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

Abstract

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.

Reevaluation of the association of seven candidate genes with blood pressure and hypertension: a replication study and meta-analysis with a larger sample size

“…Because AGT rs699 and CYP11B2 rs1799998 themselves and/or their proxies are included in the list of SNPs that are assayed by most of the GWA scan platforms, it is unlikely that these SNPs have failed to be tested for BP trait associations in the previous GWA studies. [4][5][6][7][8][9][10][11][12][13] Rather, it is probable that the associations were not followed up in the multistaged screening approach, principally because their statistical significance in the discovery stage did not attain a given threshold (for example, Po1 Â 10 À5 ). This value may not indicate the lack of modest association at these loci, as we reported in the present study (Figure 3).…”

“…With recent technological advances, genome-wide association (GWA) studies, which interrogate a large proportion of the common genetic variants (that is, by genotyping hundreds of thousands of common single-nucleotide polymorphisms (SNPs)) throughout the genome, have allowed the investigation of genetic susceptibility to these traits without a priori hypotheses regarding the underlying pathophysiology. 3 In the first wave of GWA studies, [4][5][6][7][8][9] few studies appeared to identify loci associated with BP traits at a genome-wide significance level (Po5 Â 10 À8 ) when adjusted for multiple testing. In 2009, two large-scale meta-analyses of GWA studies from the Global BP Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortia identified a total of 13 independent loci significantly associated with BP.…”

“…Most of these associations are in or near genes that had not been suspected of involvement in BP regulation. The sample size of genome-wide exploration in these meta-analyses (n ¼ 19608-69395) [10][11][12][13] was much larger than that of the previous GWA studies of BP traits, [4][5][6][7][8][9] indicating that very large samples are required to identify molecular variants with modest genetic effects on BP variation in the general population. In addition, continuous BP traits are implied to have greater power than dichotomous hypertension traits, at least for the genetic loci commonly affecting both types of traits; that is, the chances of obtaining significant results are higher with a continuous trait, either systolic (SBP) or diastolic (DBP) BP.…”

Ambulatory pulse pressure as a novel predictor for long-term prognosis in essential hypertensive patients

“…Further, previous studies were mainly conducted in Europe 3,4,6 and Japan. 5 Both environmental and genetic factors 9 of hypertension may be different among different ethic populations. Given the fact that hypertension is one of the major leading causes of CV events and death in Chinese, this study was conducted to systemically assess the prognostic value of these ABPM parameters on CV morbidity and mortality in an ethnic Chinese population in Taiwan.…”

Quality over quantity? No, quality and quantity

“…A cross-sectional study using 8800 subjects and a case-control study using 1200 cases and 1200 controls were performed in Korea and in Taiwan, respectively. 10,11 It remains a subject of debate whether the Japanese Society of Hypertension will take the initiative to organize a largerscale GWAS in Japan.…”