Association of circadian genes with diurnal blood pressure changes and non-dipper essential hypertension: a genetic association with young-onset hypertension.

Recent studies have suggested that circadian genes have important roles in maintaining the circadian rhythm of the cardiovascular system. However, the associations between diurnal BP changes and circadian genes remain undetermined. We conducted a genetic association study of young-onset hypertension, in which 24-h ambulatory blood pressure (BP) monitoring was performed. A total of 23 tag single-nucleotide polymorphisms (SNPs) on 11 genes involved in circadian rhythms were genotyped for correlations with diurnal BP variation phenotypes. A permutation test was used to correct for multiple testing. Five tag SNPs within five loci, including rs3888170 in NPAS2, rs6431590 in PER2, rs1410225 in RORßß, rs3816358 in BMAL1 and rs10519096 in RORα, were significantly associated with the non-dipper phenotype in 372 young hypertensive patients. A genetic risk score was generated by counting the risk alleles and effects for each individual. Genotyping was performed in an additional independent set of 619 young-onset hypertensive subjects. Altogether, non-dippers had a higher weighted genetic risk score than dippers (1.67±0.56 vs. 1.54±0.55, P<0.001), and the additive genetic risk score also indicated a graded association with decreased diurnal BP changes (P=0.006), as well as a non-dipper phenotype (P=0.031). After multivariable logistic analysis, only the circadian genetic risk score (odds ratio (OR), 1550; 95% confidence interval (CI), 1.225-1.961, P<0.001) and the use of ß-blockers (OR, 1.519; 95% CI, 1.164-1.982, P=0.003) were independently associated with the presence of non-dippers among subjects with young-onset hypertension. Genetic variants in circadian genes were associated with the diurnal phenotype of hypertension, suggesting a genetic association with diurnal BP changes in essential hypertension.

Lower serum triglyceride level is a risk factor for in-hospital and late major adverse events in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention- a cohort study.

BACKGROUND: Whether serum triglyceride level correlates with clinical outcomes of patients with ST segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI) remains unclear. METHODS: From June 2008 to February 2012, all patients with STEMI who were treated with pPCI in this tertiary referral hospital and then had fasting lipid profiles measured within 24 hours were included and dichotomized into lower- (≦ 150 mg/dl) and higher-triglyceridemic (>150 mg/dl) groups. Baseline characteristics, in-hospital outcomes, and late major adverse cardiovascular events (MACE) were compared in-between. Independent predictors for in-hospital death and late adverse events were identified by multivariate logistic and Cox regression analyses. RESULTS: A total of 247 patients were enrolled, including 163 lower-triglyceridemic and 84 higher-triglyceridemic subjects. The angiographic characteristics, pPCI results and in-hospital outcomes were similar between the two groups. However, multivariate logistic analysis identified triglyceride level as a negative predictor for in-hospital death (OR 0.963, 95% CI 0.931-0.995, p = 0.023). At follow-up for a mean period of 1.23 to 1.40 years, compared with the high-triglyceridemic group, low-triglyceridemic patients had fewer cumulative incidences of target vessel revascularization (TVR) (21.7% vs. 9.5%, p = 0.011) and overall MACE (26.1% vs. 11.9%, p = 0.0137). Cox regression analysis confirmed serum triglyceride as a negative predictor for TVR and overall MACE. CONCLUSIONS: Serum triglyceride level inversely correlates with in-hospital death and late outcomes in patients with STEMI treated with pPCI. Thus, when managing such patients, a high serum triglyceride level can be regarded as a benign factor but not a target for aggressive therapy.

A novel SNP associated with nighttime pulse pressure in young-onset hypertension patients could be a genetic prognostic factor for cardiovascular events in a general cohort in Taiwan.

BACKGROUND: Pulse pressure (PP) is a risk factor for cardiovascular disease. It has been reported that ambulatory blood pressure (BP) and nighttime BP parameters are heritable traits. However, the genetic association of pulse pressure and its clinical impact remain undetermined. METHOD AND RESULTS: We conducted a genome-wide association study of PP using ambulatory BP monitoring in young-onset hypertensive patients and found a significant association between nighttime PP and SNP rs897876 (p = 0.009) at chromosome 2p14, which contains the predicted gene FLJ16124. Young-onset hypertension patients carrying TT genotypes at rs897876 had higher nighttime PP than those with CT and CC genotypes (TT, 41.6 ± 7.3 mm Hg; CT, 39.1 ± 6.0 mm Hg; CC, 38.9 ± 6.3 mm Hg; p<0.05,). The T risk allele resulted in a cumulative increase in nighttime PP (ß = 1.036 mm Hg, se. = 0.298, p<0.001 per T allele). An independent community-based cohort containing 3325 Taiwanese individuals (mean age, 50.2 years) was studied to investigate the genetic impact of rs897876 polymorphisms in determining future cardiovascular events. After an average 7.79 ± 0.28 years of follow-up, the TT genotype of rs897876 was independently associated with an increased risk (in a recessive model) of coronary artery disease (HR, 2.20; 95% CI, 1.20-4.03; p = 0.01) and total cardiovascular events (HR, 1.99; 95% CI, 1.29-3.06; p = 0.002), suggesting that the TT genotype of rs897876C, which is associated with nighttime pulse pressure in young-onset hypertension patients, could be a genetic prognostic factor of cardiovascular events in the general cohort. CONCLUSION: The TT genotype of rs897876C at 2p14 identified in young-onset hypertensive had higher nighttime PP and could be a genetic prognostic factor of cardiovascular events in the general cohort in Taiwan.

A three-stage genome-wide association study combining multilocus test and gene expression analysis for young-onset hypertension in Taiwan Han Chinese.

BACKGROUND: Although many large-scale genome-wide association studies (GWASs) have been performed, only a few studies have successfully identified replicable, large-impact hypertension loci; even fewer studies have been done on Chinese subjects. Young-onset hypertension (YOH) is considered to be a more promising target disorder to investigate than late-onset hypertension because of its stronger genetic component. METHODS: To map YOH genetic variants, we performed a 3-stage study combining 1st-stage multilocus GWASs, 2nd-stage gene expression analysis, and 3rd-stage multilocus confirmatory study. RESULTS: In the 1st stage, Illumina550K data from 400 case-control pairs were used, and 22 genes flanked by 14 single nucleotide polymorphism (SNP) septets (P values adjusted for false discovery rate (pFDR) < 3.16×10(-7)) were identified. In the 2nd stage, differential gene expression analysis was carried out for these genes, and 5 genes were selected (pFDR < 0.05). In the 3rd stage, we re-examined the finding with an independent set of 592 case-control pairs and with the joint samples (n = 992 case-control pairs). A total of 6 SNP septets flanking C1orf135, GSN, LARS, and ACTN4 remained significant in all 3 stages. Among them, the same septet flanking ACTN4 was also associated with blood pressure traits in the Hong Kong Hypertension Study (HKHS) and in the Wellcome Trust Case-Control Consortium Hypertension Study (WTCCCHS). LARS was detected in the HKHS, but not in the WTCCCHS. GSN may be specific to Taiwanese individuals because it was not found by either the HKHS or the WTCCCHS. CONCLUSIONS: Our study identified 4 previously unknown YOH loci in Han Chinese. Identification of these genes enriches the hypertension susceptibility gene list, thereby shedding light on the etiology of hypertension in Han Chinese.

Common quantitative trait locus downstream of RETN gene identified by genome-wide association study is associated with risk of type 2 diabetes mellitus in Han Chinese: a Mendelian randomization effect.

OBJECTIVE: Plasma resistin level is a potential molecular link between obesity and diabetes. Causal role of resistin, type 2 diabetes mellitus (T2DM) and genetic variants have not been thoroughly investigated. Therefore, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci associated with resistin levels and investigated whether these variants were prospectively associated with the development of metabolic syndrome (MetS) and T2DM in an independent community-based cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS). RESEARCH DESIGN AND METHODS: We genotyped 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 chips and searched for quantitative trait loci (QTLs) of resistin in the 1(st) stage GWAS and confirmed the finding in another 559 YOH subjects. Logistic regression was used to examine the Mendelian randomization effects between genotypes of confirmed QTLs and metabolic outcomes in 3400 subjects of CVDFACTS. RESULTS: Two single nucleotide polymorphisms (SNP) (rs3745367 and rs1423096) were significantly associated with resistin levels (p = 5.52 × 10(-15) and p = 2.54 × 10(-20) ) and replicated in another 559 YOH subjects (p = 1.29 × 10(-3) and p = 1.13 × 10(-7) ), respectively. The SNP rs1423096 was further associated with the levels of HDL-C (p = 0.006), the risk of MetS (OR = 2.21, p = 0.0034) and T2DM (OR = 1.62, p = 0.0063) in the CVDFACTS. People with the haplotypes A-G and G-G determined by rs3745367 and rs1423096 showed a significantly increased T2DM risk (p = 0.0068 and p = 0.0035, respectively) compared with those with A-A haplotype. CONCLUSION: We have found that rs3745367 and rs1423096 on the RETN gene were significantly associated with resistin levels. However, rs1423096, downstream of RETN, seems to be associated with MetS and T2DM risk more so than rs3745367. The established genotype-disease association points to a causal association of resistin and T2DM.

Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study.

Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to Taiwanese populations, because they were not validated by the two replication studies. Identification of these genes enriches the collection of hypertension susceptibility genes, thereby shedding light on the etiology of hypertension in Han Chinese populations.

A two-stage matched case-control study on multiple hypertensive candidate genes in Han Chinese.

BACKGROUND: Hypertension affects about 1/3 of adults worldwide, ~3.8 million in Taiwan, 160 million in China, and 1 billion worldwide. It is a major risk factor leading to stroke, cardiovascular disease, and end-stage renal disease. In each year, more than 13.5 million deaths are due to hypertension-related diseases worldwide. METHODS: We performed a two-stage association study of hypertension using genotype data of single-nucleotide polymorphisms (SNPs) from 992 young-onset hypertensive cases and 992 matched controls of Han Chinese in Taiwan. A total of 238 SNPs of 36 highly replicated hypertension candidate genes with functional importance were investigated. Association analysis was carried out using conditional logistic regression. RESULTS: We identified two SNPs that were strongly associated with hypertension in both the first and the second stages. The first SNP (rs2301339) is located at guanine nucleotide-binding protein ß3 subunit (GNB3) and the other one (rs17254521) is located at insulin receptor (INSR). CONCLUSIONS: SNP rs2301339 is perfectly linked in linkage disequilibrium (LD) with C825T (rs5443) which has been associated with hypertension in Caucasian, but inconsistent in Asian populations. However, we found that in our sample this SNP has an opposite effect with the previous findings. In summary, this study identified one novel SNP in GNB3 and one novel SNP in INSR that are strongly associated with young-onset hypertension. Due to relatively small sample size, the results should still be interpreted with caution and need to be replicated in other studies.

A genome-wide association study reveals a quantitative trait locus of adiponectin on CDH13 that predicts cardiometabolic outcomes.

OBJECTIVE: The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community-based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS: The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10(-9)). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10(-17)). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS: These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

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 (-log(10)(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (-log(10)(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.