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
{"title":"颈动脉内膜中层厚度对中风风险的表型和遗传影响","authors":"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","doi":"10.1007/s00439-024-02666-1","DOIUrl":null,"url":null,"abstract":"<p>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 (<i>N</i> = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (<i>N</i> = 45,185) and any stroke (AS, N<sub>case</sub>/N<sub>control</sub>=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT<sub>max</sub>-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09–1.79; cIMT<sub>mean</sub>-AS: HR = 1.39, 95%CI = 1.09–1.78; cIMT<sub>min</sub>-AS: HR = 1.32, 95%CI = 1.04–1.68). A positive global genetic correlation was observed (cIMT<sub>max</sub>-AS: <span>\\({r}_{g}\\)</span>=0.23, <i>P</i>=9.44 × 10<sup>−5</sup>; cIMT<sub>mean</sub>-AS: <span>\\({r}_{g}\\)</span>=0.21, <i>P</i>=3.00 × 10<sup>−4</sup>; cIMT<sub>min</sub>-AS: <span>\\({r}_{g}\\)</span>=0.16, <i>P</i>=6.30 × 10<sup>−3</sup>). 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<sub>max</sub>-AS: odds ratio (OR)=1.12, 95%CI=0.97–1.28; cIMT<sub>mean</sub>-AS: OR=1.09, 95%CI=0.93–1.26; cIMT<sub>min</sub>-AS: OR=1.03, 95%CI = 0.90–1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT<sub>max</sub>: beta=0.07, 95%CI = 0.01–0.13; AS-cIMT<sub>mean</sub>: beta=0.08, 95%CI = 0.01–0.15; AS-cIMT<sub>min</sub>: 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.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke\",\"authors\":\"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\",\"doi\":\"10.1007/s00439-024-02666-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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 (<i>N</i> = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (<i>N</i> = 45,185) and any stroke (AS, N<sub>case</sub>/N<sub>control</sub>=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT<sub>max</sub>-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09–1.79; cIMT<sub>mean</sub>-AS: HR = 1.39, 95%CI = 1.09–1.78; cIMT<sub>min</sub>-AS: HR = 1.32, 95%CI = 1.04–1.68). A positive global genetic correlation was observed (cIMT<sub>max</sub>-AS: <span>\\\\({r}_{g}\\\\)</span>=0.23, <i>P</i>=9.44 × 10<sup>−5</sup>; cIMT<sub>mean</sub>-AS: <span>\\\\({r}_{g}\\\\)</span>=0.21, <i>P</i>=3.00 × 10<sup>−4</sup>; cIMT<sub>min</sub>-AS: <span>\\\\({r}_{g}\\\\)</span>=0.16, <i>P</i>=6.30 × 10<sup>−3</sup>). 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<sub>max</sub>-AS: odds ratio (OR)=1.12, 95%CI=0.97–1.28; cIMT<sub>mean</sub>-AS: OR=1.09, 95%CI=0.93–1.26; cIMT<sub>min</sub>-AS: OR=1.03, 95%CI = 0.90–1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT<sub>max</sub>: beta=0.07, 95%CI = 0.01–0.13; AS-cIMT<sub>mean</sub>: beta=0.08, 95%CI = 0.01–0.15; AS-cIMT<sub>min</sub>: 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.</p>\",\"PeriodicalId\":13175,\"journal\":{\"name\":\"Human Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-04-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Human Genetics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s00439-024-02666-1\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00439-024-02666-1","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke
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, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (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). A positive global genetic correlation was observed (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). 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 (cIMTmax-AS: odds ratio (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). A putative association was observed for genetically predicted stroke on cIMT (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) 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.
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.
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