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Causal association of circulating cholesterol levels with dementia: a mendelian randomization meta-analysis.

ABSTRACT: Prospective studies have shown that abnormally circulating cholesterol is associated with the risk of dementia. However, whether the association is causal or not remains unclear. We attempt to infer the causal association in a MR meta-analysis by using ApoE gene polymorphisms as instrument variables. Studies with dementia risk (27 studies) or circulating lipid levels (7 studies) were included, with totally 3136 dementia patients and 3103 healthy controls. The analyses showed that carriers of ε2 allele significantly were of decreased risk of AD (OR = 0.70; 95% CI: 0.58-0.84; P < 0.01), whereas carriers of ε4 allele were of increased risk of AD (OR = 3.62; 95% CI: 3.03-4.32; P < 0.05), compared to these of ε3 allele. Circulating TC was significantly reduced in carriers of ε2 allele (WMD = - 0.29 mmol/L; 95% CI: -0.54 to -0.03; P < 0.05) and increased in carriers of ε4 allele (WMD = 0.42 mmol/l; 95% CI: 0.001-0.84; P < 0.05). In addition, carriers of ε4 allele had reduction in circulating HDL-C (WMD = - 0.04 mmol/L; 95% CI: - 0.07 to -0.001; P < 0.05). In comparing allele ε2 with ε3, the predicted OR of having AD for 1 mg/dL increment in circulating TC was 0.97 (95% CI: 0.86-0.98; P < 0.05). Comparing allele ε4 with ε3, the predicted OR for a 1 mg/dL increment in TC was 1.08 (95% CI: 1.05-17.58; P < 0.05), and reduction in HDL-C was 2.30 (95% CI: 1.51-43.99; P < 0.05). Our findings demonstrate that high circulating TC and reduced HDL-C levels might be potential risk factors of the development of AD.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7217910 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundObservational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR).MethodsWe performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.ResultsWe found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates.ConclusionThis MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.

Project description:In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10-49 ) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (β = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (β = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Project description:The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability.

Project description:The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-sensing pathway is a central regulator of cell growth and metabolism and is dysregulated in diabetes. The eukaryotic translation initiation factor 4E (EIF-4E) protein, a key regulator of gene translation and protein function, is controlled by mTORC1 and EIF-4E Binding Proteins (EIF4EBPs). Both EIF4EBPs and ribosomal protein S6K kinase (RP-S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K circulating levels using Mendelian Randomization. We estimated the causal role of EIF-4F complex, EIF4EBP, and S6K in the circulation on type 2 diabetes, based on independent single nucleotide polymorphisms strongly associated (p = 5 × 10-6) with EIF-4E (16 SNPs), EIF-4A (11 SNPs), EIF-4G (6 SNPs), EIF4EBP2 (12 SNPs), and RP-S6K (16 SNPs). The exposure data were obtained from the INTERVAL study. We applied these SNPs for each exposure to publically available genetic associations with diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676) and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald-estimates using inverse variance weighting with multiplicative random effects and conducted sensitivity analysis. Mendelian Randomization (MR-Base) R package was used in the analysis. The PhenoScanner curated database was used to identify disease associations with SNP gene variants. EIF-4E is associated with a lowered risk of type 2 diabetes with an odds ratio (OR) 0.94, 95% confidence interval (0.88, 0.99, p = 0.03) with similar estimates from the weighted median and MR-Egger. Similarly, EIF-4A was associated with lower risk of type 2 diabetes with odds ratio (OR) 0.90, 95% confidence interval (0.85, 0.97, p = 0.0003). Sensitivity analysis using MR-Egger and weighed median analysis does not indicate that there is a pleiotropic effect. This unbiased Mendelian Randomization estimate is consistent with a protective causal association of EIF-4E and EIF-4A on type 2 diabetes. EIF-4E and EIF-4A may be targeted for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes.

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Causal association of circulating cholesterol levels with dementia: a mendelian randomization meta-analysis.

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