POS1086 USING GENETICS TO UNDERSTAND THE ROLE OF ANTIHYPERTENSIVE DRUGS IN RHEUMATOID ARTHRITIS
Authors: Song S. , Zhao R. , Qiao J. , Wang C. , Zhang S. X. , LI X. 
Published: June 2023

Background

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease, which is characterized by synovitis and extra-articular inflammation, whose pathophysiology involves a complex interplay of environmental and genetic factors. The patients with RA are at higher risk of morbidity and mortality from cardiovascular disease. Hypertension has been reported to be the strongest risk factor for cardiovascular events in RA patients in several studies[1]. Alpha-adrenoceptor blockers, Angiotensin converting enzyme inhibitors (ACEI), Beta-adrenoceptor blockers (BB) and/or Calcium channel blockers (CCB) are commonly used as the first-line antihypertensive therapy. However, data on their relative impact on patients with RA are limited.

Objectives

We leveraged genetic variants mimicking antihypertensive drugs to investigate their effects on risk of RA.

Methods

We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with rheumatoid arthritis (RA). Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants[2].Correlated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10−8) in Alpha-adrenoceptor blockers, ACEI, BB and CCB drug target gene regions(± 100kB) were selected as proxies for drug target perturbation. To increase the number of genetic variants available, for targets without genetic instrument, we included correlated genetic variants with r2 < 0.8, within ± 1MB gene regions. Summary statistics for RA were derived from a genome-wide association studies (GWAS) meta-analysis including 14,361 cases and 42,923 controls[3]. MR estimates were performed using the inverse variance weighted (IVW), MR-Egger, Weighted median (WM), simple mode, Weighted mode or, for single SNP instruments, the Wald ratio.

Results

Genetically predicted Alpha-adrenoceptor blockers was associated with the decreased risk for RA (WM method: odds ratios [ORs] = 0.928, 95% CI: 0.885, 0.974, p = 0.002), while genetic proxies for BB were associated with increased risk of RA (WM method: OR=1.059, 95% CI 1.010, 1.111, p = 0.018; IVW method: OR=1.039, 95% CI 1.002, 1.078) (Figure 1).. ACEI and CCB had no effect on RA (p > 0.05). We also found no evidence that antihypertensives had effect on RA when combining all protein targets.

Conclusion

Our findings suggest the genetically proxied Alpha-adrenoceptor blockers reduce risk of RA, while genetic proxies for beta-blockers may be related to higher risk of RA. The ACEI or CCB is unlikely to affect the risk of developing RA. These data support further study on the effects of different antihypertensive drugs on RA susceptible population.

References

[1] Hadwen, Brook et al. “Risk factors for hypertension in rheumatoid arthritis patients-A systematic review.” Autoimmunity reviews vol. 20,4 (2021): 102786.

[2] Evangelou, Evangelos et al. “Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.” Nature genetics vol. 50,10 (2018): 1412-1425.

[3] Okada, Yukinori et al. “Genetics of rheumatoid arthritis contributes to biology and drug discovery.” Nature vol. 506,7488 (2014): 376-81.

Acknowledgements:

NIL.

Disclosure of Interests

None Declared.