The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Abstract

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation.

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…Common genetic variants at the solute carrier family 39 member 8 (SLC39A8) genomic locus are significantly associated genome wide with whole-blood manganese (Mn) (1) as well as a variety of other traits and diseases, including blood pressure (2,3), HDL cholesterol (HDL-C) (4,5), BMI (6), and schizophrenia (7,8). Importantly, the lead variant for blood Mn and all of the other traits is a coding variant, rs13107325 (Ala391Thr), that has an 8% minor allele frequency in people of European ancestry (9) and has been reported to encode a protein with reduced function (10,11).…”

CONTRIBUTION OF GENETIC MARKERS AND PRODUCTION FACTORS IN THE DEVELOPMENT OF ARTERIAL HYPERTENSION IN MEN IN AN ORGANIzED WORKERS COHORT OF MACHINE-BUILDING PLANT

“…Генетическая основа АГ включает в себя множество полиморфных локусов. Так, с помощью полногеномных исследований ассо-циаций (genome-wide association studies -GWAS) было выявлено более 100 генов различных сигналь-ных путей и еще больше однонуклеотидных поли-морфизмов (ОНП), ассоциированных с повышен-ным артериальным давлением и гипертонией [8][9][10]. Однако, несмотря на выявление на сегодняшний день большого количества генов и ОНП, ассоциированных с АГ, каждый в отдельности генетический вариант имеет слабое влияние на развитие АГ, объясняет очень малую долю наследственности в развитии заболевания и, таким образом, имеет ограниченную предсказатель-ную ценность [11].…”

“…Одним из решений повышения предсказательной ценности генетического тестирова-ния является объединение информации о нескольких ОНП в единую систему оценки риска, часто называе-мую как "шкала генетического риска" (ШГР). В насто-ящее время показана предсказательная ценность ШГР, включающих от 6 до 66 ОНП [8,9,12,13].…”

Genomics and Precision Medicine for Clinicians and Scientists in Hypertension

“…Further data with potential clinical significance have been generated by even larger meta-analyses published recently [15][16][17] . In one of these studies, Surendran et al, 15 genotyped nearly 350,000 individuals to identify 30 new blood pressure or hypertension-associated risk loci.…”