Publications by authors named "Michella Ghassibe-Sabbagh"

22 Publications

  • Page 1 of 1

New susceptibility alleles associated with severe coronary artery stenosis in the Lebanese population.

BMC Med Genomics 2021 Mar 25;14(1):90. Epub 2021 Mar 25.

School of Medicine, Lebanese American University, Beirut, Lebanon.

Background: Coronary Artery Disease (CAD) is the narrowing or blockage of the coronary arteries. It is closely associated with numerous genetics and environmental factors that have been extensively evaluated in various populations. In recent studies, severe phenotypes have been strongly linked to genetic risk factors.

Methods: This study investigated the association of clinical, demographic, and genetic factors with severe coronary artery stenosis phenotypes in our population composed of 1734 individuals with severe coronary stenosis (≥ 50% in coronary vessels) and comparing them to 757 controls with no evidence of stenosis on angiography. We performed generalized linear model (GLM) genome-wide association studies to evaluate three stratification models and their associations to characteristics of the clinical disease. In model 1, patients were not stratified. In model 2, patients were stratified based on presence or absence of CAD family history (FxCAD). In model 3, patients were stratified by young age of CAD onset.

Results: Eight SNPs (single nucleotide polymorphism) were significantly associated with severe CAD phenotypes in the various models [Formula: see text], four of these SNPs were associated with severe CAD and the four others were specifically significant for young CAD patients. While these SNPs were not previously reported for association with CAD, six of them are present in genes that have already been linked to coronary disease.

Conclusion: In conclusion, this study presents new genetic factors associated with severe stenosis and highlights different risk factors associated with a young age at diagnosis of CAD.
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http://dx.doi.org/10.1186/s12920-021-00942-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993530PMC
March 2021

Osteogenic potential of dental and oral derived stem cells in bone tissue engineering among animal models: An update.

Tissue Cell 2021 Feb 24;71:101515. Epub 2021 Feb 24.

Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath- Beirut, Lebanon. Electronic address:

Small bone defects can heal spontaneously through the bone modeling process due to their physiological environmental conditions. The bone modeling cycle preserves the reliability of the skeleton through the well-adjusted activities of its fundamental cell. Stem cells are a source of pluripotent cells with a capacity to differentiate into any tissue in the existence of a suitable medium. The concept of bone engineering is based on stem cells that can differentiate into bone cells. Mesenchymal stromal cells have been evaluated in bone tissue engineering due to their capacity to differentiate in osteoblasts. They can be isolated from bone marrow and from several adults oral and dental tissues such as permanent or deciduous teeth dental pulp, periodontal ligament, apical dental papilla, dental follicle precursor cells usually isolated from the follicle surrounding the third molar, gingival tissue, periosteum-derived cells, dental alveolar socket, and maxillary sinus Schneiderian membrane-derived cells. Therefore, a suitable animal model is a crucial step, as preclinical trials, to study the outcomes of mesenchymal cells on the healing of bone defects. We will discuss, through this paper, the use of mesenchymal stem cells obtained from several oral tissues mixed with different types of scaffolds tested in different animal models for bone tissue engineering. We will explore and link the comparisons between human and animal models and emphasized the factors that we need to take into consideration when choosing animals. The pig is considered as the animal of choice when testing large size and multiple defects for bone tissue engineering.
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http://dx.doi.org/10.1016/j.tice.2021.101515DOI Listing
February 2021

Comparing the osteogenic potential of schneiderian membrane and dental pulp mesenchymal stem cells: an in vitro study.

Cell Tissue Bank 2021 Jan 1. Epub 2021 Jan 1.

Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon.

Mesenchymal stem cells, being characterized by high self-renewal capacity and multi-lineage differentiation potential, are widely used in regenerative medicine especially for repair of bone defects in patients with poor bone regenerative capacity. In this study, we aimed to compare the osteogenic potential of human maxillary schneiderian sinus membrane (hMSSM)-derived stem cells versus permanent teeth dental pulp stem cells (DPSCs). Both cells types were cultivated in osteogenic and non-osteogenic inductive media. Alkaline phosphatase (ALP) activity assay and quantitative real-time PCR analysis were carried out to assess osteogenic differentiation. We showed that ALP activity and osteoblastic markers transcription levels were more striking in hMSSM-derived stem cells than DPSCs. Our results highlight hMSSM-derived stem cells as a recommended stem cell type for usage during bone tissue regenerative therapy.
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http://dx.doi.org/10.1007/s10561-020-09887-4DOI Listing
January 2021

Differences in osteogenic and odontogenic differentiation potential of DPSCs and SHED.

J Dent 2020 10 22;101:103413. Epub 2020 Jun 22.

Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath- Beirut, Lebanon. Electronic address:

Objective: Dental pulp stem cells (DPSCs) and stem cells from human exfoliated deciduous teeth (SHED) are types of human dental tissue-derived mesenchymal stem cells (MSCs) that have emerged as an interesting and promising source of stem cells in the field of tissue engineering. The aim of this work is to isolate stem cells from DPSCs and SHED, cultivate them in vitro and compare their odontogenic differentiation potential.

Methods: DPSCs and SHED were extracted from molars, premolars and canines of six healthy subjects aged 5-29 years. The cells were characterized, using flow cytometry, for mesenchymal stem cell surface markers. MTT colorimetric assay was applied to assess cell viability. Alizarin red staining, alkaline phosphatase (ALP) activity, quantitative real-time PCR (qRT-PCR) and western blot were carried out to determine DPSCs and SHED osteogenic/odontogenic differentiation.

Results: DPSCs express higher STRO-1 and CD44 levels compared to SHED. Moreover, the cells differentiate and acquire columnar shape with a level of calcium deposition and mineralization that is the same between DPSCs and SHED. ALP activity, ALP, COLI, DMP-1, DSPP, OC, and RUNX2 (osteogenic/odontogenic differentiation markers) expression levels were higher in DPSCs.

Conclusions: DPSCs and SHED express MSCs markers. Although both cell types had calcium deposits, DPSCs presented a higher ALP activity level. In addition, DPSCs showed higher levels of osteogenic and odontogenic differentiation markers such as COLI, DSPP, OC, RUNX2, and DMP-1. These results suggest that DPSCs are closer to the phenotype of odontoblasts than SHED and may improve the efficacy of human dental tissue-derived mesenchymal stem cells therapeutic protocols.

'clinical Significance': DPSCs are closer than t SHED to the phenotype of odontoblasts. This would be helpful to enable better therapeutic decisions when applying MSCs-based therapy in the field of dentistry.
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http://dx.doi.org/10.1016/j.jdent.2020.103413DOI Listing
October 2020

Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review.

Diagn Pathol 2019 Nov 4;14(1):123. Epub 2019 Nov 4.

Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.

Background: Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population.

Case Presentation: Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis.

Conclusion: Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.
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http://dx.doi.org/10.1186/s13000-019-0902-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829978PMC
November 2019

Genome-wide association analysis of HDL-C in a Lebanese cohort.

PLoS One 2019 18;14(6):e0218443. Epub 2019 Jun 18.

Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon.

Low serum levels of high-density lipoprotein cholesterol (HDL-C) have been shown to be a risk factor for coronary artery disease independent of low-density lipoprotein cholesterol (LDL-C) in different populations. In this study, we investigated genetic variants through genome-wide association studies to determine their association with HDL-C levels in a sample of 2,700 patients. We identified several SNPs associated with HDL-C levels in the Lebanese population using unadjusted and adjusted by biological factors models. We replicated the association of rs3764261 within CETP with HDL-C levels in the study population, and found other previously unidentified SNPs to be significant at the suggestive level, in both previously identified and unidentified genes. This paper reports the first genome-wide analysis of HDL-C in the Lebanese, Middle Eastern, population and supports the importance of genome-wide association studies across different and minor ethnicities to understand better the etiology of complex human diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581269PMC
February 2020

Gestational diabetes mellitus and macrosomia predispose to diabetes in the Lebanese population.

J Clin Transl Endocrinol 2019 Jun 20;16:100185. Epub 2019 Feb 20.

School of Medicine, Lebanese American University, Beirut, Lebanon.

Aims: The Middle East has the fastest rising rate of Type 2 Diabetes Mellitus (T2DM) worldwide, with Lebanon having 15.8% of its population affected. This study aims at studying Polycystic Ovarian Syndrome (PCOS), Gestational Diabetes Mellitus (GDM), and macrosomia as risk factors of T2DM in Lebanon. Such epidemiological and statistical study has never been conducted before in the Middle East region and would be useful for clinical diagnosis.

Methods: Our cohort is comprised of 1453 Lebanese individuals, with 897 controls and 556 patients. We tested the correlation between T2DM and the covariates GDM, PCOS, and macrosomia independently. We conducted multinomial logistic regression and cross tabulations with T2DM as an outcome.

Results: The results showed a significant association of the independent factors GDM and macrosomia with T2DM. The risk of having T2DM was increased by 4.192 times with the GDM, and by 2.315 times with macrosomia respectively.

Conclusion: In conclusion, GDM and macrosomia, but not PCOS, are significant risk factors for T2DM in our Lebanese cohort. Our results, reported for the first time in the Middle East, present insights into risk factors management and disease prevention.
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http://dx.doi.org/10.1016/j.jcte.2019.100185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406007PMC
June 2019

Association of coronary artery disease and chronic kidney disease in Lebanese population.

Int J Clin Exp Med 2015 15;8(9):15866-77. Epub 2015 Sep 15.

School of Medicine, Lebanese University Beirut, Lebanon ; Division of Nephrology, Department of Internal Medicine, Rafik Hariri University Hospital Beirut, Lebanon.

Background: More evidence is emerging on the strong association between chronic kidney disease (CKD) and cardiovascular disease. We assessed the relationship between coronary artery disease (CAD) and renal dysfunction level (RDL) in a group of Lebanese patients.

Methods: A total of 1268 patients undergoing cardiac catheterization were sequentially enrolled in a multicenter cross sectional study. Angiograms were reviewed and CAD severity scores (CADSS) were determined. Estimated glomerular filtration rate (eGFR) was calculated and clinical and laboratory data were obtained. CKD was defined as eGFR < 60 ml/min. Logistic regression model was performed using multivariate analysis including all traditional risk factors associated with both diseases. ANOVA and the Tukeytestswere used to compare subgroups of patients and to assess the impact of each disease on the severity of the other.

Results: Among the 82% patients who exhibited variable degrees of CAD, 20.6% had an eGFR < 60 ml/min. Logistic regression analysis revealed a bidirectional independent association between CAD and CKD with an OR = 2.01 (P < 0.01) and an OR = 1.99 (P < 0.01) for CAD and CKD frequencies, respectively. We observed a steady increase in the CADSS mean as eGFR declined and a progressive reduction in renal function with the worsening of CAD (P < 0.05). This correlation remained highly significant despite considerable inter-patient variability and was at its highest at the most advanced stages of both diseases.

Conclusions: Our results show a strong, independent and graded bidirectional relationship between CAD severity and RDL. We propose to add CAD to the list of risk factors for the development and progression of CKD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658979PMC
December 2015

Caffeine Impact on Metabolic Syndrome Components Is Modulated by a CYP1A2 Variant.

Ann Nutr Metab 2016 21;68(1):1-11. Epub 2015 Nov 21.

Lebanese American University, School of Medicine, Beirut, Lebanon.

Cultural, dietary, and lifestyle factors are the main modulators of type 2 diabetes mellitus (T2DM) disease risk. Coffee is one of the most popular worldwide beverages, and recent epidemiological studies have showed that coffee consumption is associated with a lower risk of T2DM. This study investigates the impact of coffee intake on T2DM risk and assesses the effect of CYP variants with caffeine exposures on T2DM. Data from 7,607 study subjects were analyzed by logistic regression models, among whom 3,290 GWAS data were available for CYP variants association studies using Plink analysis. These data suggest a protective relationship for women, but not for men; however, the results were not statistically significant in this dataset and there is a significant interaction in favor of women regarding heavy coffee consumption. The interaction between male gender and heavy coffee consumption becomes significant, thereby tending to cancel the protective effect of coffee for males. CYP rs2470890 allele 'C' increases the odds of T2DM by a factor of around 1.2 but decreases the odds of caffeine boosting T2DM of 1.7 by a factor of 0.77. rs2470890 showed an association with T2DM only when the interaction with coffee was considered, thereby setting an example of genetic activation by dietary changes associating with metabolic syndrome.
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http://dx.doi.org/10.1159/000441481DOI Listing
September 2016

Impact of inflammation, gene variants, and cigarette smoking on coronary artery disease risk.

Inflamm Res 2015 Jun 24;64(6):415-22. Epub 2015 Apr 24.

School of Medicine, Lebanese American University, P.O Box 36, Byblos, Lebanon.

Background: The role of inflammation in coronary artery disease (CAD) pathogenesis is well recognized. Moreover, smoking inhalation increases the activity of inflammatory mediators through an increase in leukotriene synthesis essential in atherosclerosis pathogenesis.

Aim: The aim of this study is to investigate the effect of "selected" genetic variants within the leukotriene (LT) pathway and other variants on the development of CAD.

Methods: CAD was detected by cardiac catheterization. Logistic regression was performed to investigate the association of smoking and selected susceptibility variants in the LT pathway including ALOX5AP, LTA4H, LTC4S, PON1, and LTA as well as CYP1A1 on CAD risk while controlling for age, gender, BMI, family history, diabetes, hyperlipidemia, and hypertension.

Results: rs4769874 (ALOX5AP), rs854560 (PON1), and rs4646903 (CYP1A1 MspI polymorphism) are significantly associated with an increased risk of CAD with respective odds ratios of 1.53703, 1.67710, and 1.35520; the genetic variant rs9579646 (ALOX5AP) is significantly associated with a decreased risk of CAD (OR 0.76163). Moreover, a significant smoking-gene interaction is determined with CYP1A1 MspI polymorphism rs4646903 and is associated with a decreased risk of CAD in current smokers (OR 0.52137).

Conclusion: This study provides further evidence that genetic variation of the LT pathway, PON1, and CYP1A1 can modulate the atherogenic processes and eventually increase the risk of CAD in our study population. Moreover, it also shows the effect of smoking-gene interaction on CAD risk, where the CYP1A1 MspI polymorphism revealed a decreased risk in current smokers.
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http://dx.doi.org/10.1007/s00011-015-0821-1DOI Listing
June 2015

T2DM GWAS in the Lebanese population confirms the role of TCF7L2 and CDKAL1 in disease susceptibility.

Sci Rep 2014 Dec 8;4:7351. Epub 2014 Dec 8.

1] Lebanese American University, School of Medicine, Beirut 1102 2801, Lebanon [2] Harvard School of Public Health, Boston MA 02215, USA.

Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are crucial to the understanding of Type 2 Diabetes Mellitus (T2DM) pathophysiology. We report a GWAS on the genetic basis of T2DM in a 3,286 Lebanese participants. More than 5,000,000 SNPs were directly genotyped or imputed using the 1000 Genomes Project reference panels. We identify genome-wide significant variants in two loci CDKAL1 and TCF7L2, independent of sex, age and BMI, with leading variants rs7766070 (OR = 1.39, P = 4.77 × 10(-9)) and rs34872471 (OR = 1.35, P = 1.01 × 10(-8)) respectively. The current study is the first GWAS to find genomic regions implicated in T2DM in the Lebanese population. The results support a central role of CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations and provide a plausible component for understanding molecular mechanisms involved in the disease.
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http://dx.doi.org/10.1038/srep07351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376673PMC
December 2014

Association of hypertension with coronary artery disease onset in the Lebanese population.

Springerplus 2014 16;3:533. Epub 2014 Sep 16.

Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.

The onset of coronary artery disease (CAD) is influenced by cardiovascular risk factors that often occur in clusters and may build on one another. The objective of this study is to examine the relationship between hypertension and CAD age of onset in the Lebanese population. This retrospective analysis was performed on data extracted from Lebanese patients (n = 3,753). Logistic regression examined the association of hypertension with the age at CAD diagnosis after controlling for other traditional risk factors. The effect of antihypertensive drugs and lifestyle changes on the onset of CAD was also investigated. Results showed that hypertension is associated with late onset CAD (OR=0.656, 95% CI=0.504-0.853, p=0.001). Use of antihypertensive drugs showed a similar association with delayed CAD onset. When comparing age of onset in CAD patients with traditional risk factors such as hypertension, diabetes, hyperlipidemia, obesity, smoking and family history of CAD, the age of onset was significantly higher for patients with hypertension compared to those with any of the other risk factors studied (p < 0.001). In conclusion, hypertension and its treatment are associated with late coronary atherosclerotic manifestations in Lebanese population. This observation is currently under investigation to clarify its genetic and/or environmental mechanisms.
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http://dx.doi.org/10.1186/2193-1801-3-533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176843PMC
October 2014

Multivariate epidemiologic analysis of type 2 diabetes mellitus risks in the Lebanese population.

Diabetol Metab Syndr 2014 21;6(1):89. Epub 2014 Aug 21.

School of Medicine, Lebanese American University, Beirut, 1102 2801 Lebanon ; Harvard School of Public Health, Boston, MA 02215 USA.

Background: The burden of diabetes in Lebanon requires well-targeted interventions for screening type 2 diabetes mellitus (T2DM) and prediabetes and prevention of risk factors. Newly recruited 998 Lebanese individuals, in addition to 7,292 already available, were studied to investigate the prevalence of diabetes, prediabetes and their associated risk factors.

Methods: Participants had fasting blood sugar and glycohemoglobin tests in addition to a lipid profile. Clinical and demographic information were obtained from a detailed questionnaire. The relationship between T2DM, its risk factors, and its complications were tested. Comparisons of these risk factors among diabetics, healthy, and coronary artery disease (CAD) patients were performed.

Results: The prevalence of T2DM significantly increased with increasing BMI (p < 0.0001). Exercise activity level negatively correlated with the disease (p = 0.002), whereas the prevalence of T2DM (p < 0.0001) and CAD family history (p = 0.006) positively correlated with the affection status. The mean levels of triglycerides and LDL-C were significantly higher in diabetics (1.87; 1.35) compared to individuals with prediabetes (1.63; 1.26) and unaffected controls (1.49; 1.19). People with T2DM showed a significant decrease in HDL-C levels. A strong correlation of overall hyperlipidemia with the diabetes affection status was shown (p < 0.0001). Other comorbid factors such as hypertension (p < 0.0001) and self-reported obesity (p < 0.0001) were highly associated with T2DM and prediabetes. Reproductive health of women showed a strong correlation between giving birth to a baby with a high weight and the occurrence of T2DM and prediabetes later in life (p < 0.0001). Retinopathy and peripheral neuropathy were significantly correlated with diabetes and prediabetes (p < 0.0001).

Conclusions: The present study shows an alarming prevalence of diabetes and prediabetes in the studied subgroups representative of the Lebanese population.
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http://dx.doi.org/10.1186/1758-5996-6-89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153892PMC
September 2014

Circulating lipid levels and risk of coronary artery disease in a large group of patients undergoing coronary angiography.

J Thromb Thrombolysis 2015 Jan;39(1):15-22

Bioinformatics and Pattern Discovery, IBM T. J. Watson Research Centre, New York, NY, USA.

A main underlying pathology of coronary artery disease is the deposition of cholesterol in the arteries supplying blood to the heart that leads to stenosis and myocardial infarction. We tested if dyslipidemia is a risk factor for coronary artery disease in the Lebanese population, and studied the role of the total cholesterol/HDL cholesterol (TC/HDL-C) ratio as a biological marker of coronary artery disease. We recruited 6,180 Lebanese patients undergoing cardiac catheterization. We conducted a cross-sectional association study between TC/HDL-C ratio and the number and type of vessels occluded in catheterized patients by controlling for confounding effects. The TC/HDL-C ratio ≥4 significantly predicts ≥50 % stenosis in all vessels individually with the odds ratio (OR) ranging from 1.22 to 1.92. The OR increased with increasing number of ≥50 % stenotic vessels (1.39 for 2 vessels and 1.64 for 3-4 vessels), as did risk due to diabetes, CAD family history, gender, and age. The younger than average age of onset subgroup shows a pronounced increase in risk for occlusion of the left main coronary artery due to TC/HDL-C ≥4 (OR 3.26). In conclusion, low levels of HDL-cholesterol and high levels TC/HDL-C ratio are strong biological markers of disease occurrence and severity in the Lebanese population.
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http://dx.doi.org/10.1007/s11239-014-1069-2DOI Listing
January 2015

Y-chromosome and mtDNA genetics reveal significant contrasts in affinities of modern Middle Eastern populations with European and African populations.

PLoS One 2013 30;8(1):e54616. Epub 2013 Jan 30.

The Lebanese American University, Chouran, Beirut, Lebanon.

The Middle East was a funnel of human expansion out of Africa, a staging area for the Neolithic Agricultural Revolution, and the home to some of the earliest world empires. Post LGM expansions into the region and subsequent population movements created a striking genetic mosaic with distinct sex-based genetic differentiation. While prior studies have examined the mtDNA and Y-chromosome contrast in focal populations in the Middle East, none have undertaken a broad-spectrum survey including North and sub-Saharan Africa, Europe, and Middle Eastern populations. In this study 5,174 mtDNA and 4,658 Y-chromosome samples were investigated using PCA, MDS, mean-linkage clustering, AMOVA, and Fisher exact tests of F(ST)'s, R(ST)'s, and haplogroup frequencies. Geographic differentiation in affinities of Middle Eastern populations with Africa and Europe showed distinct contrasts between mtDNA and Y-chromosome data. Specifically, Lebanon's mtDNA shows a very strong association to Europe, while Yemen shows very strong affinity with Egypt and North and East Africa. Previous Y-chromosome results showed a Levantine coastal-inland contrast marked by J1 and J2, and a very strong North African component was evident throughout the Middle East. Neither of these patterns were observed in the mtDNA. While J2 has penetrated into Europe, the pattern of Y-chromosome diversity in Lebanon does not show the widespread affinities with Europe indicated by the mtDNA data. Lastly, while each population shows evidence of connections with expansions that now define the Middle East, Africa, and Europe, many of the populations in the Middle East show distinctive mtDNA and Y-haplogroup characteristics that indicate long standing settlement with relatively little impact from and movement into other populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054616PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559847PMC
August 2013

Genome-wide association study in a Lebanese cohort confirms PHACTR1 as a major determinant of coronary artery stenosis.

PLoS One 2012 20;7(6):e38663. Epub 2012 Jun 20.

CEA-Genomics Institute, Centre National de Génotypage, Evry, France.

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10(-5)). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10(-6)), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10(-10)). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038663PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380020PMC
November 2012

Afghanistan's ethnic groups share a Y-chromosomal heritage structured by historical events.

PLoS One 2012 28;7(3):e34288. Epub 2012 Mar 28.

The Lebanese American University, Chouran, Beirut, Lebanon.

Afghanistan has held a strategic position throughout history. It has been inhabited since the Paleolithic and later became a crossroad for expanding civilizations and empires. Afghanistan's location, history, and diverse ethnic groups present a unique opportunity to explore how nations and ethnic groups emerged, and how major cultural evolutions and technological developments in human history have influenced modern population structures. In this study we have analyzed, for the first time, the four major ethnic groups in present-day Afghanistan: Hazara, Pashtun, Tajik, and Uzbek, using 52 binary markers and 19 short tandem repeats on the non-recombinant segment of the Y-chromosome. A total of 204 Afghan samples were investigated along with more than 8,500 samples from surrounding populations important to Afghanistan's history through migrations and conquests, including Iranians, Greeks, Indians, Middle Easterners, East Europeans, and East Asians. Our results suggest that all current Afghans largely share a heritage derived from a common unstructured ancestral population that could have emerged during the Neolithic revolution and the formation of the first farming communities. Our results also indicate that inter-Afghan differentiation started during the Bronze Age, probably driven by the formation of the first civilizations in the region. Later migrations and invasions into the region have been assimilated differentially among the ethnic groups, increasing inter-population genetic differences, and giving the Afghans a unique genetic diversity in Central Asia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314501PMC
August 2012

Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk.

Atherosclerosis 2012 May 28;222(1):180-6. Epub 2012 Feb 28.

Lebanese American University, School of Medicine, Beirut 1102 2801, Lebanon.

Background: Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease.

Aims: The rationale behind this study is to explore the correlation between degree and site of coronary lesion and hyperhomocysteinemia in Lebanese CAD patients and assess environmental and genetic factors for elevated levels of total plasma homocysteine.

Methods: A total of 2644 patients were analyzed for traditional CAD risk factors. Logistic regression was performed to determine the association of hyperhomocysteinemia with degree and site of coronary lesions controlling for risk factors. Environmental and genetic factors for hyperhomocysteinemia were analyzed by logistic regression using a candidate gene approach.

Results: Traditional risk factors were correlated with stenosis. Hyperhomocysteinemia associated with increased risk of overall stenosis, and risk of mild and severe occlusion in major arteries. Hyperhomocysteinemia and hypertension were highly correlated suggesting that hyperhomocysteinemia acts as a hypertensive agent leading to CAD. Diuretics and genetic polymorphisms in MTHFR and SLCO1B1 were associated with hyperhomocysteinemia.

Conclusions: Hyperhomocysteinemia is a medical indicator of specific vessel stenosis in the Lebanese population. Hypertension is a major link between hyperhomocysteinemia and CAD occurrence. Genetic polymorphisms and diuretics' intake explain partly elevated homocysteine levels. This study has important implications in CAD risk prediction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.02.035DOI Listing
May 2012

Large scale association analysis identifies three susceptibility loci for coronary artery disease.

PLoS One 2011 27;6(12):e29427. Epub 2011 Dec 27.

School of Medicine, Lebanese American University, Beirut, Lebanon.

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246490PMC
May 2012

mtDNA lineages reveal coronary artery disease-associated structures in the Lebanese population.

Ann Hum Genet 2012 Jan 20;76(1):1-8. Epub 2011 Oct 20.

The Lebanese American University, Chouran, Beirut, Lebanon.

Population origins and ancestry have previously been found to be important determinants of coronary artery disease (CAD). This study investigates associations of Lebanese mitochondrial DNA lineages with CAD and studies their correlation with other populations, exploring population structures that may infer mitochondria functional associations and reveal population movements and origins. Sequencing the mitochondrial hypervariable sequence 1 (HVS-1) of 363 controls and 448 cases revealed that haplogroup W was more frequent (P = 0.013) in cases compared to controls, and was associated with increased risk of CAD (OR = 5.50, 95% CI = 1.50-35.30, P = 0.026) among Lebanese samples. Haplogroup A was only found in controls (P = 0.029). We have detected stronger geographic correlation between haplogroup W and CAD (Pearson's r = 0.316, P < 0.001) than between haplogroup A and CAD (r = 0.149, P < 0.001). HVS-1 phylogenetic network of haplogroup W shows controls are restricted to European clusters while cases belong mostly to Middle Eastern natives. The network of haplogroup A shows that the controls belong to a cluster dominated by Central Asians. Our results show evidence of a gene flow into Lebanon, creating CAD-associated population structures that are similar to those in the source populations, maintained by limited admixture, and probably encompassing variations on the nuclear and/or the mitochondrial genome that are correlated with the disease.
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http://dx.doi.org/10.1111/j.1469-1809.2011.00682.xDOI Listing
January 2012

FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish.

Am J Hum Genet 2011 Feb 3;88(2):150-61. Epub 2011 Feb 3.

Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.
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http://dx.doi.org/10.1016/j.ajhg.2011.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035709PMC
February 2011