Dissecting the Polygenic Basis of Primary Hypertension: Identification of Key Pathway-Specific Components

Frontiers in Cardiovascular Medicine

article

Carlo Maj¹  Erika Salvi²  Lorena Citterio³  Oleg Borisov¹  Marco Simonini³  Valeria Glorioso⁴  Cristina Barlassina⁵  Nicola Glorioso⁶  Lutgarde Thijs⁷  Tatiana Kuznetsova⁷  Francesco P. Cappuccio⁸  Zhen-Yu Zhang⁷  Jan A. Staessen⁹  Daniele Cusi^1,11  Chiara Lanzani³  Paolo Manunta³ 

[1] Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn;Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico “Carlo Besta”;Genomics of Renal Diseases and Hypertension Unit, Istituto di Ricovero e Cura a Carattere Scientifico IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University;Department of Statistics and Quantitative Methods, University of Milano-Bicocca;Department of Health Sciences, University of Milan;Department of Clinical and Experimental Medicine, Hypertension and Related Diseases Centre, University of Sassari;Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven;Warwick Medical School, and UHCW NHS Trust, University of Warwick;Research Institute Alliance for the Promotion of Preventive Medicine;Biomedical Science Group, Faculty of Medicine, University of Leuven;Institute of Biomedical Technologies Milano National Research Council of Italy;Bio4Dreams Scientific Unit, Bio4Dreams-Business Nursery for Life Sciences

关键词: hypertension;    genome-wide association studies;    polygenic risk score;    prediction;    pathway analysis;   

DOI  :  10.3389/fcvm.2022.814502

学科分类：地球科学(综合)

来源: Frontiers

【 摘 要 】

Introduction and Objectives Genome-wide association studies have identified a high number of genetic loci associated with hypertension suggesting the presence of an underlying polygenic architecture. In this study, we aimed to dissect the polygenic component of primary hypertension searching also for pathway-specific components. Methods The polygenic risk score (PRS) models, based on the UK biobank genetic signals for hypertension status, were obtained on a target Italian case/control cohort including 561 cases and 731 hyper-normal controls from HYPERGENES, and were then applied to an independent validation cohort composed by multi-countries European-based samples including 1,284 cases and 960 hyper-normal controls. Results The resulting genome-wide PRS was capable of stratifying the individuals for hypertension risk by comparing between individuals in the last PRS decile and the median decile: we observed an odds ratio (OR) of 3.62, CI = [2.01, 6.32] ( P = 9.01E-07) and 3.22, 95% CI = [2.06, 5.10] ( P = 6.47E-08) in the target and validation cohorts, respectively. The relatively high case/control ORs across PRS quantiles corroborates the presence of strong polygenic components which could be driven by an enrichment of risk alleles within the cases but also by potential enrichment of protective alleles in the old normotensive controls. Moreover, novel pathway-specific PRS revealed an enrichment of the polygenic signal attributable to specific biological pathways. Among those the most significantly associated with hypertension status was the calcium signaling pathway together with other mainly related such as the phosphatidylinositol/inositol phosphate pathways. Conclusions The development of pathway-specific PRS could prioritize biological mechanisms, according to their contribution to the genetic susceptibility, whose regulations might be a potential pharmacological preventive target.

【 授权许可】

CC BY