Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings

Perola, Markus; Kainulainen, Katariina; Pajukanta, Päivi; Terwilliger, Joseph D.; Hiekkalinna, Tero; Ellonen, Pekka; Kaprio, Jaakko; Koskenvuo, Markku; Kontula, Kimmo; Peltonen, Leena

doi:10.1097/00004872-200018110-00008

Cited by 106 publications

(66 citation statements)

References 21 publications

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“…11 A Finnish study based on 47 families of concordant sib pairs (mostly twins) with early-onset hypertension (onset before age 50 years) showed linkage to chromosome 3q (near Type 1 angiotensin II receptor) and suggestive linkage to 2q, 22q, and Xp. 12 Our genome scan shows evidence of linkage, though not significant, supporting previously linked loci on chromosomes 2, 4,8 11, 10 and 17 6 (Table 3). On chromosome 18 our genome scan identifies a locus different from previously reported loci of essential hypertension.…”

Section: Discussionsupporting

confidence: 84%

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Linkage of Essential Hypertension to Chromosome 18q

et al. 2002

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Abstract-We performed a genomewide scan with 904 microsatellite markers using 120 extended Icelandic families with 490 hypertensive patients. The families were identified by cross-matching a list of hypertensive patients from the Hypertension Clinic of the University Hospital (Landspitalinn) in Iceland with a genealogy database of the entire Icelandic nation. After adding 5 markers, we found linkage to chromosome 18q with an allele-sharing LOD score of 4.60 (Pϭ2.1ϫ10 Ϫ6). These results provide evidence for a novel susceptibility gene for essential hypertension on chromosome 18q and show that it is possible to study the genetics of essential hypertension without stratifying by subphenotypes.

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Section: Discussionsupporting

confidence: 84%

“…3 There have been several genomewide linkage scans of familial blood pressure distribution/variation 4 -10 and for essential hypertension. [11][12][13] Here, we report significant linkage to chromosome 18q in our genomewide linkage study of 490 Icelandic hypertensive patients in 120 families.…”

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Linkage of Essential Hypertension to Chromosome 18q

et al. 2002

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“…However, a comparison with linkage scans for resting hemodynamic phenotypes reveals some common chromosomal areas. The submaximal exercise SV and Q training response QTL in chromosome 2q31 in the present study maps to the same region where previous studies have reported QTLs for familial dilated cardiomyopathy (31) and for resting diastolic blood pressure in Old Order Amish (16) and in a geographically defined subgroup of Finnish dizygotic twins (21). The linkage with baseline SV50 and Q50 in chromosome 10p14 coincides with a QTL for arrhythmogenic right-ventricular dysplasia (20) and a linkage region for resting systolic blood pressure in the Quebec Family Study (26).…”

Section: Discussionsupporting

confidence: 72%

Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study

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et al. 2002

Physiological Genomics

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. Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study. Physiol Genomics 10: 57-62, 2002. First published June 5, 2002 10.1152/physiolgenomics.00043.2002A genome-wide linkage scan was performed for genes affecting submaximal exercise cardiac output (Q) and stroke volume (SV) in the sedentary state and their responses to a standardized 20-wk endurance training program. A total of 509 polymorphic markers were used, and 328 pairs of siblings from 99 white nuclear families and 102 sibling pairs from 105 black family units were available. Q and SV were measured in relative steady state during exercise at 50 W (Q50 and SV50, respectively). Baseline phenotypes were adjusted for age, sex, and body surface area (BSA), and the training responses (post-training Ϫ baseline, ⌬) were adjusted for age, sex, baseline BSA, and baseline value of the phenotype. Three analytical strategies were used: a multipoint variance components linkage analysis using all the family data, and regression-based single-and multipoint linkage analyses using pairs of siblings. In whites, baseline SV50 and ⌬SV50 showed promising linkages (P Ͻ 0.0023) with markers on chromosomes 14q31.1 and 10p11.2, respectively. Suggestive evidence of linkage (0.01 Ͼ P Ͼ 0.0023) for ⌬SV50 and ⌬Q50 was detected on chromosome 2q31.1 and for baseline SV50 and Q50 on chromosome 9q32-q33. In blacks, markers on 18q11.2 showed promising linkages with baseline Q50. Suggestive evidence of linkage was found in three regions for baseline SV50 (1p21.3, 3q13.3, 12q13.2) and one for baseline SV50 and Q50 (10p14). All these chromosomal regions include several potential candidate genes and therefore warrant further studies in the HERITAGE cohort and other studies. genomic scan; exercise training; linkage analysis THE COMPLETION of the Human Genome Project holds great promise for the development of new insights into biological mechanisms contributing to interindividual differences in responsiveness to acute exercise and exercise training. It has been reported that genetic factors account for a significant proportion of variability in exercise-related phenotypes, such as maximal oxygen uptake (VO 2 max ) and exercise blood pressure, both in the sedentary state and in response to endurance training (2, 4-6). Identification of the genes and mutations responsible for these genetic effects would lead to a better understanding of the biology of adaptation to exercise and, ultimately, enable individualized prescription of exercise training for performance enhancement and for prevention and treatment of several public health problems.Exercise-related phenotypes are typically multifactorial, i.e., they are affected by both environmental and genetic factors. The genetic effect is usually polygenic, i.e., it is determined by a combination of several individual genes, each having a small to moderate effect. Moreover, potential gene-gene and gene-environment interactions further complicate the dissection of the phenotypic variance. Genome-wide linkag...

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“…30 However, no reported information has suggested a relationship between the (P)RR and hypertension in humans. Recently, a population study showed a significant association between (P)RR gene polymorphisms and blood pressure levels in 1112 Japanese subjects.…”

Section: Genetic Analyses In Population Studiesmentioning

confidence: 99%

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

et al. 2009

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Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and blood pressure levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries. However, recent studies have shown that the (P)RR is divided into its soluble form and a residual hydrophobic part, which includes ATPase 6 associated protein 2, within cells. Therefore, the (P)RR may have a more complex function than previously thought. In addition, the physiological roles of the (P)RR remain undetermined, because the construction of (P)RR null mice has not been successful. As a next step for research in this area, a method for determining the soluble (P)RR levels in plasma and urine and the construction of tissue-specific (P)RR-knockout mice are needed to elucidate the roles of the (P)RR in physiology and pathophysiology. Hypertension Research (2010) 33, 177-180; doi:10.1038/hr.2009 published online 18 December 2009 Keywords: angiotensin; ATP6ap2; handle region peptide; prorenin; vacuolar H + -ATPase INTRODUCTIONThe pathophysiological roles of the (pro)renin receptor ((P)RR) are a growing concern because numerous experimental studies conducted since this receptor was first discovered in 2002 1 have suggested that the pro(renin) receptor has its own intracellular signaling pathways and is involved in the tissue renin-angiotensin system. However, the clinical relevance of the human (P)RR remains uncertain because only a few clinical studies examining the (P)RR have been performed. In this review article of previous studies and new findings, we attempt to elucidate the possible role of the (P)RR in humans. SUGGESTIONS FROM IN VITRO STUDIESThe (P)RR was first reported to be capable of binding both renin and prorenin in vitro. 1 However, Batenburg et al. 2 showed that prorenin, but not renin, was capable of binding to the (P)RR in cultured vascular smooth muscle cells, suggesting that prorenin is an endogenous agonist of the (P)RR. In addition, Nabi et al. 3 provided clear evidence that receptor-bound prorenin gains 'renin activity' without undergoing the proteolytic cleavage of the prosegment of prorenin as a result of a conformational change, although the enzymatic activity of receptor-bound renin is similar to that of free renin. On the basis of these findings, renin may be an endogenous inhibitor for the binding of prorenin to the (P)RR.Stimulation of the (P)RR by renin and prorenin reportedly results in the activation of intracellular signaling pathways, including MAP kinases, in mesangial cells, 4-6 vascular smooth muscle cells, 7 cardiomyocytes 8 and renal tubular epithelial cells. 9 However, the significance of the (P)RR-dependent intracellular signals in vivo remains undetermined. SUGGESTIONS FROM ANIMAL MODELS OF DIAB...

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Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings

Abstract: Our results establish the role of the AT1 locus, on a genome-wide scale, as a major contributing locus to essential hypertension in this study sample.

Cited by 106 publications

References 21 publications

Linkage of Essential Hypertension to Chromosome 18q

Linkage of Essential Hypertension to Chromosome 18q

Genome-wide linkage scan for exercise stroke volume and cardiac output in the HERITAGE Family Study

Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings

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