Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study.
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ABSTRACT:
SUBMITTER: Zhao JV
PROVIDER: S-EPMC8632960 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveRecent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health.MethodsUnivariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model.ResultsUnivariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed.ConclusionLonger LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.
| S-EPMC10834216 | biostudies-literature
Project description:PurposeSmall dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design.MethodsWe identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis.ResultsIn univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002).ConclusionsFindings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.
| S-EPMC11317295 | biostudies-literature
Project description:BackgroundWhether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders.MethodsUnivariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10- 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium.ResultsWe observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85-0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71-0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003-1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74-0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD.ConclusionsOur results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.
| S-EPMC10585856 | biostudies-literature
Project description:ObjectiveIn this study, we employed a Mendelian randomization (MR) approach to investigate the independent causal associations of six body composition traits with gestational diabetes mellitus (GDM).MethodsGenome-wide significant levels (P < 10 × 5-8 ) of single nucleotide polymorphisms associated with body water mass, total protein, whole body fat-free mass, weight, whole body fat mass, and body fat percentage were used as instrumental variables. Data on GDM were obtained from the FinnGen Consortium, and both univariable and multivariable Mendelian randomization were performed. We utilized five different analytical methods including inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode to assess the robustness of the results.ResultsWith univariable Mendelian randomization, the risk of GDM increased per 1-standard deviation (SD) increase in weight (ORweight = 1.297, P = 3.06 × 10-5 ), whole body fat mass (ORwhole body fat mass = 1.408, P = 1.32 × 10-6 ), and the risk of GDM increased per percent increase in body fat percentage (ORbody fat percentage = 1.661, P = 1.01 × 10-8 ). Total protein had a protective effect on the risk of GDM (ORtotal protein = 0.880, P = 0.048). However, there was no significant causal association between increases in body water mass and whole body fat-free mass per SD and the risk of GDM. Causal associations between weight, whole body fat mass, body fat percentage, and total protein with GDM were reduced to null in multivariable Mendelian randomization.ConclusionThe present study furnishes genetic evidence to elucidate the causal relationship between body composition traits and GDM. Additionally, further studies are imperative to establish a causal connection between body composition traits and gestational diabetes mellitus.
| S-EPMC10906022 | biostudies-literature
Project description:BackgroundMental health has been found to be associated with risk of osteoarthritis (OA), but the causal relationship was not fully clarified.MethodsTwo-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between neuroticism (n = 329,821) and the two most frequently affected parts of osteoarthritis (OA) (knee OA: case/control =24,955/378,169; hip OA: case/control = 15,704/378,169) using large scale summary genome-wide association study (GWAS) data. Inverse variance weighted (IVW), weighted median, and MR-Egger were used to estimate the causal effects. Multiple sensitivity analyses were conducted to examine the robustness of the causal estimates. Multivariable MR analysis was used to estimate the direct effects of neuroticism on OA after accounting for the other OA risk factors. Two-step MR approach was employed to explore the potential mediators of the causal relationship.ResultsUnivariable MR analysis indicated that 1-SD increase in genetically predicted neuroticism score was associated with an increased risk of knee OA (IVW: OR, 1.17; 95% CI, 1.087-1.26; p = 2.72E-05) but not with hip OA. The causal effects remained significant after accounting for the effects of BMI, alcohol drinking, and vigorous physical activity but were attenuated with adjustment of smoking. Further mediation analysis revealed that smoking initiation mediated a significant proportion of the causal effects of neuroticism on knee OA (proportion of mediation effects in total effects: 22.3%; 95% CI, 5.9%-38.6%; p = 7.60E-03).ConclusionsNeuroticism has significant causal effects on knee OA risk. Smoking might partly mediate the causal relationship. Further studies were warranted to explore the underlying mechanisms and potential use of neuroticism management for OA treatment.
| S-EPMC10957734 | biostudies-literature
Project description:ObjectiveIn observational studies, testosterone has been reported to be associated with some types of cancers. However, the direction and magnitude of the causal association between testosterone and different types of cancer remain unclear. This Mendelian randomization study assessed the causal associations of total testosterone (TT) and bioavailable testosterone (BT) with cancer risk in men.MethodsWe performed two-sample Mendelian randomization using publicly available GWAS summary statistics to investigate the genetically causal association between testosterone and the risk of 22 kinds of cancers in men. Causal estimates were calculated by the inverse variance weighted method. We also performed additional sensitivity tests to evaluate the validity of the casualty.ResultsGenetically predicted BT level were significantly associated with an increased risk of prostate cancer [odds ratio (OR) = 1.17 95% confidence interval (CI): 1.09-1.26, P = 2.51E-05] in the MR analysis with the IVW method. TT was found to be the suggestive protective factor against stomach cancer (OR = 0.66, 95% CI: 0.48-0.93, P = 0.0116) as well as pancreatic cancer (OR = 0.59, 95% CI: 0.36-0.96, P = 0.0346). A suggestive association was found between TT and the occurrence of small intestine cancer (OR = 1.0004, 95% CI: 1.0001-1.0007, P = 0.0116). However, testosterone had no significant association with other cancers.ConclusionThis study investigated the role of testosterone in the development of prostate cancer, stomach cancer, pancreatic cancer, and small intestine cancer but found no strong association with the other cancers in men.
| S-EPMC9730605 | biostudies-literature
Project description:Background Red blood cell (RBC) transfusion and erythropoiesis-stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome-wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best-fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance-weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05-1.41) with VTE. Sensitivity analyses (mendelian randomization-Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.
| S-EPMC7660720 | biostudies-literature
Project description:Background: It is not clarified whether the elevation of adiponectin is the results of kidney damage, or the cause of kidney function injury. To explore the causal association of adiponectin on estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), this study was performed. Materials and methods: The genetic association of adiponectin were retrieved from one genome-wide association studies with 39,883 participants. The summary-level statistics regarding the eGFR (133,413 participants) and CKD (12,385 CKD cases and 104,780 controls) were retrieved from the CKDGen consortium in the European ancestry. Single-variable Mendelian randomization (MR), bilateral and multivariable MR analyses were used to verify the causal association between adiponectin, eGFR, and CKD. Results: Genetically predicted adiponectin reduces the risk of CKD (OR = 0.71, 95% CI = 0.57-0.89, p = 0.002) and increases the eGFR (β = 0.014, 95% CI = 0.001-0.026, p = 0.034) by the inverse variance weighting (IVW) estimator. These findings remain consistent in the sensitivity analyses. No heterogeneity and pleiotropy were detected in this study (P for MR-Egger 0.617, P for global test > 0.05, and P for Cochran's Q statistics = 0.617). The bilateral MR identified no causal association of CKD on adiponectin (OR = 1.01, 95% CI = 0.96-1.07, p = 0.658), nor did it support the association of eGFR on adiponectin (OR = 0.86, 95% CI = 0.68-1.09, p = 0.207) by the IVW estimator. All the sensitivity analyses reported similar findings (p > 0.05). Additionally, after adjusting for cigarette consumption, alcohol consumption, body mass index, low density lipoprotein, and total cholesterol, the ORs for CKD are 0.70 (95% CI = 0.55-0.90, p = 0.005), 0.75 (95% CI = 0.58-0.97, p = 0.027), 0.82 (95% CI = 0.68-0.99, p = 0.039), 0.74 (95% CI = 0.59-0.93, p = 0.011), and 0.79 (95% CI = 0.61-0.95, p = 0.018), respectively. Conclusion: Using genetic data, this study provides novel causal evidence that adiponectin can protect the kidney function and further reduce the risk of CKD.
| S-EPMC9360570 | biostudies-literature
Project description:We performed univariable and multivariable Mendelian randomization (MR) analysis to evaluate the association between blood lipids and risk of atrial fibrillation (AF), including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), Apolipoprotein A1, and Apolipoprotein B. Data on the single nucleotide polymorphisms (SNPs) related to blood lipids were obtained from the UK Biobank study with more than 300,000 subjects of White British European ancestry, and data for AF were from the latest meta-analysis of Genome-wide association study (GWASs) with six independent cohorts with more than 1,000,000 subjects of European ancestry. The univariable MR analysis was conducted to explore whether genetic evidence of individual lipid-related traits was significantly associated with AF risks and multivariable MR analysis with three models was performed to assess the independent effects of lipid-related traits. The IVW estimate showed that genetically predicted LDL-C (OR: 1.016, 95% CI: 0.962-1.073, p = 0.560), HDL-C (OR: 0.951, 95% CI: 0.895-1.010, p = 0.102), TG (OR: 0.961, 95% CI: 0.889-1.038, p = 0.313), Apolipoprotein A1 (OR: 0.978, 95% CI: 0.933-1.025, p = 0.356), and Apolipoprotein B (OR: 1.008, 95% CI: 0.959-1.070, p = 0.794) were not causally associated with the risk of AF. Sample mode (OR: 0.852, 95% CI: 0.731-0.993, p = 0.043) and weighted mode (OR: 0.907, 95% CI: 0.841-0.979, p = 0.013) showed that a 1-unit increase in TG (mmol/L) was causally associated with a 14.8% and 9.3% relative decrease in AF risk, respectively. The multivariable MR analysis with model 1, 2, and 3 indicated that TG, LDL-C, HDL-C, Apolipoprotein A1, and Apolipoprotein B were not associated with the lower risk for AF. Our multivariable Mendelian randomization analysis (MVMR) finding suggested no genetic evidence of lipid traits was significantly associated with AF risk. Furthermore, more work is warranted to confirm the potential association between lipid traits and AF risks.
| S-EPMC8746968 | biostudies-literature
Project description:BackgroundAlthough observational studies have demonstrated that blood lipids are associated with female infertility, the causality of this association remains unclear. We performed a univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal relationship between blood lipids and female infertility.MethodsSingle-nucleotide polymorphisms associated with lipid traits in univariate analysis were obtained from the Million Veteran Program (MVP) and Global Lipids Genetics Consortium (GLGC), involving up to 215,551 and 188,577 European individuals, respectively. Blood lipids in multivariate analysis were obtained from the latest genome-wide association study meta-analysis with lipid levels in 73 studies encompassing >300,000 participants. Data on female infertility were obtained from the FinnGen Consortium R6 release, which included 6481 samples and 75,450 controls. Subsequently, MR analysis was performed using inverse variance-weighted (IVW), weighted median, weighted-mode, simple-mode and MR-Egger regression to demonstrate the causal relationship between lipids and female infertility.ResultsAfter controlling confounding factors including body mass index and age at menarche, two-sample MR demonstrated that genetically predicted LDL-C and TC were causally associated with the risk of female infertility (When the genetic instruments come from the MVP database, LDL-C and female infertility, IVW OR: 1.13, 95% CI: 1.001-1.269, p = 0.047; TC and female infertility, IVW OR: 1.16, 95% CI: 1.018-1.317, p = 0.025, and when the genetic instruments came from the GLGC database, LDL-C and female infertility, IVW OR: 1.10, 95% CI: 1.008-1.210, p = 0.033; TC and female infertility, IVW OR: 1.14, 95% CI: 1.024-1.258, p = 0.015). However, the IVW estimate showed that HDL-C was not significantly associated with the risk of female infertility (when the genetic instruments came from the MVP database, IVW OR: 1.00, 95% CI: 0.887-1.128, p = 0.999; when the genetic instruments came from the GLGC database, IVW OR: 1.00, 95% CI: 0.896-1.111, p = 0.968). The multivariable MR analysis also provided evidence that LDL-C (OR: 1.12, 95% CI: 1.006-1.243, p = 0.042) was significantly associated with the risk of female infertility after considering the correlation of all lipid-related traits.ConclusionThese findings support a causal relationship between increased LDL-cholesterol and increased female infertility risk. Furthermore, the association between lipid-related traits and female infertility risk merits more studies.
| S-EPMC10384410 | biostudies-literature