Role of Selected Genetic Polymorphisms in the Development of Rheumatoid Arthritis in a British White Population

Abstract

Background: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease.

Aims: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes.

Methods: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined.

Results: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t₂₈₅ = 5.387, p < 0.001) and weighted (mean difference = 2.75, t₂₈₅ = 6.437, p < 0.001) results.

Conclusion: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.

Keywords: HLADRB1; IL4590; PTPN22; Polygenic Risk Score (PRS); TNFα; TRAF1.

Figure 1

Overview of identified risk factors for RA development and disease impacts. (a) Lifestyle factors; (b) Genetic factors—see Table 1; (c) Affected joint impacts—may include deformity, swelling, pain, limited ROM [2]; (d) Quality of life impacts—may include cessation of work [4], lower functional ability, fatigue [1]; (e) Systemic impacts—may include eye inflammation [8], nerve compression [9], pericarditis [10]. RA risk factors and impacts are not limited to the above.

Figure 2

Unweighted and weighted polygenic risk scores.