Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases

Zhang, Haihua; Wang, Tao; Han, Zhifa; Liu, Guiyou

doi:10.1007/s10072-020-04381-x

Cited by 14 publications

(9 citation statements)

References 42 publications

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“…With MR analysis, body mass index and serum 25-hydroxyvitamin D have been confirmed to be casually linked to the development of MS ( 16 ). But only a few MR studies addressed the causal relationship between circulating cytokines and MS. One previous MR study has verified significant association of genetically increased serum IL-6 receptor (IL-6R) levels with reduced risk of MS, and speculated that inhibiting IL-6 signaling (such as tocilizumab treatment) would be an effective therapy for MS ( 17 ). While an atlas on risk factors for MS did not found causal role of TNF on the risk of MS ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Zhang

et al. 2021

Front. Immunol.

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BackgroundPrevious research have implicated critical roles of systemic inflammation in the development of Multiple Sclerosis (MS). But the causal relationship between interleukins (ILs) and MS has not been fully elucidated.ObjectiveIn this study, we applied Mendelian randomization (MR) approaches to address the causal associations between genetically determined circulating levels of ILs and the risk of MS.MethodsGenetic instruments for circulating IL-1 receptor antagonist (IL-1Ra), IL-2 receptor α subunit (IL-2Rα), IL-6, IL-16, IL-17, and IL-18 were obtained from recently published genome-wide association studies (GWAS). Summary-level data for MS were obtained from the International Multiple Sclerosis Genetics Consortium. MR analyses were performed using the R software (version 3.6.1, The R Foundation) and the TwoSampleMR package.ResultsGenetic predisposition to higher circulating levels of IL-2Rα were significantly associated with MS risk. The odds ratio (OR) was 1.22 (95% confidence interval [CI], 1.12–1.32; p < 0.001) per one standard deviation increase in circulating IL-2Rα levels. There was a suggestive association of circulating IL-1Ra with MS risk (OR, 0.94; 95% CI, 0.88–0.99; p = 0.027). The other ILs were not associated with the outcome.ConclusionOur results indicated that circulating IL-2Rα was causally associated with risk of MS.

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Section: Introductionmentioning

confidence: 99%

Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Zhang

et al. 2021

Front. Immunol.

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“…1, a flow chart about our MR study design. The second and third assumptions are collectively known as independence from pleiotropy, as described in recent studies [16][17][18].…”

Section: Methodsmentioning

confidence: 99%

Effect of plasma vitamin C levels on Parkinson’s disease and age at onset: a Mendelian randomization study

Liu

Zhang

et al. 2021

J Transl Med

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Background Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. Methods We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. Results We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: [− 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: [− 3.396, − 0.105], P = 0.037) and MR-Egger (beta = − 2.592, 95% CI: [− 4.623, − 0.560], P = 0.012). Conclusions We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

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“…Third, genetic variants should affect the risk of the outcome (IS) only through the exposure (educational attainment) (assumption 3) (Emdin et al, 2017;Larsson et al, 2017a). Recent studies have provided the more detailed information about the three principal assumptions (Liu et al, 2018;Liu et al, 2019;Zhang et al, 2020;Liu et al, 2021a;Liu et al, 2021b;Sun et al, 2021). This study is based on the publicly available, large-scale GWAS summary datasets.…”

Section: Study Mesignmentioning

confidence: 99%

Educational Attainment and Ischemic Stroke: A Mendelian Randomization Study

Gao

Wang

et al. 2022

Front. Genet.

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Observational studies have evaluated the potential association of socioeconomic factors such as higher education with the risk of stroke but reported controversial findings. The objective of our study was to evaluate the potential causal association between higher education and the risk of stroke. Here, we performed a Mendelian randomization analysis to evaluate the potential association of educational attainment with ischemic stroke (IS) using large-scale GWAS datasets from the Social Science Genetic Association Consortium (SSGAC, 293,723 individuals), UK Biobank (111,349 individuals), and METASTROKE consortium (74,393 individuals). We selected three Mendelian randomization methods including inverse-variance-weighted meta-analysis (IVW), weighted median regression, and MR–Egger regression. IVW showed that each additional 3.6-year increase in years of schooling was significantly associated with a reduced IS risk (OR = 0.54, 95% CI: 0.41–0.71, and p = 1.16 × 10–5). Importantly, the estimates from weighted median (OR = 0.49, 95% CI: 0.33–0.73, and p = 1.00 × 10–3) and MR–Egger estimate (OR = 0.18, 95% CI: 0.06–0.60, and p = 5.00 × 10–3) were consistent with the IVW estimate in terms of direction and magnitude. In summary, we provide genetic evidence that high education could reduce IS risk.

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Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases

Cited by 14 publications

References 42 publications

Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Circulating Interleukins and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Effect of plasma vitamin C levels on Parkinson’s disease and age at onset: a Mendelian randomization study

Educational Attainment and Ischemic Stroke: A Mendelian Randomization Study

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