Exploring the genetic characteristics of diverse populations to guide drug development for cardiometabolic and immune mediated diseases

以银屑病、系统性红斑狼疮和类风湿性关节炎形式表现的慢性炎症与心脏代谢疾病的加速发展有关。糖尿病、血脂异常和高血压导致欧洲血统人群未来发生不良心脏事件的风险增加两倍，在血统多样化的人群中，如东南亚人，风险增加至7倍。尽管疾病风险存在这种差异，但大多数成功确定与免疫和心血管疾病相关的遗传位点的研究都是在欧洲人群中进行的，而祖先多样的人群在遗传研究中的代表性严重不足。此外，祖先多样化的人群更有可能对目前用于治疗心血管和免疫介导疾病的药物无反应，或发生严重的药物不良反应。该项目旨在确定与不同祖先人群中发生心脏代谢和免疫介导疾病风险增加相关的遗传位点，并评估其作为药物靶点的潜力。该研究的第一部分侧重于使用跨种族共定位从可用的汇总统计、基因分型和测序数据中识别英国生物库和基因与健康队列中欧洲、非洲和东亚人群的跨种族和祖先特异性基因座。来自英国生物库的混合人群将通过当地血统推断进行去卷积，并基于其祖先单倍型剂量纳入人群特异性分析。本研究的第二部分旨在探索这些新基因座作为治疗心脏代谢和免疫介导疾病的潜在药物靶点的作用。将使用eQTLGen和GTEx数据库中的表达数量性状基因座（eQTL）和Interval和SCALLOP Consortium中的蛋白表达数量性状（pQTL）数据以及文献中可用的祖先特异性数量性状基因座，进行药物靶标孟德尔随机化，以评估在转录物或蛋白表达水平上修饰药物靶标是否可以降低各祖先的疾病风险。最后，该项目将探索许可药物、失败化合物和临床前候选药物的再利用机会和潜在副作用。

Chronic inflammation manifested in the form of psoriasis, systemic lupus erythematosus and rheumatoid arthritis has been associated with accelerated development of cardiometabolic diseases. Diabetes, dyslipidemia and hypertension lead to a two-fold risk of developing future adverse cardiac events in populations of European ancestry, the risk increasing to up to seven-folds in ancestrally diverse populations, such as South-East Asians. Despite this discrepancy in disease risk, most of the studies that have successfully identified genetic loci associated with immune and cardiovascular diseases have been conducted in European populations, while ancestrally diverse populations are severely under-represented in genetic studies. Moreover, ancestrally diverse population are more likely to be unresponsive to currently available drugs prescribed for the treatment of cardiovascular and immune mediated diseases or experience severe adverse drug reactions. This project aims to identify genetic loci associated with an increased risk of developing cardiometabolic and immune mediated diseases across ancestrally diverse populations and assess their potential as drug targets. The first part of the study focuses on identifying trans-ethic and ancestry specific loci across European, African and East Asian populations in the UK Biobank and Genes&Health cohorts from available summary statistics, genotyping and sequencing data using trans-ethic colocalization. Admixed populations from the UK Biobank will be deconvolved by local ancestry inference and included in population specific analysis based on their ancestral haplotype dosage. The second part of the study aims to explore the role of these novel loci as potential drug targets for the treatment of cardiometabolic and immune mediated diseases. Drug target mendelian randomization will be performed to assess whether modification of drug targets at transcript or protein expression level can reduce disease risk across ancestries, using expression quantitative trait loci (eQTL) from eQTLGen and GTEx databases and protein expression quantitative trait (pQTL) data from Interval and SCALLOP Consortium, as well as ancestry specific quantitative trait loci available in the literature. Finally, this project will explore the repurposing opportunities and potential side effects of licensed drugs, failed compounds and pre-clinical candidates across ancestries.