Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population

Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Primary aldosteronism - actual epidemics or false alarm?

The prevalence of "primary aldosteronism" (PAL) cannot be precisely determined at this time, given 1) lack of a universally accepted definition, and 2) normotensive as well as normokalemic phases in the evolutionary development of a disease eventually characterized by hypertension and hypokalemia. The exception is fully genetically characterised forms such as glucocorticoid-suppressible hyperaldosteronism, the true prevalence of which could be proven today by universal screening using a single blood sample, but this is neither practical nor appropriate. Controversy has arisen regarding the rareness, or otherwise, of PAL because of 1) rediscovery in the last 12 years of the normokalemic phase described by Conn, 2) application of widely available methods for measurement of aldosterone and renin to "screening", 3) variable quality of these methods, and of their application, and 4) lack of the necessary "diagnostic", in addition to "screening", tests in some studies. PAL is significantly more common than previously thought, and a very important potentially curable form of hypertension. Early diagnosis and specific treatment avoids morbidity. The current focus on increased detection is essential, and will help to resolve the question of prevalence