AbstractLow concentrations of circulating 25-hydroxy-vitamin D are observationally associated with an increased risk of subclinical atherosclerosis and cardiovascular disease. However, randomized controlled trials have not reported the beneficial effects of vitamin D supplementation on atherosclerotic cardiovascular disease (ASCVD) outcomes.

低浓度的循环25-羟基维生素D与亚临床动脉粥样硬化和心血管疾病的风险增加有关。然而，随机对照试验尚未报道补充维生素D对动脉粥样硬化性心血管疾病（ASCVD）结局的有益作用。

Whether genetically predicted vitamin D status confers protection against the development of carotid artery plaque, a powerful predictor of subclinical atherosclerosis, remains unknown. We conducted a two-sample Mendelian randomization (MR) study to explore the association of genetically predicted vitamin D status and deficiency with the risk of developing carotid artery plaque.

遗传预测的维生素D状态是否可以防止颈动脉斑块的发展，颈动脉斑块是亚临床动脉粥样硬化的有力预测因子，目前尚不清楚。我们进行了一项双样本孟德尔随机化（MR）研究，以探讨遗传预测的维生素D状态和缺乏与颈动脉斑块发生风险的关系。

We leveraged three genome-wide association studies (GWAS) of vitamin D status and one GWAS of vitamin D deficiency. We used the inverse-variance weighted (IVW) approach as our main method, and MR-Egger, weighted-median, and radialMR as MR sensitivity analyses. We also conducted sensitivity analyses using biologically plausible genetic instruments located within genes encoding for vitamin D metabolism (GC, CYP2R1, DHCR7, CYP24A1).

我们利用了维生素D状态的三项全基因组关联研究（GWAS）和维生素D缺乏症的一项GWAS。我们使用逆方差加权（IVW）方法作为主要方法，MR-Egger，加权中位数和radialMR作为MR敏感性分析。。

We did not find significant associations between genetically predicted vitamin D status (Odds ratio (OR) = 0.99, P = 0.91) and deficiency (OR = 1.00, P = 0.97) with the risk of carotid artery plaque. We additionally explored the potential causal effect of vitamin D status on coronary artery calcification (CAC) and carotid intima-media thickness (cIMT), two additional markers of subclinical atherosclerosis, and we did not find any significant association (βCAC = − 0.14, P = 0.23; βcIMT = 0.005, P = 0.19).

。我们还探讨了维生素D状态对冠状动脉钙化（CAC）和颈动脉内膜中层厚度（cIMT）的潜在因果关系，这是亚临床动脉粥样硬化的另外两个标志物，我们没有发现任何显着的相关性（βCAC=-0.14，P=0.23；βcIMT=0.005，P=0.19）。

These findings did not support the causal effects of vitamin D status and deficiency on the risk of developing subclinical atheros.

这些发现不支持维生素D状态和缺乏对发生亚临床动脉粥样硬化风险的因果关系。

IntroductionCirculating 25-hydroxyvitamin D, or 25(OH)D, is a reliable biomarker of vitamin D status, an essential nutrient that can be obtained through exposure to ultraviolet light, dietary intake and supplementation. Beyond its established role in bone and calcium metabolism, vitamin D has emerged as an important factor in cardiovascular health1.

引言循环25-羟基维生素D或25（OH）D是维生素D状态的可靠生物标志物，维生素D是一种必需营养素，可以通过暴露于紫外线，饮食摄入和补充来获得。除了在骨骼和钙代谢中的既定作用外，维生素D已成为心血管健康的重要因素1。

Vitamin D deficiency and insufficiency have been associated with subclinical atherosclerosis, which is in turn associated with an increased risk of cardiovascular events2,3. Associations between circulating 25(OH)D and carotid artery plaque, coronary artery calcification (CAC) and carotid intima-media thickness (cIMT), markers of subclinical atherosclerosis, have also been reported4,5.

维生素D缺乏和不足与亚临床动脉粥样硬化有关，而亚临床动脉粥样硬化又与心血管事件风险增加有关2,3。循环25（OH）D与颈动脉斑块，冠状动脉钙化（CAC）和颈动脉内膜中层厚度（cIMT）（亚临床动脉粥样硬化的标志物）之间的关联也有报道[4,5]。

However, whether these associations are causal remains unknown. The prevalence of vitamin D deficiency (defined as serum < 20 ng/mL) worldwide is high (40% in Europe, 24% in the United States, 37% in Canada)6, and there is a need to better understand the clinical and subclinical consequences of vitamin D status and deficiency.Mendelian randomization (MR) is a statistical method that employs genetic variation as an instrumental variable to assess the causal relationship between exposures and outcomes of interest.

然而，这些关联是否是因果关系仍然未知。全世界维生素D缺乏症（定义为血清<20 ng/mL）的患病率很高（欧洲为40%，美国为24%，加拿大为37%）6，需要更好地了解维生素D状态和缺乏的临床和亚临床后果。孟德尔随机化（MR）是一种统计方法，它使用遗传变异作为工具变量来评估暴露与感兴趣结果之间的因果关系。

MR is analogous to a randomized controlled experiment whereby genetic variants are randomly allocated to offspring at conception. This approach mitigates the risk of confounding and reverse causality that are commonly found in traditional epidemiological studies. Previous MR studies have shown that vitamin D deficiency may play a causal role in the development of hypertension7,8, a known risk factor of cardiovascular disease (CVD), while others have reported limited evidence supporting a causal effect on cardiovascular traits9,10.

MR类似于随机对照实验，即在受孕时将遗传变异随机分配给后代。这种方法减轻了传统流行病学研究中常见的混淆和反向因果关系的风险。先前的MR研究表明，维生素D缺乏可能在高血压的发展中起因果作用7,8，高血压是心血管疾病（CVD）的已知危险因素，而其他人则报道了有限的证据支持对心血管疾病的因果关系9,10。

Howe.

豪。

Table 1 Data sources used for two-sample Mendelian randomization (MR) analyses.Full size tableGenetic predictors of vitamin D statusWe obtained genetic estimates for circulating 25-hydroxyvitamin D concentrations from three different sources (Table 1). The first is a GWAS of 417,580 individuals of European ancestry in the UK Biobank14 (ID: ebi-a-GCST90000618; https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90000618/).

表1用于双样本孟德尔随机化（MR）分析的数据来源。维生素D状态的全尺寸表遗传预测因子我们从三个不同来源获得了循环25-羟基维生素D浓度的遗传估计（表1）。第一个是英国生物库14中417580名欧洲血统的GWAS（ID:ebi-a-GCST90000618；https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90000618/)。

Circulatory levels of 25(OH)D were measured in blood samples using a chemiluminescent immunoassay that measures total concentrations of 25(OH)D (25(OH)D3 and 25(OH)D2). The second GWAS was performed in the UK Biobank population15 (N = 441,291; ID: ieu-b-4812; https://gwas.mrcieu.ac.uk/datasets/ieu-b-4812/).

使用化学发光免疫测定法测量血液样品中25（OH）D的循环水平，该测定法测量25（OH）D（25（OH）D3和25（OH）D2）的总浓度。第二次GWAS在英国生物库人群中进行15（N＝441291）；编号：ieu-b-4812；https://gwas.mrcieu.ac.uk/datasets/ieu-b-4812/)。

Circulatory 25(OH)D levels (nmol/L) were measured using the Diasorin assay. For 6% of the study cohort, adjustments were made by subtracting 21.2 nmol/L from the measurements in the vitamin D supplement users. Further adjustments are described fully in the original study16. The third GWAS was a metaGWAS study of 31 studies with a total of 79,366 individuals of European descent17 (ID: ebi-a-GCST005367; https://www.ebi.ac.uk/gwas/studies/GCST005367).Genetic predictors of vitamin D deficiencyWe obtained summary statistics from the FinnGen biobank (ID: finn-b-E4_VIT_D_DEF; https://gwas.mrcieu.ac.uk/datasets/finn-b-E4_VIT_D_DEF/) on vitamin D deficiency from Ncases = 182 and Ncontrols 209,607 (Table 1).

使用Diasorin测定法测量循环25（OH）D水平（nmol/L）。对于6%的研究队列，通过从维生素D补充剂使用者的测量值中减去21.2 nmol/L进行调整。。第三个GWAS是31项研究的metaGWAS研究，共有79366名欧洲后裔17（ID:ebi-a-GCST005367；https://www.ebi.ac.uk/gwas/studies/GCST005367)。维生素D缺乏的遗传预测因子我们从FinnGen生物库获得了汇总统计数据（ID:finn-b-E4\u VIT\u D\u DEF；https://gwas.mrcieu.ac.uk/datasets/finn-b-E4_VIT_D_DEF/)来自NCase=182和Ncontrols 209607的维生素D缺乏症（表1）。

Further details on the endpoint definition can be found at https://risteys.finregistry.fi/endpoints/E4_VIT_D_DEF (ICD-10 E50-E64)18.GWAS summary statistics of carotid artery plaque cIMT, and CACGenetic associations of carotid artery plaque and cIMT were obtained from a meta-analysis of genome-wide association study (GWAS) from 17 studies from the Cohorts for Hea.

有关端点定义的更多详细信息，请访问https://risteys.finregistry.fi/endpoints/E4_VIT_D_DEF（ICD-10 E50-E64）18.GWAS颈动脉斑块cIMT的总结统计以及颈动脉斑块和cIMT的CACGenetic关联是从来自Hea队列的17项研究的全基因组关联研究（GWAS）的荟萃分析中获得的。

Data availability

数据可用性

All GWAS summary statistics used in this study are publicly available for download and a link was provided for each dataset in the Method section. The carotid artery plaque GWAS summary statistics data that support the findings of this study was obtained from database of Genotypes and Phenotypes (dbGaP) under the CHARGE acquisition number (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000930.v6.p1; accession phs000930.v6.p1)..

本研究中使用的所有GWAS摘要统计数据均可公开下载，并且在方法部分为每个数据集提供了链接。颈动脉斑块GWAS总结统计数据支持这项研究的结果是从基因型和表型数据库（dbGaP）中获得的(https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000930.v6.p1；登录号phs000930.v6.p1）。。

Code availability

代码可用性

The following software packages were used for data analysis: R (https://www.r-project.org) R version 4.3.1 (2023-06-16), ‘TwoSampleMR’ version 0.5.7, ‘RadialMR’ version 1.126, ‘MRPRESSO’ version 1.025. The code used to run the current analysis will be made available on GitHub (https://github.com/Jingxian-Huang/vit_d_carotid_plaque_mr)..

(https://www.r-project.org)R版本4.3.1（2023-06-16），“TwoSampleMR”版本0.5.7，“RadialMR”版本1.126，“MRPRESSO”版本1.025。用于运行当前分析的代码将在GitHub上提供(https://github.com/Jingxian-Huang/vit_d_carotid_plaque_mr)。。

ReferencesTheodoratou, E., Tzoulaki, I., Zgaga, L. & Ioannidis, J. P. Vitamin D and multiple health outcomes: Umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 348, g2035. https://doi.org/10.1136/bmj.g2035 (2014).Article

参考文献Theodoratou，E.，Tzoulaki，I.，Zgaga，L。＆Ioannidis，J.P。维生素D和多种健康结果：观察性研究和随机试验的系统评价和荟萃分析的综述。BMJ 348，g2035。https://doi.org/10.1136/bmj.g2035（2014年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Carrelli, A. L. et al. Vitamin D deficiency is associated with subclinical carotid atherosclerosis. Stroke 42, 2240–2245. https://doi.org/10.1161/STROKEAHA.110.608539 (2011).Article

Carrelli，A.L.等人维生素D缺乏与亚临床颈动脉粥样硬化有关。。https://doi.org/10.1161/STROKEAHA.110.608539（2011年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Lupoli, R. et al. Impact of vitamin D deficiency on subclinical carotid atherosclerosis: A pooled analysis of cohort studies. J. Clin. Endocrinol. Metab. 102, 2146–2153. https://doi.org/10.1210/jc.2017-00342 (2017).Article

Lupoli，R。等人。维生素D缺乏对亚临床颈动脉粥样硬化的影响：队列研究的汇总分析。J、 临床。内分泌。代谢。1022146-2153年。https://doi.org/10.1210/jc.2017-00342（2017年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Ding, Y. H. et al. Association between serum 25-hydroxyvitamin D and carotid atherosclerotic plaque in Chinese type 2 diabetic patients. Medicine (Baltimore) 96, e6445. https://doi.org/10.1097/md.0000000000006445 (2017).Article

丁，Y。H。等。中国2型糖尿病患者血清25-羟基维生素D与颈动脉粥样硬化斑块的关系。医学（巴尔的摩）96，e6445。https://doi.org/10.1097/md.0000000000006445（2017年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Säidifard, N., Tangestani, H., Djafarian, K. & Shab-Bidar, S. Serum vitamin D level and carotid intima-media thickness: A systematic review and meta-analysis of observational studies and randomized control trials. Horm. Metab. Res. 52, 305–315. https://doi.org/10.1055/a-1153-0657 (2020).Article .

Säidifard，N.，Tangestani，H.，Djafarian，K。＆Shab Bidar，S。血清维生素D水平和颈动脉内膜中层厚度：观察性研究和随机对照试验的系统评价和荟萃分析。霍姆。代谢。第52305-315号决议。https://doi.org/10.1055/a-1153-0657（2020年）。。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Amrein, K. et al. Vitamin D deficiency 2.0: An update on the current status worldwide. Eur. J. Clin. Nutr. 74, 1498–1513. https://doi.org/10.1038/s41430-020-0558-y (2020).Article

Amrein，K.等人，《维生素D缺乏症2.0：全球现状的最新进展》。欧洲临床杂志。营养。741498-1513年。https://doi.org/10.1038/s41430-020-0558-y（2020年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Afzal, S. & Nordestgaard, B. G. Vitamin D, hypertension, and ischemic stroke in 116 655 individuals from the general population: A genetic study. Hypertension https://doi.org/10.1161/HYPERTENSIONAHA.117.09411 (2017).Article

Afzal，S.＆Nordestgaard，B.G。来自普通人群的116 655个人的维生素D，高血压和缺血性中风：一项基因研究。高血压https://doi.org/10.1161/HYPERTENSIONAHA.117.09411（2017年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Vimaleswaran, K. S. et al. Association of vitamin D status with arterial blood pressure and hypertension risk: A Mendelian randomisation study. Lancet Diabetes Endocrinol. 2, 719–729. https://doi.org/10.1016/S2213-8587(14)70113-5 (2014).Article

Vimaleswaran，K.S.等人。维生素D状态与动脉血压和高血压风险的关系：孟德尔随机研究。柳叶刀糖尿病内分泌。2719-729。https://doi.org/10.1016/S2213-8587（14） 70113-5（2014）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jiang, X., Ge, T. & Chen, C. Y. The causal role of circulating vitamin D concentrations in human complex traits and diseases: A large-scale Mendelian randomization study. Sci. Rep. 11, 184. https://doi.org/10.1038/s41598-020-80655-w (2021).Article

。科学。代表11184。https://doi.org/10.1038/s41598-020-80655-w（2021年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration. Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: Observational and Mendelian randomisation analyses. Lancet Diabetes Endocrinol. 9, 837–846.

新兴风险因素合作/EPIC-CVD/维生素D研究合作。估计维生素D与冠心病，中风和全因死亡率的剂量反应关系：观察性和孟德尔随机分析。柳叶刀糖尿病内分泌。9837-846。

https://doi.org/10.1016/s2213-8587(21)00263-1 (2021).Article .

https://doi.org/10.1016/s2213-8587(21)00263-1 (2021).文章联盟。

CAS

中科院

Google Scholar

谷歌学者

Sun, J. et al. Carotid plaque lipid content and fibrous cap status predict systemic CV outcomes: The MRI substudy in AIM-HIGH. JACC Cardiovasc. Imaging 10, 241–249. https://doi.org/10.1016/j.jcmg.2016.06.017 (2017).Article

Sun，J。等人。颈动脉斑块脂质含量和纤维帽状态预测全身CV结果：AIM-HIGH的MRI亚研究。JACC心血管。成像10241-249。https://doi.org/10.1016/j.jcmg.2016.06.017（2017年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Touboul, P.-J., Grobbee, D. E. & Ruijter, H. D. Assessment of subclinical atherosclerosis by carotid intima media thickness: Technical issues. Eur. J. Prev. Cardiol. 19, 18–24. https://doi.org/10.1177/2047487312448990 (2012).Article

Touboul，P.-J.，Grobbee，D.E。和Ruijter，H.D。通过颈动脉内膜中层厚度评估亚临床动脉粥样硬化：技术问题。欧元J.前。心脏病。19、18-24岁。https://doi.org/10.1177/2047487312448990（2012年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Onnis, C. et al. Coronary artery calcification: Current concepts and clinical implications. Circulation 149, 251–266. https://doi.org/10.1161/CIRCULATIONAHA.123.065657 (2024).Article

Onnis，C。等人。冠状动脉钙化：当前的概念和临床意义。发行量149251-266。https://doi.org/10.1161/CIRCULATIONAHA.123.065657（2024年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Revez, J. A. et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat. Commun. 11, 1647. https://doi.org/10.1038/s41467-020-15421-7 (2020).Article

Revez，J.A.等人的全基因组关联研究确定了143个与25-羟基维生素D浓度相关的基因座。国家公社。111647年。https://doi.org/10.1038/s41467-020-15421-7（2020年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Manousaki, D. et al. Genome-wide association study for vitamin D levels reveals 69 independent loci. Am. J. Hum. Genet. 106, 327–337. https://doi.org/10.1016/j.ajhg.2020.01.017 (2020).Article

Manousaki，D。等人。维生素D水平的全基因组关联研究揭示了69个独立基因座。上午J。嗯。Genet。106327-337。https://doi.org/10.1016/j.ajhg.2020.01.017（2020年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Boef, A. G., Dekkers, O. M. & le Cessie, S. Mendelian randomization studies: A review of the approaches used and the quality of reporting. Int. J. Epidemiol. 44, 496–511. https://doi.org/10.1093/ije/dyv071 (2015).Article

Boef，A.G.，Dekkers，O.M。＆le Cessie，S。孟德尔随机化研究：对所用方法和报告质量的回顾。国际流行病学杂志。44496-511。https://doi.org/10.1093/ije/dyv071（2015年）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Jiang, X. et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat. Commun. 9, 260. https://doi.org/10.1038/s41467-017-02662-2 (2018).Article

Jiang，X。等人。对79366名欧洲血统个体进行的全基因组关联研究揭示了25-羟基维生素D水平的遗传结构。国家公社。9260页。https://doi.org/10.1038/s41467-017-02662-2（2018年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kurki, M. I. et al. FinnGen: Unique genetic insights from combining isolated population and national health register data. medRxiv https://doi.org/10.1101/2022.03.03.22271360 (2022).Article

Kurki，M.I.等人，FinnGen：结合孤立人群和国家健康登记数据的独特遗传见解。medRxiv公司https://doi.org/10.1101/2022.03.03.22271360（2022年）。文章

Google Scholar

谷歌学者

Franceschini, N. et al. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nat. Commun. 9, 5141. https://doi.org/10.1038/s41467-018-07340-5 (2018).Article

Franceschini，N。等人GWAS和共定位分析暗示颈动脉内膜中层厚度和颈动脉斑块位点在心血管结局中的作用。国家公社。95141页。https://doi.org/10.1038/s41467-018-07340-5（2018年）。文章

ADS

广告

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kavousi, M. et al. Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. Nat. Genet. 55, 1651–1664. https://doi.org/10.1038/s41588-023-01518-4 (2023).Article

Kavousi，M。等人。多血统全基因组研究确定了冠状动脉钙化的效应基因和可药物途径。纳特·吉内特。551651-1664年。https://doi.org/10.1038/s41588-023-01518-4（2023年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Burgess, S., Small, D. S. & Thompson, S. G. A review of instrumental variable estimators for Mendelian randomization. Stat. Methods Med. Res. 26, 2333–2355. https://doi.org/10.1177/0962280215597579 (2017).Article

Burgess，S.，Small，D.S。＆Thompson，S.G。孟德尔随机化工具变量估计的综述。《统计方法医学》第262333-2355号决议。https://doi.org/10.1177/0962280215597579（2017年）。文章

MathSciNet

MathSciNet

PubMed

PubMed

Google Scholar

谷歌学者

Lawlor, D. A., Harbord, R. M., Sterne, J. A., Timpson, N. & DaveySmith, G. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat. Med. 27, 1133–1163. https://doi.org/10.1002/sim.3034 (2008).Article

Lawlor，D.A.，Harbord，R.M.，Sterne，J.A.，Timpson，N。＆DaveySmith，G。孟德尔随机化：使用基因作为流行病学因果推断的工具。。https://doi.org/10.1002/sim.3034（2008年）。文章

MathSciNet

MathSciNet

PubMed

PubMed

Google Scholar

谷歌学者

Burgess, S. & Thompson, S. G. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur. J. Epidemiol. 32, 377–389. https://doi.org/10.1007/s10654-017-0255-x (2017).Article

Burgess，S.＆Thompson，S.G.使用MR-Egger方法解释孟德尔随机化的发现。欧洲流行病学杂志。32377-389。https://doi.org/10.1007/s10654-017-0255-x（2017年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314. https://doi.org/10.1002/gepi.21965 (2016).Article

Bowden，J.，Davey-Smith，G.，Haycock，P.C。＆Burgess，S。使用加权中值估计量在孟德尔随机化中使用一些无效工具进行一致估计。基因。流行病。40304–314。https://doi.org/10.1002/gepi.21965（2016年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Verbanck, M., Chen, C. Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693–698. https://doi.org/10.1038/s41588-018-0099-7 (2018).Article

Verbanck，M.，Chen，C.Y.，Neale，B。＆Do，R。从复杂性状和疾病之间的孟德尔随机化推断的因果关系中检测广泛的水平多效性。纳特·吉内特。50693-698。https://doi.org/10.1038/s41588-018-0099-7（2018年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Bowden, J. et al. Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. Int. J. Epidemiol. 47, 1264–1278. https://doi.org/10.1093/ije/dyy101 (2018).Article

Bowden，J.等人。通过径向图和径向回归改进双样本汇总数据孟德尔随机化的可视化，解释和分析。国际流行病学杂志。471264-1278年。https://doi.org/10.1093/ije/dyy101（2018年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Hemani, G., Tilling, K. & Davey Smith, G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 13, e1007081. https://doi.org/10.1371/journal.pgen.1007081 (2017).Article

Hemani，G.，Tilling，K。＆Davey Smith，G。使用GWAS摘要数据确定不精确测量的性状之间的因果关系。PLoS Genet。13，e1007081。https://doi.org/10.1371/journal.pgen.1007081（2017年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Garcia, V. C. & Martini, L. A. Vitamin D and cardiovascular disease. Nutrients 2, 426–437. https://doi.org/10.3390/nu2040426 (2010).Article

Garcia，V.C。和Martini，L.A。维生素D和心血管疾病。。https://doi.org/10.3390/nu2040426（2010年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Martens, P. J., Gysemans, C., Verstuyf, A. & Mathieu, A. C. Vitamin D’s effect on immune function. Nutrients https://doi.org/10.3390/nu12051248 (2020).Article

Martens，P.J.，Gysemans，C.，Verstuyf，A。＆Mathieu，A.C。维生素D对免疫功能的影响。营养素https://doi.org/10.3390/nu12051248（2020年）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Norman, A. W. From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 88, 491s–499s. https://doi.org/10.1093/ajcn/88.2.491S (2008).Article

从维生素D到激素D：维生素D内分泌系统的基本原理对健康至关重要。美国J.克林。营养。88491S–499s。https://doi.org/10.1093/ajcn/88.2.491S（2008年）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Zhou, A., Selvanayagam, J. B. & Hyppönen, E. Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. Eur. Heart J. 43, 1731–1739. https://doi.org/10.1093/eurheartj/ehab809 (2021).Article

Zhou，A.，Selvanayagam，J。B。和Hyppönen，E。非线性孟德尔随机化分析支持维生素D缺乏在心血管疾病风险中的作用。《欧洲心脏杂志》431731-1739。https://doi.org/10.1093/eurheartj/ehab809（2021年）。文章

CAS

中科院

Google Scholar

谷歌学者

Burgess, S. & Gill, D. Genetic evidence for vitamin D and cardiovascular disease: Choice of variants is critical. Eur. Heart J. 43, 1740–1742. https://doi.org/10.1093/eurheartj/ehab870 (2021).Article

Burgess，S。＆Gill，D。维生素D和心血管疾病的遗传证据：变体的选择至关重要。欧洲心脏杂志431740-1742。https://doi.org/10.1093/eurheartj/ehab870（2021年）。文章

Google Scholar

谷歌学者

Smith, G. D. Mendelian randomisation and vitamin D: The importance of model assumptions. Lancet Diabetes Endocrinol. 11, 14. https://doi.org/10.1016/s2213-8587(22)00345-x (2023).Article

Smith，G.D。孟德尔随机化和维生素D：模型假设的重要性。柳叶刀糖尿病内分泌。11，14。https://doi.org/10.1016/s2213-8587（22）00345-x（2023）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Tian, H., Mason, A. M., Liu, C. & Burgess, S. Relaxing parametric assumptions for non-linear Mendelian randomization using a doubly-ranked stratification method. PLoS Genet. 19, e1010823. https://doi.org/10.1371/journal.pgen.1010823 (2023).Article

Tian，H.，Mason，A.M.，Liu，C.＆Burgess，S。使用双重分层方法放松非线性孟德尔随机化的参数假设。PLoS Genet。19，e1010823。https://doi.org/10.1371/journal.pgen.1010823（2023年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Forouhi, N. G. et al. Effects of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk among people at risk of type 2 diabetes: Results of a randomized double-blind placebo-controlled trial. Diabetes Obes. Metab. 18, 392–400. https://doi.org/10.1111/dom.12625 (2016).Article .

Forouhi，N.G.等人，《补充维生素D2或D3对2型糖尿病风险人群血糖控制和心脏代谢风险的影响：一项随机双盲安慰剂对照试验的结果》。糖尿病Obes。代谢。18392-400。https://doi.org/10.1111/dom.12625（2016年）。。

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Huang, T. et al. Vitamin D and cause-specific vascular disease and mortality: A Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults. BMC Med. 17, 160. https://doi.org/10.1186/s12916-019-1401-y (2019).Article

Huang，T.等人，《维生素D与特定原因的血管疾病和死亡率：一项涉及99012名中国人和106911名欧洲成年人的孟德尔随机研究》。BMC医学杂志17160。https://doi.org/10.1186/s12916-019-1401-y（2019年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Brondum-Jacobsen, P., Benn, M., Jensen, G. B. & Nordestgaard, B. G. 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: Population-based study and meta-analyses of 18 and 17 studies. Arterioscler. Thromb. Vasc. Biol. 32, 2794–2802. https://doi.org/10.1161/ATVBAHA.112.248039 (2012).Article .

Brondum Jacobsen，P.，Benn，M.，Jensen，G.B。＆Nordestgaard，B.G。25-羟基维生素d水平与缺血性心脏病，心肌梗塞和早期死亡的风险：基于人群的研究和18和17项研究的荟萃分析。动脉硬化。血栓。Vasc。生物学322794-2802。https://doi.org/10.1161/ATVBAHA.112.248039（2012年）。。

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Afzal, S., Brondum-Jacobsen, P., Bojesen, S. E. & Nordestgaard, B. G. Vitamin D concentration, obesity, and risk of diabetes: A Mendelian randomisation study. Lancet Diabetes Endocrinol. 2, 298–306. https://doi.org/10.1016/S2213-8587(13)70200-6 (2014).Article

Afzal，S.，Brondum Jacobsen，P.，Bojesen，S.E。和Nordestgaard，B.G。维生素D浓度，肥胖和糖尿病风险：孟德尔随机研究。柳叶刀糖尿病内分泌。2298-306。https://doi.org/10.1016/S2213-8587（13） 70200-6（2014）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Afzal, S., Brondum-Jacobsen, P., Bojesen, S. E. & Nordestgaard, B. G. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ 349, g6330. https://doi.org/10.1136/bmj.g6330 (2014).Article

Afzal，S.，Brondum Jacobsen，P.，Bojesen，S.E。和Nordestgaard，B.G。遗传性低维生素D浓度和死亡率增加：三个大型队列的孟德尔随机分析。BMJ 349，g6330。https://doi.org/10.1136/bmj.g6330（2014年）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsThe authors would like to thank the staff and participants who contributed to the UK Biobank, CHARGE, UCLEB, SUNLIGHT, and FinnGen consortia for making the resources available.FundingWe acknowledge support from the Imperial College British Heart Foundation Centre for Research Excellence (RE/18/4/34215), the UK Dementia Research Institute at Imperial College London (MC_PC_17114).Author informationAuthor notesThese authors contributed equally: Devendra Meena, Marie-Joe Dib and Jingxian Huang.Authors and AffiliationsDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UKDevendra Meena, Jingxian Huang, Alexander Smith, Jian Huang, Dipender Gill, Abbas Dehghan & Ioanna TzoulakiDivision of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, USAMarie-Joe DibSingapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore City, SingaporeJian HuangCardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UKAmrit S.

下载参考文献致谢作者要感谢为英国生物库，CHARGE，UCLEB，SUNLIGHT和FinnGen consortia提供资源的工作人员和参与者。资助我们感谢帝国理工学院英国心脏基金会卓越研究中心（RE/18/4/34215），伦敦帝国理工学院英国痴呆症研究所（MC\U PC\U 17114）的支持。作者信息作者注意到这些作者做出了同样的贡献：Devendra Meena，Marie Joe Dib和Jingxian Huang。作者和附属机构伦敦帝国理工学院公共卫生学院流行病学和生物统计学系，伦敦，UKDevendra Meena，Jingxian Huang，Alexander Smith，Jian Huang，Dipender Gill，Abbas Dehghan＆Ionana Tzoulaki宾夕法尼亚大学医院心血管医学系，费城，USAMarie Joe DibSingapore Institute for Clinical Sciences（SICS），科学，技术和研究机构（A*STAR），新加坡市，新加坡皇家布朗普顿医院心血管磁共振室，悉尼街，伦敦，SW3 6NP，UKAmrit S。

Lota & Sanjay K. PrasadBritish Heart Foundation Centre of Excellence, Imperial College London, London, UKIoanna TzoulakiDementia Research Centre, Imperial College London, London, UKAbbas Dehghan & Ioanna TzoulakiCentre for Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, GreeceIoanna TzoulakiAuthorsDevendra MeenaView author publicationsYou can also search for this author in.

伦敦帝国理工学院Lota＆Sanjay K.PrasadBritish Heart Foundation卓越中心，伦敦帝国理工学院UKIoanna TzoulakiDementia研究中心，伦敦帝国理工学院，UKAbbas Dehghan＆Ioanna TzoulakiCentre for Systems Biology，生物医学研究基金会，雅典雅典学院，GreeceIoanna TzoulakiAuthorsDevendra MeenaView author Publications你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsD.M. designed the study. D.M., M.-J.D., and J.H. conducted statistical analyses and visualization of results, and drafted the initial version of the manuscript. D.M., M.-J.D., and J.H. contributed equally to this paper. All the co-authors contributed to the interpretation of the findings and critical revision of the manuscript, and all the co-authors approved the final version for publication.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleMeena, D., Dib, MJ., Huang, J. et al. Associations of genetically predicted vitamin D status and deficiency with the risk of carotid artery plaque: a Mendelian randomization study.

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