Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY

Human Genetics Pub Date : 2024-04-05 DOI:10.1007/s00439-024-02666-1

Wenqiang Zhang, Jingwei Zhu, Xuan Wu, Tianle Feng, Wei Liao, Xuan Li, Jianci Chen, Li Zhang, Chenghan Xiao, Huijie Cui, Chao Yang, Peijing Yan, Yutong Wang, Mingshuang Tang, Lin Chen, Yunjie Liu, Yanqiu Zou, Xueyao Wu, Ling Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Xia Jiang, Ben Zhang

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引用次数: 0

Abstract

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, N_case/N_control=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT_max-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09–1.79; cIMT_mean-AS: HR = 1.39, 95%CI = 1.09–1.78; cIMT_min-AS: HR = 1.32, 95%CI = 1.04–1.68). A positive global genetic correlation was observed (cIMT_max-AS: \({r}_{g}\)=0.23, P=9.44 × 10⁻⁵; cIMT_mean-AS: \({r}_{g}\)=0.21, P=3.00 × 10⁻⁴; cIMT_min-AS: \({r}_{g}\)=0.16, P=6.30 × 10⁻³). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMT_max-AS: odds ratio (OR)=1.12, 95%CI=0.97–1.28; cIMT_mean-AS: OR=1.09, 95%CI=0.93–1.26; cIMT_min-AS: OR=1.03, 95%CI = 0.90–1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT_max: beta=0.07, 95%CI = 0.01–0.13; AS-cIMT_mean: beta=0.08, 95%CI = 0.01–0.15; AS-cIMT_min: beta = 0.08, 95%CI = 0.01–0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

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颈动脉内膜中层厚度对中风风险的表型和遗传影响

虽然颈动脉内膜中层厚度（cIMT）作为动脉粥样硬化的无创替代测量指标被广泛认为是中风的风险因素之一，但 cIMT 与中风之间的内在联系尚未完全明了。我们旨在通过研究 cIMT 与中风之间的表型和遗传关系，评估 cIMT 在中风中的临床价值。我们利用英国生物库（UK Biobank）的观察数据（N = 21526）评估了表型关联。然后，我们利用主要是欧洲血统的基因组数据调查了 cIMT（N = 45,185 例）和任何中风（AS，Ncase/Ncontrol=40,585/406,111 例）的遗传关系。观察分析表明，cIMT 每增加一个标准差，中风的风险就会增加（cIMTmax-AS：风险比 (HR) = 1.39，95%CI = 1.09-1.79；cIMTmean-AS：HR = 1.39，95%CI = 1.09-1.78；cIMTmin-AS：HR = 1.32，95%CI = 1.04-1.68）。观察到全基因正相关（cIMTmax-AS：\({r}_{g}\)=0.23，P=9.44 × 10-5；cIMTmean-AS：\({r}_{g}\)=0.21，P=3.00 × 10-4；cIMTmin-AS：\({r}_{g}\)=0.16，P=6.30 × 10-3）。5个共享的独立位点和15个共享的表达-性状关联进一步证实了这一点。孟德尔随机分析表明，cIMT 对卒中没有因果效应（cIMTmax-AS：几率比（OR）=1.12，95%CI=0.97-1.28；cIMTmean-AS：OR=1.09，95%CI=0.93-1.26；cIMTmin-AS：OR=1.03，95%CI=0.90-1.17）。在反方向 MR 中观察到基因预测卒中与 cIMT 的假定相关性（AS-cIMTmax：beta=0.07，95%CI=0.01-0.13；AS-cIMTmean：beta=0.08，95%CI=0.01-0.15；AS-cIMTmin：beta=0.08，95%CI=0.01-0.16），但在敏感性分析中减弱为不显著。我们的研究没有发现支持 cIMT 与中风之间因果关系的证据。明显的 cIMT 与中风的关联是内在的，主要归因于共同的遗传因素。在普通人群中，cIMT 作为中风风险替代标志物的临床价值可能有限。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.