An Updated Meta-Analysis of Genome Scans for Hypertension and Blood Pressure in the NHLBI Family Blood Pressure Program (FBPP)

Wu, Xiaodong; Kan, Donghui; Province, Michael A.; Quertermous, Thomas; Rao, D. C.; Chang, Christy; Mosley, Thomas H.; Curb, David; Boerwinkle, Eric; Cooper, Richard S.

doi:10.1016/j.amjhyper.2005.07.010

Cited by 35 publications

(27 citation statements)

References 14 publications

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“…Although hypertension demonstrates significant familial aggregation, genomewide linkage studies have not provided consistent results, and in general the strength of various associations between putative loci of interest and blood pressure has been modest. 15 At the same time, strong evidence supports the notion of environmental inputs into the subsequent development of hypertension, including overweight and elevated salt intake. 16 In this context, acute intervention studies indicate that L-arginine may influence blood pressure.…”

Section: Discussionmentioning

confidence: 79%

Identification of a Novel Polymorphism in the 3′UTR of the l -Arginine Transporter Gene SLC7A1

et al. 2007

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Background-Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension. We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism. Methods and Results-We have identified a novel C/T polymorphism in the 3ЈUTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, yϩ system), member 1 gene (SLC7A1). The minor T allele significantly attenuates reporter gene expression (PϽ0.01) and is impaired in its capacity to form DNA-protein complexes (PϽ0.05). In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects (PϽ0.001). Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives (PϽ0.001). To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing L-arginine transporter SLC7A1. The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (Ϫlog EC 50 for wild-type versus Slc7A1 transgenic: 6.87Ϯ0.10 versus 7.56Ϯ0.13; PϽ0.001). This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells. Conclusions-The present study identifies a key, functionally active polymorphism in the 3ЈUTR of SLC7A1. As such, this polymorphism may account for the apparent link between altered endothelial function, L-arginine, and nitric oxide metabolism and predisposition to essential hypertension.

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Section: Discussionmentioning

confidence: 79%

Identification of a Novel Polymorphism in the 3′UTR of the l -Arginine Transporter Gene SLC7A1

et al. 2007

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“…In the same metaanalysis, OFS WCT HR and ΔWCT LVET overlaps with a locus on chromosome 3 for EH+DBP and EH+SBP and EH with significant LOD scores ranging from 3.3-4.69 (Koivukoski et al, 2004). In another meta-analysis, OFS WCT HR and ΔWCT LVET and ΔCPT IC overlaps with EH+DBP and EH+SBP on the same chromosome and locus of the later study (Wu et al, 2006). On chromosome 7, OFS CPT SV overlaps with a locus for DBP and also on chromosome 10, OFS ΔCPT TPR overlaps with a locus for DBP in Nigerian families (Cooper et al, 2002).…”

Section: Figurementioning

confidence: 88%

Genome-Wide Linkage Analysis of Hemodynamic Parameters Under Mental and Physical Stress in Extended Omani Arab Pedigrees: The Oman Family Study

Hassan¹,

Jaju

Voruganti

et al. 2011

Twin Res Hum Genet

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Background:We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests.Methods:The Oman Family Study subjects (N= 1277) were recruited from five extended families of ~10 generations. Hemodynamic phenotypes were computed from beat-to-beat BP, electrocardiography and impedance cardiography. Multi-point linkage was performed for resting, mental (word conflict test, WCT) and cold pressor (CPT) stress and their reactivity scores (s), using variance components decomposition-based methods implemented in SOLAR.Results:Genome-wide scans for BP phenotypes identified quantitative trait loci (QTLs) with significant evidence of linkage on chromosomes 1 and 12 for WCT-linked cardiac output (LOD = 3.1) and systolic BP (LOD = 3.5). Evidence for suggestive linkage for WCT was found on chromosomes 3, 17 and 1 for heart rate (LOD = 2.3), DBP (LOD = 2.4) and left ventricular ejection time (LVET), respectively. For △WCT, suggestive QTLs were detected for CO on chr11 (LOD = 2.5), LVET on chr3 (LOD = 2.0) and EDI on chr9 (LOD = 2.1). For CPT, suggestive QTLs for HR and LVET shared the same region on chr22 (LOD 2.3 and 2.8, respectively) and on chr9 (LOD = 2.3) for SBP, chr7 (LOD = 2.4) for SV and chr19 (LOD = 2.6) for CO. For △CPT, CO and TPR top signals were detected on chr15 and 10 (LOD; 2.40, 2.08) respectively. Conclusion: Mental stress revealed the largest number of significant and suggestive loci for normal BP reported to date. The study of BP and its intermediate phenotypes under mental and physical stress may help reveal the genes involved in the pathogenesis of essential hypertension.

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“…Metaanalysis, whereby information from several independent studies is combined to obtain a consensus value for linkage (or association), is one method to overcome the limited statistical power inherent in genome-wide linkage analysis. There has been much international co-operation between research groups to enable this for body mass index [44], T2D [45,46], hypertension [47], schizophrenia [48], bipolar disorder [49], inflammatory bowel disease [50], osteoporosis [51], T1D [52], systemic lupus erythematosus [53], RA [54], ankylosing spondylitis [55], psoriasis [56], multiple sclerosis [57], autism [58] and heart disease [59]. Whilst the success of the positional candidate approach (that is, identification of disease-associated genes within regions of linkage) rivals that of the candidate gene approach, it is fair to say that the number of common disease genes identified by genome-wide linkage analysis has not met expectations.…”

Section: 25mentioning

confidence: 99%

The human genome and understanding of common disease: present and future technologies

McKinney

Merriman

2007

Cell. Mol. Life Sci.

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The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual's disease still remains a challenge.

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An Updated Meta-Analysis of Genome Scans for Hypertension and Blood Pressure in the NHLBI Family Blood Pressure Program (FBPP)

Cited by 35 publications

References 14 publications

Identification of a Novel Polymorphism in the 3′UTR of the l -Arginine Transporter Gene SLC7A1

Identification of a Novel Polymorphism in the 3′UTR of the l -Arginine Transporter Gene SLC7A1

Genome-Wide Linkage Analysis of Hemodynamic Parameters Under Mental and Physical Stress in Extended Omani Arab Pedigrees: The Oman Family Study

The human genome and understanding of common disease: present and future technologies

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