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Fadi J Charchar

Publications and source records attributed to Fadi J Charchar.

At least 19 recordsLinked to original sources
PubMed2007

Studies of an association in boys of blood pressure and the Y chromosome.

BACKGROUND: Variations in the Y chromosome have shown significant, albeit inconsistent, associations with hypertension in men. Studies of peripubertal subjects might reveal more information on the origins of the Y chromosome's influence on blood pressure (BP). In the current study, we examined the association of a HindIII restriction site on the Y chromosome with BP in a cohort of young men. METHODS: Pubertal growth-based analyses were performed in 80 unrelated males with multiple measurements spanning time points beginning before and extending to after their pubertal growth. Blood pressure, height, and weight were measured approximately every 6 months. The period of pubertal growth was used to approximate the time for puberty. The association of the HindIII restriction site to systolic and diastolic BP was determined using a mixed model ANOVA. RESULTS: Estimated systolic and diastolic BPs were higher in HindIII(-) males in the period before, as well as in the period after pubertal growth (systolic BP 2.6 +/- 1.3 mm Hg higher, P < .05), and diastolic BP 2.3 +/- 1.2 mm Hg higher, P = .050). In addition, HindIII(-) males were younger at onset of peak height velocity (12.7 +/- 0.1 v 13.3 +/- 0.1 years, P < .001). In African Americans, an earlier age of maximal height velocity was associated with a higher systolic and diastolic BP (P < .05 and .02, respectively). CONCLUSIONS: The results suggest that variations in genes on the Y chromosome may affect BP in peripubertal males, possibly even before onset of puberty.

Adolescent↗
PubMed2006

Genetic information in the diagnosis and treatment of hypertension.

Advancement in cardiovascular science should be measured by a number of new diagnostic and therapeutic options applied in clinical practice as a result of translational research. Hypertension genetics is a good example of such a successful transfer of knowledge from bench to bedside. There are genetic methods currently used as diagnostic tools in patients presenting with secondary forms of hypertension, including primary hyperaldosteronism, Cushing's syndrome, pheochromocytoma, and chronic kidney disease. Directed treatment that corrects pathophysiologic abnormalities is available for several monogenic forms of hypertension as a result of uncovering their underlying genetic mechanisms. Progress in hypertension pharmacogenetics and pharmacogenomics brings closer a perspective of personalized antihypertensive treatment and gene transfer strategies, which, although still considered as innovative approaches, may soon become options to treat, control, and, possibly, cure hypertension.

Adrenocortical Hyperfunction↗
PubMed2005

Corcoran Lecture. Cardiovascular genomics and oxidative stress.

The majority of modifiable cardiovascular risk factors are complex, polygenic, or at least oligogenic traits, with genetic and environmental determinants playing important roles in disease risk and its phenotypic expression. The Human Genome Project and subsequent mouse and rat genome data have provided powerful tools to commence the dissection of genetic determinants of hypertension and other cardiovascular risk factors. Despite several new methodologies such as genome-wide scans, genome-wide gene expression profiling, and proteomic screens, it is fair to say that the progress of genetic studies designed as nonhypothesis driven has been relatively slow. On the other hand, several interesting candidate pathways have been identified, where investigators allowed for hypothesis-driven functional studies. One example of such pathway is vascular oxidative stress with its extensive network of genes and proteins, many with proven contributions to cardiovascular disease. Therefore, in parallel to genome-wide or proteome-wide studies, it will be constructive to pursue "pathwayomics" defined here as functional studies of a candidate pathway for disease pathogenesis.

Animals↗
PubMed2005

Genetic determinants of metabolic syndrome components in the stroke-prone spontaneously hypertensive rat.

OBJECTIVE: The metabolic syndrome is a complex multifactorial disease, which results from interactions between genes on multiple chromosomes and environmental factors. Animal models may facilitate genetic analysis of complex phenotypes by allowing complete control of environmental conditions and the ability to produce designer strains. METHODS: Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rat strains were used to construct congenic (SP.WKYGla2a), consomic (SP.WKYGlaYw, WKY.SPGlaYs) and double-introgressed (SP.WKYGla2aYw) strains, which were characterized for metabolic syndrome phenotypes (systolic blood pressure, glucose tolerance and lipid profile) after feeding a 60% fructose diet for 14 days. RESULTS: The Y consomic strain (SP.WKYGlaYw) demonstrated that the WKY Y chromosome significantly lowered triglyceride levels (3.77 +/- 0.60 versus 9.09 +/- 1.47 mmol/l; P < 0.001) and improved glucose tolerance [area under the curve (AUC): 26.93 +/- 0.81 versus 31.47 +/- 0.89; P < 0.05] compared with SHRSP. The chromosome 2 congenic strain (SP.WKYGla2a) exhibited significantly improved glucose tolerance (AUC: 28.19 +/- 1.17 versus 31.47 +/- 0.89; P < 0.05) and lower systolic blood pressure (161.2 +/- 6.2 versus 179.7 +/- 3.9 mmHg; P < 0.05) compared with SHRSP. 2 x 2 factorial ANOVA identified a significant interaction for glucose metabolism (P = 0.004) in the double-introgressed strain (SP.WKYGla2aYw) between chromosome 2 and Y. CONCLUSIONS: These results identify novel interacting regions on chromosome 2 and the Y chromosome influencing a cluster of metabolic and cardiovascular phenotypes. Translation to clinical studies will facilitate genetic dissection of human metabolic syndrome.

Animals↗
PubMed2004

Epistatic interaction between beta2-adrenergic receptor and neuropeptide Y genes influences LDL-cholesterol in hypertension.

Beta2-adrenergic receptor gene and neuropeptide Y gene may potentially influence lipid metabolism and overall energy balance. Therefore, we examined associations of these genes with lipid fractions and obesity-related phenotypes in hypertensive subjects. A total of 638 white individuals from 212 Polish families with clustering of essential hypertension were phenotyped for cardiovascular risk determinants. Each subject was genotyped for functional polymorphisms of beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu) and neuropeptide Y (Leu7Pro). Of 3 common haplotypes of beta2-adrenergic receptor gene, Arg16Gln27 was overtransmitted to offspring with elevated levels of total cholesterol (Z=2.2; P=0.026) and LDL-cholesterol (Z=3.2; P=0.002). Individually, Leu7Pro was not associated with any of the metabolic phenotypes in family-based tests or case-control analyses. However, in the presence of Arg allele of Arg16Gly and Gln allele of Gln27Glu, homozygosity for Leu variant of the Leu7Pro polymorphism was associated with 2.1-increased odds ratio (confidence interval, 1.10 to 3.81; P=0.024) of elevated LDL in hypertensive subjects, independent of age, gender, body mass index, adjusted blood pressures, antihypertensive therapy, and use of nonselective beta-blockers and diuretics. Consistently, there was a significant multilocus association among variants of Arg16Gly, Gln27Glu, and Leu7Pro in hypertensive probands with elevated LDL (cases; P=0.028) but not in hypertensive subjects with normal LDL (controls). This study revealed an association of LDL-cholesterol with beta2-adrenergic receptor gene haplotype and provided evidence for epistatic interaction between beta2-adrenergic receptor gene and neuropeptide Y gene in determination of LDL-cholesterol in patients with essential hypertension.

Cholesterol, LDL↗
PubMed2004

Serum C-reactive protein and lipids in ultra-Marathon runners.

In this investigation, we compared lipid and inflammatory parameters in regular long distance runners with matched sedentary controls. Long distance runners had significantly lower low-density lipoprotein cholesterol and C-reactive protein levels than the control group. This exercise-induced reduction in low-density lipoprotein cholesterol was independent of the decrease in C-reactive protein levels.

Adult↗
PubMed2004

Functional genomics in rodent models of hypertension.

Inbred strains of rodents have been used to study mammalian physiology and pathophysiology in an attempt to understand the contribution of genes in the pathogenesis of the disease process. In this review we focus on experimental animal models to identify quantitative trait loci (QTL) and possible strategies for identifying underlying genetic determinants responsible for hypertension. Confirmation of the existence of the QTL and dissection of the implicated region can be undertaken by production of either recombinant inbred, consomic or congenic strains. Despite complex interactions and the relatively few confirmed causative genes underlying QTL, recent developments in rat genome resources and advancement in statistical and bioinformatic methods will facilitate the identification of major gene(s) responsible for complex, polygenic traits.

Animals↗
PubMed2003

Association of the human Y chromosome with cholesterol levels in the general population.

OBJECTIVE: Males are at higher risk of cardiovascular diseases than females. The aim of the study was to test whether the potential of the Y chromosome to affect cardiovascular risk could be attributed to its influence on lipids. METHODS AND RESULTS: 1288 Polish men (1157 subjects from young healthy cohort and 131 individuals from middle-aged hypertensive population) were phenotyped for determinants of cardiovascular risk including BMI, blood pressures, lipids, and testosterone. Each subject was genotyped for the HindIII(+/-) polymorphism within the nonrecombining region of the Y chromosome. Men with the HindIII(-) variant exhibited significantly higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels than subjects with the HindIII(+) genotype in both populations. The differences between the genotypes were 0.15 mmol/L (P=0.0107) and 0.45 mmol/L (P=0.0377) in TC and 0.15 mmol/L (P=0.0059) and 0.41 mmol/L (P=0.0432) in LDL among young apparently healthy men and middle-aged hypertensive men, respectively. The HindIII(+) was associated with a significant increase in blood pressure of the middle-aged men. Testosterone serum concentrations correlated positively with HDL-cholesterol levels, and this association was independent of the Y chromosome. CONCLUSIONS: The results indicate that a locus/loci on the Y chromosome may influence LDL levels, independent of testosterone levels.

Adult↗
PubMed2003

Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity: how low can you go?

OBJECTIVE: This study was undertaken to evaluate to what extent C-reactive protein (CRP) can be reduced by exercise by examining its circulating concentrations in male ultramarathon runners and to determine if low leptin as a robust circulating marker of fat mass could account for low CRP in such men. METHODS AND RESULTS: Sixty-seven male ultramarathon runners and 63 sedentary male controls of similar age and body mass index were recruited. CRP and leptin were measured by ELISA and radioimmunoassay, respectively. Median CRP concentration in lean (body mass index <25 kg/m2) marathon runners was less than half control median (0.4 [0.2 to 0.9] mg/L versus 0.9 [0.5 to 2.7] mg/L, P=0.0013) and, more strikingly, in nonlean runners was approximately 26% of control median (0.4 [0.3 to 0.8] mg/L versus 1.5 [0.9 to 2.5] mg/L, P=0.0002). Circulating leptin levels were also substantially lower in lean (45% less) and nonlean (63% less, both P<0.0001) ultramarathon runners. However, interleukin-6 levels were not different. Furthermore, leptin adjustment only minimally attenuated the case-control difference in CRP, suggesting that mechanisms other than fat mass reduction contribute to low concentrations of CRP in marathon runners. CONCLUSIONS: This study suggests that circulating CRP concentrations can be markedly suppressed, independently of total adiposity or indeed fat mass, by intense regular physical exercise.

Adult↗
PubMed2003

Comparative and functional analyses of LYL1 loci establish marsupial sequences as a model for phylogenetic footprinting.

Comparative genomic sequence analysis is a powerful technique for identifying regulatory regions in genomic DNA. However, its utility largely depends on the evolutionary distances between the species involved. Here we describe the screening of a genomic BAC library from the stripe-faced dunnart, Sminthopsis macroura, formerly known as the narrow-footed marsupial mouse. We isolated a clone containing the LYL1 locus, completely sequenced the 60.6-kb insert, and compared it with orthologous human and mouse sequences. Noncoding homology was substantially reduced in the human/dunnart analysis compared with human/mouse, yet we could readily identify all promoters and exons. Human/mouse/dunnart alignments of the LYL1 candidate promoter allowed us to identify putative transcription factor binding sites, revealing a pattern highly reminiscent of critical regulatory regions of the LYL1 paralogue, SCL. This newly identified LYL1 promoter showed strong activity in myeloid progenitor cells and was bound in vivo by Fli1, Elf1, and Gata2-transcription factors all previously shown to bind to the SCL stem cell enhancer. This study represents the first large-scale comparative analysis involving marsupial genomic sequence and demonstrates that such comparisons provide a powerful approach to characterizing mammalian regulatory elements.

Amino Acid Sequence↗
PubMed2003

Complex events in the evolution of the human pseudoautosomal region 2 (PAR2).

The 320-kb human pseudoautosomal region 2 (PAR2) at the tips of the long arms of the X and Y chromosomes is thought to have been duplicated onto the Y chromosome recently in primate evolution. The four genes within PAR2 have been proposed to constitute two zones with different base ratios and transcription, one of which was added recently to the X chromosome. To test this hypothesis, we cloned and mapped PAR2 genes in other species, the lemur, the cat, and a marsupial, the tammar wallaby. None of the human PAR2 genes colocalized with human PAR1 genes in the marsupial genome, confirming that the human PAR1 and PAR2 evolved independently. Of the four PAR2 genes, only SYBL1 was located on the X chromosome in all species, including marsupials, so it was part of the ancient X. HSPRY3 localized to the X in all the eutherians, but not marsupial, so it must have been added to the X 80-130 million years ago. CXYorf1 was present on the X in primates and also in mouse, but autosomal in wallaby, suggesting a later addition 70-130 million years ago, and IL9R was on the X only in primate, suggesting addition 60-70 million years ago. The results therefore demonstrate that at least two independent additions were necessary for PAR2 evolution. The present gene order on the human X also requires two inversions. The complicated evolutionary pathway supports the hypothesis that terminal interchromosomal rearrangements are common in regions unpaired at meiosis.

Animals↗
PubMed2002

Microarray analysis of rat chromosome 2 congenic strains.

Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of human essential hypertension, and a number of reproducible blood pressure regulation quantitative trait loci have been found to map to rat chromosome 2. The SP.WKYGla2c* congenic strain was produced by introgressing a region of rat chromosome 2 from the normotensive Wistar Kyoto (WKY) strain into the genetic background of the SHRSP. Systolic and diastolic blood pressures were significantly reduced in the SP.WKYGla2c* compared with the SHRSP parental strain (198/134+/-6.1/3.3 versus 172/120+/-3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013). Genome-wide microarray expression profiling was undertaken to identify differentially expressed genes among the parental SHRSP, WKY, and congenic strain. We identified a significant reduction in expression of glutathione S-transferase mu-type 2, a gene involved in the defense against oxidative stress. Quantitative reverse transcription-polymerase chain reaction relative to a beta-actin standard confirmed the microarray results with SHRSP mRNA at 8.56 x 10(-4) +/-1.6 x 10(-4) compared with SP.WKYGla2c* 3.67 x 10(-3)+/-2.8 x 10(-4) (95% CI -3.9 x 10(-3) to -1.8 x 10(-3); P=0.0034) and WKY 4.03 x 10(-3)+/-5.1 x 10(-4); (95% CI -5.4 x 10(-3) to -8.9 x 10(-4); P=0.027). We also identified regions of conserved synteny, each containing the Gstm2 gene, on mouse chromosome 3 and human chromosome 1.

Animals↗
PubMed2002

Genetic and gender determinants of cerebrovascular disease.

This article reviews genetic studies of stroke, bearing insight into human evidence by using studies on twins as well as on monogenic forms of stroke. Focus will be given to inbred animal models that have been used to improve genetic homogeneity and to control environmental influences. Such animal studies have lead to the identification of quantitative trait loci harboring putative genes for stroke susceptibility and sensitivity. The major strategies for gene identification are discussed. Experimental animal models of stroke have also revealed a sexual dimorphism in stroke susceptibility and sensitivity and this article reviews 2 possible candidates, namely, the Y chromosome and estrogens.

Animals↗
PubMed2002

Genetic aspects of stroke: human and experimental studies.

As one of the leading causes of death within both the developed and developing world, stroke is a worldwide problem. Risk factors can be identified and controlled at the level of lifestyle changes; however, genetic components of stroke have yet to be identified. The identification of such genetic components is critical in the understanding, diagnosis, and treatment of stroke in the future. This review focuses on the genetic determinants of stroke in both human and experimental systems. Mendelian disorders, candidate genes, and twin studies provide evidence for a strong genetic component of stroke. Genome-wide scanning in both human and animal models has led to the identification of regions of the genome that contain genes for stroke susceptibility and sensitivity. Animal models of stroke allow for environmental control and genetic homogeneity, not possible within a human population, and therefore are essential for the dissection of this complex, multifactorial disorder. Future genetic and genomic strategies and their role in ultimate causative gene identification are discussed.

Animals↗
PubMed2002

Essential hypertension and beta2-adrenergic receptor gene: linkage and association analysis.

A region on human chromosome 5 (5q31.1-qter) contains several genes that encode important blood pressure regulators and thus is a good candidate for analysis of linkage and association with hypertension. We recruited 638 individuals from 212 Polish pedigrees with clustering of essential hypertension. These subjects were genotyped for 11 microsatellite markers that span this region to test for linkage to essential hypertension and systolic and diastolic blood pressures. The segment of this region of approximately 7 cM delineated by D5S1480 and D5S500 markers was linked to blood pressures in multipoint analysis. In 2-point analysis, D5S1480--the marker in close proximity to beta2-adrenergic receptor gene--reached the maximal linkage to essential hypertension and adjusted systolic and diastolic blood pressures, implicating this gene as a positional candidate for further association studies. Arg16Gly, Gln27Glu, and Thr164Ile--3 functional single nucleotide polymorphisms within the beta2-adrenergic receptor gene--were tested for association with essential hypertension. None of these polymorphisms showed a significant association with essential hypertension, separately or in the haplotype analysis. This study provided evidence of linkage of 5q31.1-5qter region to essential hypertension in the European population. Moreover, it implicated the chromosomal segment in close proximity to D5S1480 and D5S500. The detailed analysis of 3 single nucleotide polymorphisms does not support the role of the beta2-adrenergic receptor gene as a major causative gene for the detected linkage.

Adult↗
PubMed2002

The Y chromosome effect on blood pressure in two European populations.

Higher blood pressure (BP) in males compared with females is well documented and is thought to be influenced in part by the Y chromosome. To examine whether there is an association between BP and a polymorphic HindIII biallelic marker in the nonrecombining region of the Y chromosome, we genotyped 155 males from a Polish study group and 762 males from a Scottish study group. We also tested for possible interaction between the Y chromosome and a mutation in the steroidogenic factor binding site of the aldosterone synthase gene by genotyping the same group from Scotland. There was no significant difference in age or body mass index between 2 Y chromosome genotypes in both study groups. Men with the HindIII(+) genotype had significantly higher systolic and diastolic pressures than those with the HindIII(-) genotype in both the Polish and Scottish studies. This difference between the genotypes was 5.27 mm Hg (P=0.0014) and 3.14 mm Hg (P=0.0005) for adjusted systolic BP and 2.6 mm Hg (P=0.0045) and 1.44 mm Hg (P=0.0084) for adjusted diastolic BP in the Polish and the Scottish studied, respectively. On binary logistic regression analysis, males with the HindIII(+)/TT SF1 genotype combination had an odds ratio for elevated BP of 3.92 (CI 1.21 to 12.68, P=0.023). Our results indicate that the Y chromosome harbors a locus or loci that contribute to BP variation in hypertensive and normotensive men. The polymorphism in the aldosterone synthase gene may interact with the Y chromosome to increase the odds of an individual's developing higher BP.

Adult↗