College of Acu-moxibustion and Massage, Heilongjiang University Of Chinese Medicine, Haerbin, Heilongjiang Province, China.
Department of Rheumatology and Immunology, The Third People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China.
PLoS One. 2024 Aug 30;19(8):e0307958. doi: 10.1371/journal.pone.0307958. eCollection 2024.
Several observational studies have revealed a potential relationship between menstrual reproductive factors (MRF) and osteoarthritis (OA). However, the precise causal relationship remains elusive. This study performed Mendelian randomization (MR) to provide deeper insights into this relationship.
Utilizing summary statistics of genome-wide association studies (GWAS), we conducted univariate MR to estimate 2 menstrual factors (Age at menarche, AAM; Age at menopause, AMP) and 5 reproductive factors (Age at first live birth, AFB; Age at last live birth, ALB; Number of live births, NLB; Age first had sexual intercourse, AFSI; Age started oral contraceptive pill, ASOC) on OA (overall OA, OOA; knee OA, KOA and hip OA, HOA). The sample size of MRF ranged from 123846 to 406457, and the OA sample size range from 393873 to 484598. Inverse variance weighted (IVW) method was used as the primary MR analysis methods, and MR Egger, weighted median was performed as supplements. Sensitivity analysis was employed to test for heterogeneity and horizontal pleiotropy. Finally, multivariable MR was utilized to adjust for the influence of BMI on OA.
After conducting multiple tests (P<0.0023) and adjusting for BMI, MR analysis indicated that a lower AFB will increase the risk of OOA (odds ratio [OR] = 0.97, 95% confidence interval [CI]: 0.95-0.99, P = 3.39×10-4) and KOA (OR = 0.60, 95% CI: 0.47-0.78, P = 1.07×10-4). ALB (OR = 0.61, 95% CI: 0.45-0.84, P = 2.06×10-3) and Age AFSI (OR = 0.66, 95% CI: 0.53-0.82, P = 2.42×10-4) were negatively associated with KOA. In addition, our results showed that earlier AMP adversely affected HOA (OR = 1.12, 95% CI: 1.01-1.23, P = 0.033), and earlier ASOC promote the development of OOA (OR = 0.97, 95% CI: 0.95-1.00, P = 0.032) and KOA (OR = 0.58, 95% CI: 0.40-0.84, P = 4.49×10-3). ALB (OR = 0.98, 95% CI: 0.96-1.00, P = 0.030) and AFSI (OR = 0.98, 95% CI: 0.97-0.99, P = 2.66×10-3) also showed a negative association with OOA but they all did not pass multiple tests. The effects of AAM and NLB on OA were insignificant after BMI correction.
This research Certificates that Early AFB promotes the development of OOA, meanwhile early AFB, ALB, and AFSI are also risk factors of KOA. Reproductive factors, especially those related to birth, may have the greatest impact on KOA. It provides guidance for promoting women's appropriate age fertility and strengthening perinatal care.
几项观察性研究表明，月经生殖因素（MRF）与骨关节炎（OA）之间存在潜在关系。然而，确切的因果关系仍难以捉摸。本研究采用孟德尔随机化（MR）方法深入探讨这种关系。
利用全基因组关联研究（GWAS）的汇总统计数据，我们进行了单变量 MR 分析，以估计 2 个月经因素（初潮年龄，AAM；绝经年龄，AMP）和 5 个生殖因素（首次活产年龄，AFB；末次活产年龄，ALB；活产数，NLB；首次发生性行为年龄，AFSI；开始口服避孕药年龄，ASOC）对 OA（总体 OA，OOA；膝 OA，KOA 和髋 OA，HOA）的影响。MRF 的样本量范围为 123846 至 406457，OA 的样本量范围为 393873 至 484598。采用逆方差加权（IVW）法作为主要的 MR 分析方法，并进行加权中位数 MR Egger 分析作为补充。采用敏感性分析来检测异质性和水平多效性。最后，采用多变量 MR 来调整 BMI 对 OA 的影响。
经过多次检验（P<0.0023）并调整 BMI 后，MR 分析表明，较低的 AFB 会增加 OOA 的风险（比值比[OR] = 0.97，95%置信区间[CI]：0.95-0.99，P = 3.39×10-4）和 KOA（OR = 0.60，95% CI：0.47-0.78，P = 1.07×10-4）。ALB（OR = 0.61，95% CI：0.45-0.84，P = 2.06×10-3）和 AFSI 年龄（OR = 0.66，95% CI：0.53-0.82，P = 2.42×10-4）与 KOA 呈负相关。此外，我们的结果表明，较早的 AMP 不利地影响 HOA（OR = 1.12，95% CI：1.01-1.23，P = 0.033），较早的 ASOC 促进 OOA（OR = 0.97，95% CI：0.95-1.00，P = 0.032）和 KOA（OR = 0.58，95% CI：0.40-0.84，P = 4.49×10-3）的发展。ALB（OR = 0.98，95% CI：0.96-1.00，P = 0.030）和 AFSI（OR = 0.98，95% CI：0.97-0.99，P = 2.66×10-3）也与 OOA 呈负相关，但均未通过多次检验。AFB 年龄和 NLB 对 OA 的影响在 BMI 校正后不显著。
本研究证实，较早的 AFB 会增加 OOA 的发病风险，同时较早的 AFB、ALB 和 AFSI 也是 KOA 的危险因素。生殖因素，尤其是与分娩相关的因素，可能对 KOA 的影响最大。这为促进女性适龄生育和加强围产期护理提供了指导。
