologic status was defined as +RF/ACPA for NHS and by +ACPA for EIRA. Weighted genetic risk scores (GRS-HLA using 8 HLA shared epitope alleles, and GRS-39 using 8 HLA shared epitope alleles and 31 SNPs associated with RA) were calculated based on prior studies. GRS were dichotomized as high or low based on the 75th percentile of the GRS in controls. The joint effect of low/high GRS and no/any FH was examined using logistic regression models adjusted for matching factors and confounders (age, sex, smoking pack-years, body mass index, alcohol intake, education, parity, and occupational exposures) to estimate odds ratios (OR) and 95% confidence intervals (CI) for all, seropositive/ACPA+, and seronegative/ACPA- RA, with the reference of low GRS and no FH.

Results: We analyzed 492 cases and 501 controls among women in NHS and 1,752 cases and 1,361 controls among men and women in EIRA with available FH data. Compared to low GRS-HLA/no FH, the OR for high GRS-HLA and +FH was 8.56 (95% CI 3.87-18.93) in NHS and 6.17 (95% CI 3.86-9.85) in EIRA for all RA (Table 1). The OR for high GRS-39 and +FH was 6.63 (95% CI 3.30-13.31) in NHS and 8.24 (95% CI 4.64-14.64) in EIRA for all RA compared to low GRS-39/no FH (Table 2). There were no significant multiplicative interactions between GRS-HLA or GRS-39 and FH.

Conclusion: Using genetic risk scores and family history, we have identified groups at increased risk of developing RA. Genetic risk scores utilizing only HLA shared epitope alleles performed similarly to genetic risk scores incorporating a larger set of genetic markers for RA. Genetic testing, particularly HLA shared epitope alleles, among those with family history may identify groups at increased risk for RA.