SummaryBackgroundA sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.MethodsWe genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.FindingsOf nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.InterpretationThe human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.FundingBritish Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
Abstract-Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains Ϸ50 000 single nucleotide polymorphisms in Ͼ2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (Pϭ1.2ϫ10 Ϫ8 ). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (Pϭ5.4ϫ10 Ϫ6 ). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: Ͻ0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure. (Hypertension. 2010;56:1069-1076.) • Online Data Supplement Key Words: gene Ⅲ genetics Ⅲ blood pressure Ⅲ single nucleotide polymorphism Ⅲ association Ⅲ heritability R aised blood pressure (BP) is the single most important risk factor for cardiovascular diseases worldwide. 1 BP is a complex trait with significant heritability. [2][3][4] However, a majority of the causative genes and related molecular mechanisms remains largely unknown. Recent candidate gene studies and the first genome-wide association scans (GWAS) have revealed that at least a fraction of BP-associated genes map to functionally and/or clinically important signaling cascades of cardiovascular regulation. [5][6][7][8][9] This indicates that BP gene discovery may be greatly facilitated by large-scale systematic analysis of variants in pathways of cardiovascular regulation. The recently developed Illumina HumanCVD BeadChip, herewith called the 50K IBC array, permits simultaneous genotyping of Ϸ50 000 common and lowfrequency single nucleotide polymorphisms (SNPs) in Ͼ2000 candidate genes and loci with the highest functional relevance Received Apr...
Background-Early repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. The determinants of ER are unknown. We investigated its heritability in a large, family-based cohort. Methods and Results-The study sample comprised 1877 individuals from 505 white nuclear families representative of the British general population. Standard 12-lead ECGs were evaluated for the presence of ER, defined as J-point elevation of Ն0.1 mV in at least 2 adjacent inferior (II, III, and aVF) or anterolateral (I, aVL, and V 4 through V 6 ) leads. Narrow sense heritability estimates were computed adjusting for age, age 2 , and sex. The prevalence of ER was 7.7% (nϭ145) in the whole cohort, 5.9% (nϭ56) in parents, and 9.6% (nϭ89)
The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65310 25) and diastolic BP (P=7.61310 23) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0310 23). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP. Essential hypertension is a net product of genetic factors and environmental exposure acting together on regulatory systems in key organs for BP homeostasis. The kidney is central to BP regulation and drives the development of hypertension through numerous mechanisms including glomerular hemodynamics, tubular reabsorption of sodium, actions of the renin-angiotensin system, and natriuretic peptides. 1 Rare genetic variants that affect expression of molecules and pathways operating within the kidney lead to elevated BP in monogenic forms of hypertension. 2 Several common variants in genes associated with BP and/or susceptibility to hypertension are also believed to act through the
Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10(-9)). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4-1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10(-7)). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10(-33)). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity-subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.
BackgroundNonsyndromic 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 ResultsA 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.ConclusionsFirst‐ and second‐degree relatives of patients affected by both familial and sporadic NS‐TADs may benefit from personalized screening programs.
Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P ϭ 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5-and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P ϭ 0.04 and P ϭ 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. 22: 947-955, 201122: 947-955, . doi: 10.1681 Essential hypertension is a complex, multifactorial, heritable disease. The contribution of genetic factors to the development of hypertension is estimated at 30 to 50%, but the causative alleles and related molecular mechanisms remain largely elusive. However, it is becoming increasingly clear that genes underlying familial susceptibility to essential hypertension may not necessarily reside within the most obvious pathways involved in BP regulation. 1 Indeed, a substantial proportion of novel alleles associated with hypertension and BP in the recent genome-wide association scans map to genes that do not belong to classical systems of BP regulation (such as the sympathetic nervous system or renal sodium handling). 2,3 Fibroblast growth factor (FGF) family is an example of a novel group of mole- J Am Soc Nephrol
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