Dataset Information

Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

ABSTRACT: Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with a high resolution SNP array. Following stringent filtering criteria, we identified 208 rare, or private CNVs that were only present in our patients with hypertension related LVH. Preliminary findings from Gene Ontology and pathway analysis of this study confirmed the involvement of the genes known to be functionally involved in cardiac development and phenotypes, in line with previously reported transcriptomic studies. Network enrichment analyses suggested that the gene-set was, directly or indirectly, involved in the transcription factors regulating the "foetal cardiac gene programme" which triggered the hypertrophic cascade, confirming previous reports. These findings suggest that multiple, individually rare copy number variants altering genes may contribute to the pathogenesis of hypertension-related LVH. In summary, we have provided further supporting evidence that rare CNV could potentially impact this common and complex disease susceptibility with lower heritability.

SUBMITTER: Boon-Peng H

PROVIDER: S-EPMC4773219 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

Boon-Peng Hoh H Mat Jusoh Julia Ashazila JA Marshall Christian R CR Majid Fadhlina F Danuri Norlaila N Basir Fashieha F Thiruvahindrapuram Bhooma B Scherer Stephen W SW Yusoff Khalid K

PloS one 20160301 3

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with ...[more]

PMID: 26930585

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Project description:Copy number variations (CNVs) can contribute to variable degrees of fitness and/or disease predisposition. Recent studies show that at least 1% of any given genome is copy number variable when compared to the human reference sequence assembly. Homozygous deletions (or CNV nulls) that are found in the normal population are of particular interest because they may serve to define non-essential genes in human biology.In a genomic screen investigating CNV in Autism Spectrum Disorders (ASDs) we detected a heterozygous deletion on chromosome 10p12.1, spanning the Patched-domain containing 3 (PTCHD3) gene, at a frequency of ~1.4% (6/427). This finding seemed interesting, given recent discoveries on the role of another Patched-domain containing gene (PTCHD1) in ASD. Screening of another 177 ASD probands yielded two additional heterozygous deletions bringing the frequency to 1.3% (8/604). The deletion was found at a frequency of ~0.73% (27/3,695) in combined control population from North America and Northern Europe predominately of European ancestry. Screening of the human genome diversity panel (HGDP-CEPH) covering worldwide populations yielded deletions in 7/1,043 unrelated individuals and those detected were confined to individuals of European/Mediterranean/Middle Eastern ancestry. Breakpoint mapping yielded an identical 102,624 bp deletion in all cases and controls tested, suggesting a common ancestral event. Interestingly, this CNV occurs at a break of synteny between humans and mouse. Considering all data, however, no significant association of these rare PTCHD3 deletions with ASD was observed. Notwithstanding, our RNA expression studies detected PTCHD3 in several tissues, and a novel shorter isoform for PTCHD3 was characterized. Expression in transfected COS-7 cells showed PTCHD3 isoforms colocalize with calnexin in the endoplasmic reticulum. The presence of a patched (Ptc) domain suggested a role for PTCHD3 in various biological processes mediated through the Hedgehog (Hh) signaling pathway. However, further investigation yielded one individual harboring a homozygous deletion (PTCHD3 null) without ASD or any other overt abnormal phenotype. Exon sequencing of PTCHD3 in other individuals with deletions revealed compound point mutations also resulting in a null state.Our data suggests that PTCHD3 may be a non-essential gene in some humans and characterization of this novel CNV at 10p12.1 will facilitate population and disease studies.

Project description:BackgroundLeft ventricular hypertrophy (LVH) strongly predicts cardiovascular diseases (CVD) and death. One-fourth of Thai adults suffer from hypertension. Nevertheless, the information on LVH among Thai patients with hypertension is not well characterized. We aimed to identify the prevalence and factors associated with electrocardiographic LVH (ECG-LVH) among patients with hypertension in Thailand.MethodsThe present study obtained the dataset from the Thailand Diabetes Mellitus/Hypertension study, which included hypertension patients aged 20 years and older receiving continuous care at outpatient clinics in hospitals nationwide in 2011-2015 and 2018. Meanwhile, those without a record of 12-lead electrocardiography (ECG) were excluded from the analysis. ECG-LVH was defined as the LVH noted regarding ECG interpretation in the medical records. Multivariable logistic regression analysis was utilized for determining factors associated with ECG-LVH and presented as the adjusted odds ratio (AOR) and 95% confidence interval (CI).ResultsFrom 226,420 hypertensive patients in the Thailand Diabetes Mellitus/Hypertension study, 38,807 individuals (17.1%) with ECG data recorded were included in the analysis. The mean age was 64.8 ± 11.5 years, and 62.2% were women. Overall, 1,557 study participants had ECG-LVH, with an estimated prevalence of 4.0% (95% CI, 3.8-4.2%). Age-adjusted ECG-LVH prevalence among women and men was 3.4 and 5.1%, respectively (P < 0.001). Multivariable analysis determined factors associated with ECG-LVH, including being men (AOR, 1.49; 95% CI, 1.31-1.69), individuals aged 70 to 79 years (AOR, 1.56; 95% CI, 1.20-2.02) and ≥ 80 years (AOR, 2.10; 95% CI, 1.58-2.78) compared to individuals aged less than 50 years, current smokers (AOR, 1.26; 95% CI, 1.09-1.46) compared to those who never smoked, systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg (AOR, 1.58; 95% CI, 1.30-1.92) compared to systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg.ConclusionsThe current study illustrated the prevalence of ECG-LVH among Thai patients with hypertension who had ECG recorded and identified high-risk groups who tended to have ECG-LVH. The findings underscore the need for targeted interventions, particularly among high-risk groups such as older individuals, men, and current smokers, to address modifiable factors associated with ECG-LVH.

Dataset Information

Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

Publications

Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

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