Background/Purpose: Osteoarthritis (OA) is a prevalent joint disorder characterized by joint pain, disability, and the loss of articular cartilage, imposing a significant burden on patients worldwide. Despite its widespread impact, effective treatments for OA are still elusive. Existing evidence from observational and animal studies suggests that sex hormones (e.g. estrogen and testosterone) play an important role in OA symptoms and joint structural changes. However, there were limited number of randomized clinical trials focusing on the effect of sex hormone-related drugs on OA. Therefore, this Mendelian randomization study aimed to explore the causal effect of sex hormone-related drugs on the risk of OA.

Methods: The classification of sex hormone-related drugs was based on the WHO-endorsed Anatomical Therapeutic Chemical (ATC) classification system (https://atcddd.fhi.no/atc_ddd_index/), including systemic hormonal contraceptives, androgens, estrogens, progestins, gonadotropins and other ovulation stimulants, antiandrogens, other sex hormones and reproductive system regulators. The target genes of sex hormone-related drugs were identified using DrugBank (https://go.drugbank.com/). Whole-blood expression quantitative trait loci (eQTL) data from eQTLGen were used to assess the association between genetic instrumental variables and the expression of target genes which were the exposure of this study. The outcomes of this study included 10 OA-related traits from a meta-analysis of genome-wide association studies, including OA at any site, knee OA, hip OA, knee and/or hip OA, total knee replacement, total hip replacement, finger OA, thumb OA, hand OA, and spine OA). The summary-data-based mendelian randomization (SMR) analysis was used to estimate the association between changes in target gene expression and OA-related traits. As a sensitivity analysis, the heterogeneity in dependent instruments (HEIDI) test was performed to test the hypothesis that the association detected by the SMR test was due to pleiotropic association with a P_HEIDI < 0.01 rejecting the null hypothesis. Colocalization analysis was performed to test whether the exposure and outcome were affected by the same causal variants. A posterior probability of hypothesis 4 (PPH4) greater than 0.8 was used as a cut-off to indicate evidence of colocalization.

Results: Twelve drug targets were identified through DrugBank. Six eQTLs of drug targets, namely SRD5A1, ESR1, ESR2, NR3C2, NR3C1 and GNRHR2, were included from eQTLGen. After Bonferroni adjustment, we found the following associations between eQTLs and OA-related traits were statistically significant: 1) ESR1 and spine OA (β=-0.177, standard error (SE) = 0.082, P=0.032); 2) ESR1 and knee and hip OA (β=-0.099, SE=0.050, P=0.048); 3) ESR2 and hip OA (β=-0.117, SE=0.050, P=0.020); and 4) NR3C1 and knee OA (β=-0.255, SE=0.0129, P=0.048)). The HEIDI tests of significant results showed that our findings were robust (P_HEIDI < 0.01). No evidence of colocalization was found (PPH4 < 0.8).

Conclusion: High expression of ESR1, ESR2, and NR3C1 was protective against knee, hip, and/or spine OA, and could be the targets of future drug development for OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-causal-effect-of-sex-hormone-related-drugs-on-the-risk-of-osteoarthritis-a-mendelian-randomization-study/