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Biomedical subjects

Philippe M Frossard

Publications and source records attributed to Philippe M Frossard.

18 recordsLinked to original sources
PubMed2006

A novel haplotype in ABCA1 gene effects plasma HDL-C concentration.

BACKGROUND AND OBJECTIVES: ATP-binding cassette transporter 1 (ABCA1) is a trans-membrane protein responsible for the efflux of cholesterol and phospholipids across the cell membrane, an essential step in the reverse cholesterol transport system. This study investigates the effect of five non-synonymous SNPs of ABCA1 gene on plasma HDL-C levels in Pakistani individuals free of ischemic heart disease and stroke. METHODS: Five non-synonymous SNPs were selected after sequencing ABCA1 gene in patients of Hypoalphalipoproteinemia. The presence of these SNPs was then checked in 200 individuals by using PCR-RFLP. Plasma glucose and lipid fractions were measured in fasting state. Ethical approval was obtained from the Ethical Review Committee, Aga Khan University and informed consent was obtained from all subjects. RESULTS: LL genotype of V825L polymorphism was associated with decreased levels of HDL-C [-0.17 (-0.32 to -0.19); P=0.02] and P774 allele showed a significant increase in HDL-C levels as compared to T774 allele [-0.15 (-0.18 to -0.02); P=0.01]. R219K, A399V and V771M polymorphisms did not show any association with levels of HDL-C, LDL-C, cholesterol and triglycerides. Haplotype analysis between R219K and V825L polymorphisms showed a unique interaction between R219 allele and L825 allele. The RL haplotype was found to be associated with decreased levels of HDL-C [-0.12 (-0.22 to -0.03); P=0.001]. CONCLUSIONS: ABCA1 polymorphisms are associated with varying levels of HDL-C in Pakistani individuals. These results warrant further investigations as ABCA1 polymorphisms may have a major role in the high incidence of cardiovascular disorders in South Asians.

ATP Binding Cassette Transporter 1↗
PubMed2006

Association of endothelial nitric oxide synthase gene G894T polymorphism with essential hypertension in an adult Pakistani Pathan population.

This retrospective, case-control study was carried out to find putative correlations of eNOS G894T polymorphism with essential hypertension (EHT) amongst adult Pakistani Pathans. We investigated a sample population of 332 (154 men, 178 women) comprising groups of 146 hypertensives (HTs) and 186 normotensives (NTs) by assays based on polymerase chain reaction followed by restriction endonuclease analysis. The distribution of the genotypes or alleles was not statistically different in hypertensive and normotensive groups. In conclusion, the present study in a population of Pakistani adult Pathans does not support the association of the eNOS gene G894T polymorphism to essential hypertension.

Case-Control Studies↗
PubMed2006

Coronary heart disease in south Asia: need to redefine risk.

South Asian population has a high incidence of coronary artery disease. There are a number of risk factors that are almost unique to the south Asians. The classical risk factors do not account for such high rates of CHD as are present in south Asia. We have discussed some important aspects of CHD that can help in improving prevention in south Asia.

Asia↗
PubMed2006

3120+1 G-->A: a rare variant in Emirati CF patients.

Cystic fibrosis is a multi-system genetic disorder caused by mutation in the cystic fibrosis conductance transmembrane regulator (CFTR) gene located on chromosome 7. In United Arab Emirates (UAE), pattern of CF causing gene mutations is different than rest of the Arabs in the region and 95% of CF in Emirati families has been found due to two mutations only - -p.S549R(T>G) and p.F508del. We report the case of a homozygote for a mutation 3120 +1G-->A in the Emirati population detected in a young boy referred to CF and Respiratory Clinic at Tawam Hospital (Al Ain, UAE) for screening CFTR gene.

Cystic Fibrosis↗
PubMed2005

Strong association of a renin intronic dimorphism with essential hypertension.

The objectives of this project were two-fold: to identify the genetic mutation that has been detected as an MboI dimorphism in intron 9 of the human renin (REN) gene and to confirm a previously reported, putative association between the REN MboI dimorphism and clinical diagnosis of essential hypertension (EHT) in a population of Gulf Arabs from the United Arab Emirates. Sequencing of the MboI dimorphic site was carried out on DNA of randomly chosen cases and controls. A retrospective case-control study was carried out in 689 unrelated subjects (326 first-time, clinically diagnosed hypertensives and 363 age- and gender-matched normotensive subjects), selected from the resident population of the Abu Dhabi Emirate. A polymerase chain reaction/MboI-RFLP based method was employed to compare genotype and allele distributions. Nucleotide sequences at the MboI site of the cut and uncut alleles were determined to be GATC and GGTC, respectively. This A>G mutation is located 10,631 base pairs (bp) 3' to the start of the REN gene, and 79 bp 3' to the end of exon 9. The genotype distributions of the REN 10631A>G dimorphism were found to be significantly different between hypertensive and normotensive subjects (x2= 42.29, df=2, p<0.001). Frequencies of A alleles were 0.54 in EHT vs. 0.37 in normotensive subjects, which is even more demarcated than what was found previously. The frequency of AA genotypes was higher in the hypertensive group than in the normotensive group (34.7% vs. 14.0%). The quantification of the association of A alleles with increased risk of EHT was assessed with corresponding odds ratios (OR), which gave the following values: OR of GG vs. AG genotypes, 1.3 (95% confidence interval [CI]: 0.90-1.88); OR of GG vs. AA, 3.75 (95% CI: 2.41-5.86). In conclusion, REN 10631A alleles are significantly associated with EHT in the Emirati population. This has now been found in two different and therefore independent sample populations from the Abu Dhabi Emirate. Moreover, this genetic effect seems to be acting in a recessive fashion. Hence, either the REN gene itself, or another gene that is in linkage disequilibrium with REN 10631A>G, is implicated in the pathogenesis of EHT in Emirati.

Adult↗
PubMed2005

Association of angiotensin converting enzyme gene polymorphisms with left ventricular hypertrophy.

The angiotensin converting enzyme gene (ACE) is of much interest as a candidate gene conferring an individual's genetic susceptibility to left ventricular hypertrophy (LVH). LVH has long been thought to be an end point of essential hypertension (EH), rather than a separate entity, though it is influenced by a unique set of hormonal, vascular and genetic factors. In this study, we attempted to determine whether two representative polymorphisms of the ACE gene, ACE I/D and 2350 G>A, known to be associated with EH and to have a highly significant influence on plasma ACE levels, could implicate ACE as a quantitative trait locus (QTL) for LVH. We carried out a retrospective, case-control study of the two ACE polymorphisms amongst 180 nationals (50 LVH patients and 130 controls) from the United Arab Emirates (Emirati)--an ethnic group characterized by an absence of alcohol intake and cigarette smoking--for putative correlations with LVH. Clinical diagnoses of LVH were based on echocardiographic and ECG criteria. ACE I/D and 2350 G>A genotypes were determined by polymerase chain reaction (PCR) and restriction digestion. Univariate and multivariate logistic regression analyses revealed an association between ACE polymorphisms and LVH. Haplotype analysis further supported this finding. The ACE I/D and ACE 2350 G>A polymorphisms were in strong linkage disequilibrium and were independently associated with LVH, suggesting that ACE is likely to be a QTL for LVH. In conclusion, This is the first association study of the ACE 2350 G>A polymorphism with LVH; the results showed that this polymorphism, along with ACE I/D, is associated with LVH.

Adult↗
PubMed2005

G-protein beta-3 subunit gene 825C>T dimorphism is associated with left ventricular hypertrophy but not essential hypertension.

BACKGROUND: The human G-protein beta 3 subunit gene (GNB3) and some of its variants are known to be important genetic influences involved in essential hypertension (EH). Left ventricular hypertrophy (LVH) has long been thought to be an end point of EH, rather than a separate entity, though it is influenced by a unique set of hormonal, vascular and genetic factors. METHODS/MATERIALS: We carried out a retrospective, case-control study of a GNB3 825 C>T dimorphism among nationals from the United Arab Emirates (Emirati), an ethnic group characterized by no alcohol intake and no cigarette smoking, for putative correlations with EH and LVH. We investigated a sample population of 454 Emirati (231 men, 223 women) comprising groups of controls and patients with clinical diagnoses of LVH, based on echocardiographic and ECG criteria, and EH, based on blood pressure values. The GNB3 825 C>T genotypes were determined by PCR and restriction digestion. RESULTS: The distribution of genotypes was in Hardy-Weinberg equilibrium in all three subject groups. GNB3 T825 alleles demonstrated a strong association with LVH (OR = 2.22; 95% CI: 1.29-3.83 and P = 0.0002), but not with EH. CONCLUSIONS: GNB3 825 C>T is likely to be a significant risk factor for LVH but not for EH in the Emirati population, thereby strengthening the view that LVH is genetically a separate clinical entity.

Case-Control Studies↗
PubMed2005

Association of G-protein beta-3 subunit gene (GNB3) T825 allele with Type II diabetes.

To date, the human G-protein beta 3 subunit (GNB3) gene and some of its variants represent some of the best examples of genetic influences that are involved in the determination of hypertension and obesity, which make it a sensible candidate gene for type 2 diabetes. To assess the influence of GNB3 in type II diabetes mellitus (NIDDM), we carried out a retrospective, case-control study of variant GNB3 825C>T for putative correlations with NIDDM amongst nationals from the United Arab Emirates (Emirati) - an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 510 Emirati (257 men, 253 women) comprising two groups - 254 controls and 256 patients with clinical diagnoses of type 2 diabetes (cases). The GNB3 C825T dimorphism showed an association with NIDDM Chi2 =22.5, 2 df, P<0.001). Further analysis revealed that the GNB3 T/T 825 genotype was positively associated with NIDDM (Yates corrected Chi2=20.6, 2 df, P<0.001; odds ratio of 2.44 with a 95% confidence interval of 1.64 - 3.63) compared to pooled CC/CT genotypes. Our data shows that GNB3 T825 allele may be involved in the pathogenesis of DM through a pathway that is different from the one implicated in obesity.

Adult↗
PubMed2005

Association of ACE polymorphisms with left ventricular hypertrophy.

The angiotensin converting enzyme gene (ACE) is a candidate gene for an individual's genetic susceptibility to left ventricular hypertrophy (LVH). LVH has long been thought to be an end point of essential hypertension (EH), rather than a separate entity, though it is influenced by a unique set of hormonal, vascular and genetic factors. In this study, we attempted to determine whether two representative polymorphisms of the ACE gene, ACE I/D and 2350 G>A, known to be associated with EH and to influence plasma ACE levels most significantly, could implicate ACE as a quantitative trait locus (QTL) for LVH. We carried out a retrospective, case-control study of the two ACE polymorphisms amongst 180 nationals (50 LVH patients and 130 controls) from the United Arab Emirates--an ethnic group characterized by no alcohol intake and no cigarette smoking--for correlations with LVH. Clinical diagnosis of LVH was based on echocardiographic and ECG criteria. ACE I/D and 2350 G>A genotypes were determined by PCR and restriction digestion. Univariate and multivariate logistic regression analyses revealed an association between ACE polymorphisms and LVH. Haplotype analysis further supported this finding. ACE I/D and ACE 2350 G>A polymorphisms are in strong linkage disequilibrium and are associated with LVH, suggesting that ACE is likely to be a QTL for LVH.

Adult↗
PubMed2004

Xeroderma pigmentosum in four siblings with three different types of malignancies simultaneously in one.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by marked sensitivity to ultraviolet radiation that leads to the development of multiple skin malignancies. The authors describe four XP siblings in a consanguineous Pakistani family. The first patient was a boy who died at age 2 years. The second and third siblings were girls who died at age 2 and 7 years, respectively. The fourth sibling, the propositus, was a boy diagnosed with XP at age 7 years. He developed three different types of malignancies simultaneously and died at age 13. The authors conclude that it is important to be aware of multiple malignancies of different types in the same patient with XP.

Adolescent↗
PubMed2004

Head and neck cancer susceptibility: a genetic marker in the methylenetetrahydrofolate reductase gene.

Progress in the elucidation of molecular genetic changes that lead to the development of tumors should soon bring novel diagnostic and therapeutic procedures into clinical practice. In this respect, methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. DNA methylation is an epigenetic feature that influences cellular development and function. Germ line mutation C>T at nucleotide 677 of the MTHFR gene, which results in increased thermolability and diminished enzyme activity, is oncogenic, i.e. should be a contributor to molecular changes leading to cancerous phenotypes (it has also been shown independently to be implicated in cardiovascular disease phenotypes). Interestingly, it has been shown that MTHFR T677 allele homozygosity confers a sixfold increased risk for esophageal squamous cell carcinoma in Northern China. The purpose of this study was twofold: (1) to evaluate the putative association of MTHFR C677T and epithelial squamous cell carcinoma (ESCC) in Pakistan, and (2) to investigate whether de novo MTHFR C677T mutations are involved in the determination of ESCC phenotypes. We recruited 50 ESCC patients referred to the Otolaryngology Clinic of the Aga Khan University Hospital, and 54 age- and gender-matched control (disease-free) subjects. Our results show that T allele frequencies were 0.18 +/- 0.05 in cases vs. 0.24 +/- 0.05 in controls (as compared with 0.63 vs. 0.41 in the report from China). Although the association is not statistically significant, T alleles are actually more common amongst controls in the Pakistani population, which is the opposite of what would be expected and what has been reported amongst Chinese. Yet the frequency of deleterious T alleles is lower in Pakistan (range 0.18-0.24) than in other parts of the world. Our results indicate that MTHFR C677T cannot form the basis for a genetic test aimed at evaluating an individual's genetic susceptibility to ESCC in Pakistan. As the conversion of precancerous submucous fibrosis into overt cancer is a frequent occurrence in Pakistan, we proceeded to extract DNA samples in all ESCC patients, from whole blood, cancerous tissues and neighboring normal tissues. We sought to determine whether C677T genotypes were different in the three tissue samples from each ESCC patient. In all patients, identical genotypes (and therefore allele frequencies) were systematically observed in all three samples. This indicates that de novo MTHFR 677TC>T mutations are not part of the molecular etiology of ESCC. In conclusion, we can rule out a major involvement of the MTHFR gene in the determination of ESCC in Pakistan.

Adult↗
PubMed2003

Associations between the human insulin gene 5' VNTR and clinical variables of the renin-angiotensin system.

BACKGROUND: Blood pressure regulation is a complex process influenced by numerous environmental and genetic factors. Consequently, there's no cookie-cutter approach for the elucidation of of the genetic mechanism involved. One of the goals of molecular geneticists in the field of hypertension is to unravel the genetic architecture of blood pressure regulation. METHODS: With the aim of identifying quantitative trait loci participating in the control of blood pressure, we carried out a pilot study on a sample population of middle-aged, U.S. Caucasians (44 subjects). The design of the study was to search for associations between clinical variables of blood pressure regulation pertaining to the renin-angiotensin-aldosterone system (systolic and diastolic blood pressures, urinary excretion of sodium, potassium and aldosterone, plasma renin activity) and a genetic marker at a candidate gene locus - the human insulin gene (INS) RESULTS: We observed significant associations between a variable number of tandem repeats (VNTR) marker (visualized as a biallelic, class I/class III marker system) localized at the 5' end of the human INS gene, and plasma renin activity and urinary sodium, potassium and aldosterone. CONCLUSION: Our results indicate that between 6 and 10 QTLs with comparable effects could be involved in blood pressure regulation via the rennin angiotensin system.

Aldosterone↗
PubMed2002

Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates.

Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma (PPK) and transgressive keratosis with an onset in early infancy. There is no associated involvement of other organs; however, a spectrum of clinical presentations with optional and variable features has been described. Mutations in the ARS (component B)-81/s gene ( LY6LS) on chromosome 8q24-qter, which encodes SLURP-1, have recently been identified in patients with MDM. Here, we have analyzed four MDM families for mutations in SLURP-1. In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86. A different mutation in Turkish patients results in the same amino acid exchange. Some remarkable similarities are seen in the clinical picture of patients from both families. Patients of an Emirati Bedouin family have a homozygous alteration of the translation initiation codon. In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R. Our findings indicate that the MDM type of transgressive PPK is caused by SLURP-1 mutations in patients from various origins and demonstrate allelic heterogeneity for mutations in SLURP-1.

Adult↗
PubMed2002

A study of five human cytokine genes in human essential hypertension.

With a view to evaluating the putative involvement of cytokine gene variants in human essential hypertension, we carried out an association (case-control) study on 174 unrelated nationals (81 hypertensives and 93 normotensives) from the Abu Dhabi Emirate (UAE), a genetically homogeneous population also characterised by the absence of traditional confounding factors such as alcohol consumption and smoking. To that end, we targeted our investigation to five candidate gene loci-transforming growth factor beta1 (TGF-beta1), interferon gamma (IFN-gamma), epidermal growth factor (EGF), interleukin-1 beta (IL-1beta) and tumour-necrosis factor (TNF-alpha) genes. We investigated the distribution of genotypes and alleles of the six following dimorphic variants: TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C), located at codons 10 and 25, respectively, of TGF-beta1; T874A in intron 1 of IFN-gamma; G61A in exon 1 of EGF; TaqI dimorphism at +3962 (exon 5) of IL-1beta; and -308A>G in the promoter of TNF-alpha. These six bi-allelic markers were visualised by methods based on the techniques of amplification refractory mutation system-polymerase chain reaction (for TGF-beta1, IFN-gamma, EGF and TNF-alpha) and by polymerase chain reaction-TaqI restriction endonuclease analysis in the case of IL-1beta. In each of the two groups (normotensives and hypertensives), genotype frequencies of all six markers occurred in Hardy-Weinberg proportions. There were, however, no statistical differences in the allele and genotype frequencies of any of the six markers between the two groups of subjects: TGF-beta1(*)10C frequencies were 0.46 and 0.49 (chi(2)=0.61; 2 d.f.; P=0.74) and TGF-beta1(*)25C were 0.07 and 0.08 (chi(2)=0.61; 2 d.f.; P=0.74) amongst normotensives and hypertensives, respectively; p(IFN-gamma(*)A874) were 0.41 in normotensives versus 0.46 in hypertensives (chi(2)=3.07; 2 d.f.; P=0.22); p(EGF (*)G61) were 0.51 versus 0.58 (chi(2)=1.76; 2 d.f.; P=0.41); p[IL-1beta (*)TaqI(+)] were 0.43 versus 0.36 (chi(2)=2.08; 2 d.f.; P=0.35); and p(TNF-alpha(*)-308G) were 0.80 versus 0.85 (chi(2)=1.29; 2 d.f.; P=0.53). There was also no difference in distribution and frequencies of haplotypes constructed with combinations of TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C) sites. However, although they do not reach statistical significance (which may be due to the relatively restricted number of subjects included in this study), the distribution differences (in normotensives and hypertensives) observed in the cases of EGF and TNF-alpha reflect trends that could be expected from a mechanistic explanation of the pathways that underlie the patho-physiology of hypertension.

Case-Control Studies↗