Systematic review of studies that have evaluated screening tests in relatives of patients affected by nonsyndromic thoracic aortic disease

Background Nonsyndromic thoracic aortic diseases (NS‐TADs) are often silent entities until they present as life‐threatening emergencies. Despite familial inheritance being common, screening is not the current standard of care in NS‐TADs. We sought to determine the incidence of aortic diseases, the predictive accuracy of available screening tests, and the effectiveness of screening programs in relatives of patients affected by NS‐TADs. Methods and Results A systematic literature search on PubMed/MEDLINE, Embase, and the Cochrane Library was conducted from inception to the end of December 2017. The search was supplemented with the Online Mendelian Inheritance in Man database. A total of 53 studies were included, and a total of 2696 NS‐TAD relatives were screened. Screening was genetic in 49% of studies, followed by imaging techniques in 11% and a combination of the 2 in 40%. Newly affected individuals were identified in 33%, 24%, and 15% of first‐, second‐, and third‐degree relatives, respectively. Familial NS‐TADs were primarily attributed to single‐gene mutations, expressed in an autosomal dominant pattern with incomplete penetrance. Specific gene mutations were observed in 25% of the screened families. Disease subtype and genetic mutations stratified patients with respect to age of presentation, aneurysmal location, and aortic diameter before dissection. Relatives of patients with sporadic NS‐TADs were also found to be affected. No studies evaluated the predictive accuracy of imaging or genetic screening tests, or the clinical or cost‐effectiveness of an NS‐TAD screening program. Conclusions First‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs

Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis

Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC Background: Bicuspid aortic valve is the most common congenital valvular heart defect in the general population. BAV is associated with significant morbidity due to valve failure, formation of thoracic aortic aneurysm, and increased risk of infective endocarditis and aortic dissection. Loss of function mutations in NOTCH1 (OMIM 190198) has previously been associated with congenital heart disease involving the aortic valve, left ventricle outflow tract, and mitral valve that segregates in affected pedigrees as an autosomal dominant trait with variable expressivity. Methods: We performed whole-exome sequencing in four members of a three-generational family (three affected and one unaffected subject) with clinical phenotypes including aortic valve stenosis, thoracic aortic aneurysm, and ventricular septal defect. Results: We identified 16 potentially damaging genetic variants (one stop variant, one splice variant, and 14 missense variants) cosegregating with the phenotype. Of these variants, the nonsense mutation (p.Tyr291*) in NOTCH1 was the most deleterious variant identified and the most likely variant causing the disease. Conclusion: Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by the heterogeneity of clinical phenotype

Analysis of gene-gene interactions among common variants in candidate cardiovascular genes in coronary artery disease.

OBJECTIVE: Only a small fraction of coronary artery disease (CAD) heritability has been explained by common variants identified to date. Interactions between genes of importance to cardiovascular regulation may account for some of the missing heritability of CAD. This study aimed to investigate the role of gene-gene interactions in common variants in candidate cardiovascular genes in CAD. APPROACH AND RESULTS: 2,101 patients with CAD from the British Heart Foundation Family Heart Study and 2,426 CAD-free controls were included in the discovery cohort. All subjects were genotyped with the Illumina HumanCVD BeadChip enriched for genes and pathways relevant to the cardiovascular system and disease. The primary analysis in the discovery cohort examined pairwise interactions among 913 common (minor allele frequency >0.1) independent single nucleotide polymorphisms (SNPs) with at least nominal association with CAD in single locus analysis. A secondary exploratory interaction analysis was performed among all 11,332 independent common SNPs surviving quality control criteria. Replication analyses were conducted in 2,967 patients and 3,075 controls from the Myocardial Infarction Genetics Consortium. None of the interactions amongst 913 SNPs analysed in the primary analysis was statistically significant after correction for multiple testing (required P 1.7 for common variants in the primary analysis. CONCLUSIONS: Moderately large additive interactions between common SNPs in genes relevant to cardiovascular disease do not appear to play a major role in genetic predisposition to CAD. The role of genetic interactions amongst less common SNPs and with medium and small magnitude effects remain to be investigated

Urotensin-II System in Genetic Control of Blood Pressure and Renal Function

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates

Suggestive SNP-SNP interactions—primary analysis.

<p>SNP: single nucleotide polymorphism, Chr: chromosome; MAF: minor allele frequency; BHF-FHS: British Heart Foundation Family Heart Study; MIGen: Myocardial Infarction Genetics Consortium; SNPA Pvalue: level of nominal statistical significance for single marker association with coronary artery disease for SNP A; SNPB Pvalue: level of nominal statistical significance for single marker association with coronary artery disease for SNP B; Int. Pvalue BHF-FHS: interaction P value in BHF-FHS; Int. Pvalue MIGen: interaction P value in MIGen; N/A: replication not available. PDE11A: phosphodiesterase 11A; SEC1P: secretory blood group 1, pseudogene; SERPINA12: serpin peptidase inhibitor, clade A; SRI: sorcin; ZHX2: zinc fingers and homeoboxes 2; NR5A2: nuclear receptor subfamily 5, group A, member 2; ANGPTL4: angiopoietin-like 4; NRG3: neuregulin 3; RPSAP15: ribosomal protein SA pseudogene 15; CSRP3: cysteine and glycine-rich protein 3; GSTM3: glutathione S-transferase mu 3; RYR2: ryanodine receptor 2; TBXAS1: thromboxane A synthase 1; TAC1: tachykinin, precursor 1; P2RX4: purinergic receptor P2X, ligand-gated ion channel, 4; SCARB2: scavenger receptor class B, member 2; NOD1: nucleotide-binding oligomerization domain containing 1; PDGFD: platelet derived growth factor D.</p><p>Suggestive SNP-SNP interactions—primary analysis.</p

Baseline Characteristics of cases in the British Heart Foundation-Family Heart Study and the Myocardial Infarction Genetics studies.

<p>Data are means and standard deviations or counts and percentages, BHF-FHS: British Heart Foundation Family Heart Study; MIGen: Myocardial Infarction Genetics Consortium; MI: myocardial infarction; BMI: body mass index.</p><p>Baseline Characteristics of cases in the British Heart Foundation-Family Heart Study and the Myocardial Infarction Genetics studies.</p

A schematic illustration of SNP selection process for the primary analysis.

<p>A schematic illustration of SNP selection process for the primary analysis.</p

SNP selection process for the secondary analysis.

<p>SNP selection process for the secondary analysis.</p

Renal expression of Urotensin-II pathway genes.

<p>Upper panel - linear correlations in renal expression (dCT) of UTS2, UTS2D, and UTS2R (r – correlation coefficient, p – level of statistical significance). Lower panel - comparison of UTS2, UTS2D and UTSR expression between normotensive (bright grey) and hypertensive (dark grey) kidneys (p-values from multiple regression adjusted for age, sex and cohort of origin).</p

Urotensin-II pathway genes and hypertension.

<p>Figure present structure of UTS2, UTS2D and UTS2R genes - linkage disequilibrium (LD) map based on r² coefficients [intensity of colour: r² = 1 – maximal LD (dark red), r² = 0 – no LD (white)] in the GRPAHIC Study.</p