Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case–control study

Abstract

Objectives. To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals. Methods. A case–control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture. Results. European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 −7). HLA haplotype ORs in European and African ancestry individuals were highly correlated (r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 −4). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 −4) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 −5) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 −3). Conclusion. Gene–environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.

Sequencing of the MHC region definesHLA-DQA1as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population

“…Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease primarily affecting the peripheral joints. Studies indicate that RA is a heterogeneous disease where different subsets result from complex interactions between genetic and environmental factors 1–3. The major histocompatibility complex (MHC) genes represent the best described genetic risk loci linking to RA susceptibility in many populations.…”

Genetics of rheumatoid arthritis: 2018 status

“…Nevertheless, the current transethnic GWAS are still underpowered to dissect overall genetic architecture of human complex traits 26. Future efforts should therefore integrate other ethnicities 27–30…”

Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis

“…Smoking is the most widely studied environmental risk factor linked to RA development and prognosis [ 5 , 6 ]. One way that smoking is potentially linked to RA pathogenesis is through its association with the development of ACPAs [ 7 – 9 ], detected by the anti-cyclic citrullinated peptide (CCP) clinical assay.…”