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Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

ABSTRACT: Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large-scale genome-wide association studies have identified numerous genetic variants linked to OA risk factors, facilitating MR study design. In this review, we systematically identified 52 MR studies meeting specific criteria and evaluated their quality, exploring the impact of lifestyle, nutrition, comorbidities, circulating metabolites, plasma proteins, and other health factors on OA risk. We discuss the results and potential mechanisms of MR findings, addressing conflicting evidence based on existing literature and our prior research. With the ongoing expansion of genome-wide association data, we anticipate MR's role in future OA studies to broaden, particularly in drug development research using targeted MR approaches. We thus aim for this paper to offer valuable insights for researchers and clinicians in related fields.

SUBMITTER: Luo Q

PROVIDER: S-EPMC11341639 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

Luo Qingfeng Q Zhang Shiyong S Yang Qiyuan Q Deng Yuyi Y Yi Hengjing H Li Xingsheng X

Aging clinical and experimental research 20240822 1

Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large- ...[more]

PMID: 39172202

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Project description:BackgroundWhile several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors.MethodsData were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them.ResultsUnivariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified.ConclusionThis study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.

Project description:IntroductionMetabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification.MethodsTwo-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity.ResultsThe UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified.DiscussionThe MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

Project description:ObjectiveSeveral 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.MethodsUtilizing 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.ResultsAfter 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.ConclusionThis 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.

Project description:Epidemiology shows women have a higher incidence of osteoarthritis (OA) than men. However, there is not enough evidence to suggest a direct correlation between female reproductive factors and OA. Therefore, this study will employ Mendelian randomization (MR) analysis to investigate whether there is a causal relationship between the 2. This study used a 2-sample MR analysis with single nucleotide polymorphisms significantly associated with female reproductive factors as instrumental variables (IV). We used inverse variance weighted (IVW), MR-Egger regression, weighted median method to infer a causal relationship between female reproductive factors and OA, Cochran Q heterogeneity test by IVW and MR-Egger method, MR PRESSO method and IVW-radial method to detect outliers, MR_pleiotropy_test function and MR PRESSO method for multivariate validity test, and calculation of F-value was used to assess the presence of weak IVs. Finally, the stability of the findings was assessed using the leave-one-out method. Our research shows that there is no reliable causal relationship between an increase in Age at menarche (years) (AAM) and Age at menopause (years) (AM) and OA, that an increase in Age first had sexual intercourse (years) (AFS) is associated with a decreased risk of knee OA and/or hip OA and hand OA, that an increase in Age at first live birth (years) (AFB) is associated with a decreased risk of knee OA and/or hip OA and knee OA, and that an increase in Number of live births (NOB) is associated with an increased risk of knee OA and/or hip OA. This study provides genetic support for an increase in AFS as a reduced knee OA and/or hip OA and hand OA risk factor, an increase in AFB as a reduced knee OA and/or hip OA and knee OA risk factor, and an increase in NOB as an increased knee OA and/or hip OA risk factor. Further studies are needed to elucidate the potential mechanisms underlying the causal associations between AFS, AFB, and NOB and site-specific OA.

Project description:ObjectiveAlthough smoking and osteoarthritis (OA) have been linked in a number of studies, the exact cause of the association is still unknown and the conclusion is controversial. The purpose of this study was to use Mendelian randomization (MR) analysis to investigate the causal relationship between smoking phenotypes and OA risk from a genetically informed standpoint.MethodsAs instrumental variables (IVs) based on single nucleotide polymorphisms (SNPs), this study used the summary-level data of corresponding genome-wide association study (GWAS) for five smoking phenotypes involving 1,694,781 samples. The outcomes comprised both a discovery and a replication cohort. The discovery MR analysis involved 12 OA traits (177,517 cases and 649,173 controls) while the replication MR analysis incorporated an additional OA GWAS dataset consisting of 36,185 cases and 135,185 controls. The main analytic approach we used was the inverse variance weighted (IVW) method. MR Egger, Weighted median, Weighted mode, and Simple mode were among the other methods that were tested. We conducted meta-analysis to combine the MR results. To confirm the robustness of the results, sensitivity analysis using Leave-One-Out (LOO), level pleiotropy testing (MR Egger intercept test and MR-PRESSO), and heterogeneity testing were performed.ResultsSummary-level MR analysis revealed a positive correlation between genetic predisposition for smoking and the likelihood of developing OA. The meta-analysis merge showed that smoking initiation increased the risk of knee OA by 20%, hip OA by 16%, and knee/hip OA by 19% (all p < 0.001). Similarly, lifetime smoking elevated the risk of knee OA by 101%, hip OA by 55%, and knee/hip OA by 84% (all p < 0.001). The sensitivity analysis's findings reinforced the reliability of these findings.ConclusionAccording to our research, smoking increases the likelihood of developing OA from a genetic standpoint. Reducing tobacco use could, therefore, be beneficial in lowering the incidence of OA.

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Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

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Causal factors for osteoarthritis risk revealed by mendelian randomization analysis.

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