Soha Yazbek

Ancestral paternal genotype controls body weight and food intake for multiple generations

Current treatments have largely failed to slow the rapidly increasing world-wide prevalence of obesity and its co-morbidities. Despite a strong genetic contribution to obesity (40-70%), only a small percentage of heritability is explained with current knowledge of monogenic abnormalities, common sequence variants and conventional modes of inheritance. Epigenetic effects are rarely tested in humans because of difficulties arranging studies that distinguish conventional and transgenerational inheritance while simultaneously controlling environmental factors and learned behaviors. However, growing evidence from model organisms implicates genetic and environmental factors in one generation that affect phenotypes in subsequent generations. In this report, we provide the first evidence for paternal transgenerational genetic effects on body weight and food intake. This test focused on the obesity-resistant 6C2d congenic strain, which carries the Obrq2a(A/J) allele on an otherwise C57BL/6J background. Various crosses between 6C2d and the control C57BL/6J strain showed that the Obrq2a(A/J) allele in the paternal or grandpaternal generation was sufficient to inhibit diet-induced obesity and reduce food intake in the normally obesity-susceptible, high food intake C57BL/6J strain. These obesity-resistant and reduced food intake phenotypes were transmitted through the paternal lineage but not the maternal lineage with equal strength for at least two generations. Eliminating social interaction between the father and both his offspring and the pregnant dam did not significantly affect food intake levels, demonstrating that the phenotype is transmitted through the male germline rather than through social interactions. Persistence of these phenotypes across multiple generations raises the possibility that transgenerational genetic effects contribute to current metabolic conditions.

Resistance to diet-induced obesity in mice with a single substituted chromosome

Obesity and its comorbidities are taking an increasing toll on human health. Key pathways that were identified with single gene variants in humans and model organisms have led to improved understanding and treatment of rare cases of human obesity. However, similar progress remains elusive for the more common multifactorial cases of metabolic dysfunction and disease. A survey of mouse chromosome substitution strains (CSSs) provided insight into the complex genetic control of diet-induced obesity and related conditions. We now report a survey of 60 traits related to obesity and metabolic syndrome in mice with a single substituted chromosome as well as selected traits measured in congenic strains derived from the substituted strain. We found that each strain that was resistant to diet-induced obesity had a distinct phenotype that uniquely modeled different combinations of traits related to metabolic disease. For example, the chromosome 6 CSS remained insulin resistant in the absence of obesity, demonstrating an atypical relationship between body weight and insulin resistance. These results provide insights into the genetic control of constant components of this mouse model of diet-induced metabolic disease as well as phenotypes that vary depending on genetic background. A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome.

Increased mitochondrial oxidative phosphorylation in the liver is associated with obesity and insulin resistance

Obesity is the result of excess energy intake relative to expenditure, however little is known about why some individuals are more prone to weight gain than others. Inbred strains of mice also vary in their susceptibility to obesity and therefore represent a valuable model to study the genetics and physiology of weight gain and its co‐morbidities such as type 2 diabetes. C57BL/6J mice are susceptible to obesity and insulin resistance when fed an obesogenic diet, whereas A/J mice are resistant despite increased caloric intake. Analysis of B6‐ and A/J‐derived chromosome substitution strains and congenic strains revealed a complex genetic and physiological basis for this phenotype. To improve our understanding of the molecular mechanisms underlying susceptibility to metabolic disease we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains. 6C1 is susceptible whereas 6C2 is resistant to diet‐induced obesity. In addition, we demonstrate that 6C1 is glucose intolerant and insulin resistant relative to 6C2. Pathway analysis of global gene expression patterns in muscle, adipose, and liver identified expression level differences between 6C1 and 6C2 in pathways related to basal transcription factors, endocytosis, and mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain and were associated with a marked increase in mitochondrial oxidative capacity in the livers of the obese strain 6C1 relative to the obesity‐resistant strain 6C2. These data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance.

Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotypes in Follicular Lymphoma patients: Results of a pilot study

AIMS The Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotype profiling in Follicular Lymphoma has not been reported before in the literature. MATERIALS AND METHODS DNA extracted from 20 Follicular Lymphoma patients and 62 healthy controls was analyzed for KIR genotyping using a polymerase chain reaction/sequence specific primers technique (PCR/SSP) for the presence of 16 KIR gene and pseudogene loci. RESULTS The AA, AB, and BB genotype frequencies were, respectively, 20%, 60% and 20% with an A:B ratio of 1:1. KIR 2DL4, KIR 3DL2, KIR 3DL3, and KIR 3DP1*003 were presented in all individuals. No significant difference between patients and controls was detected. CONCLUSION KIR genotyping profile does not seem to be associated with Follicular Lymphoma. The results presented in this pilot research represent the first international report about this important clinical entity.

Hepatitis E Virus in the Countries of the Middle East and North Africa Region:An Awareness of an Infectious Threat to Blood Safety

Introduction: Hepatitis E virus (HEV) is mainly transmitted through contaminated water supplies which make the virus endemic in developing countries including countries of the Middle East and North Africa (MENA) region. Recent reports suggest potential risk of HEV transmission via blood transfusion particularly in endemic areas. Materials and Methods: Related articles on HEV were collected by searching through the 25 countries of the MENA region using Pubmed and Medline within the past 14 years: January 2000-August 2014. Results: One hundred articles were extracted, of which 25 were not eligible. The articles discussed the seroprevalence of HEV and HEV markers in 12 countries. Eight articles provided data on HEV in blood donors. The seroprevalence of HEV in the general MENA population ranged from 2.0%-37.5% and was higher in males than in females. Prevalence increased with age, but exposure seems to be in early life. Discussion: In the MENA region the role of HEV as an infectious threat to blood safety is under-investigated. More data are needed to quantify the risk of transmission and to assess clinical outcomes. This requires, at least, surveillance screening of donors and recipients for HEV markers using sensitive and specific serological tests. At the present time, serious consideration should be given to selective screening for certain groups of patients (e.g. immunocompromised, pregnant women and others) who commonly require blood transfusion and are at high risk of hepatic failure or chronicity from HEV infection.

A review of the diverse genetic disorders in the Lebanese population: highlighting the urgency for community genetic services

The review lists the genetic diseases reported in Lebanese individuals, surveys genetic programs and services, and highlights the absence of basic genetic health services at the individual and community level. The incidence of individual diseases is not determined, yet the variety of genetic diseases reported is tremendous, most of which follow autosomal recessive inheritance reflecting the social norms in the population, including high rates of consanguinity, which favor the increase in incidence of these diseases. Genetic services including all activities for the diagnosis, care, and prevention of genetic diseases at community level are extremely inadequate. Services are limited to some clinical and laboratory diagnostic services with no genetic counseling. These services are localized within the capital thus preventing their accessibility to high-risk communities. Screening programs, which are at the core of public health prevention services, are minimal and not nationally mandated. The absence of adequate genetic services is attributed to many factors undermining the importance of genetic diseases and their burden on society, the most important of which is genetic illiteracy at all levels of the population, including high-risk families, the general public, and most importantly health care providers and public health officials. Thus, a country like Lebanon, where genetic diseases are expected to be highly prevalent, is in utmost need for community genetics services. Strategies need to be developed to familiarize public health officials and medical professionals with medical genetics leading to a public health infrastructure that delivers community genetics services for the prevention and care of genetic disorders at community level.

Does published research on non-communicable disease (NCD) in Arab countries reflect NCD disease burden?

Objectives To review trends in non-communicable (NCD) research output in the Arab region, in terms of quantity and quality, study design, setting and focus. We also examined differences by time and place, and assessed gaps between research output and NCD burden. Methods A scoping review of a total of 3,776 NCD-related reports published between 2000 and 2013 was conducted for seven Arab countries. Countries were selected to represent diverse socio-economic development levels in the region: Regression analyses were used to assess trends in publications over time and by country. Research gaps were assessed by examining the degree of match between proportionate literature coverage of the four main NCDs (CVD, cancer, DM, and COPD) and cause-specific proportional mortality rates (PMR). Results The annual number of NCD publications rose nearly 5-fold during the study period, with higher income countries having the higher publication rates (per million populations) and the most rapid increases. The increase in the publication rate was particularly prominent for descriptive observational studies, while interventional studies and systematic reviews remained infrequent (slope coefficients = 13.484 and 0.883, respectively). Gap analysis showed a mismatch between cause-specific PMR burden and NCD research output, with a relative surplus of reports on cancer (pooled estimate +38.3%) and a relative deficit of reports on CVDs (pooled estimate -30.3%). Conclusion The widening disparity between higher and lower-income countries and the discordance between research output and disease burden call for the need for ongoing collaboration among Arab academic institutions, funding agencies and researchers to guide country-specific and regional research agendas, support and conduct.

Mapping genetic research in non-communicable disease publications in selected Arab countries: first step towards a guided research agenda

BackgroundIn the Arab world, intervention and policy response to non-communicable diseases (NCD) has been weak despite extensive epidemiological evidence highlighting the alarmingly increased prevalence of chronic diseases. Generating genetic information is one key component to promote efficient disease management strategies. This study undertook a scoping review to generate the profile of the undertaken research on genetics of NCD publications in selected Arab countries. An analysis of the research produced examined the extent, range, nature, topic and methods of published research. The study aimed at identifying the gaps in genetic NCD research to inform policy action for NCD prevention and control.MethodsThe scoping review was conducted based on the five-stage methodological framework and included countries in Arab region selected to represent various economies and epidemiological transitions.ResultsThe search identified 555 articles that focus on genetics-NCD research in the selected Arab countries over the duration of this study (January 2000 to December 2013). The most commonly conducted research was descriptive and clinically focused, rather than etiologically focused. Country-specific carrier and risk screening studies were not among the top research designs. The genetic component of certain highly heritable diseases, as well as diabetes, obesity, hypertension, chronic lung dysfunction and metabolic syndrome were all under investigated.ConclusionsThis scoping review identified gaps for further research in the context of bioinformatics and genome-wide association studies. Genetic research in the Arab region has to be redirected towards NCDs with the highest morbidity, heritability and health burden within each country. A focused research plan to include community genetics is required for its proper integration in the Arab community.

SLC35B4, an Inhibitor of Gluconeogenesis, Responds to Glucose Stimulation and Downregulates Hsp60 among Other Proteins in HepG2 Liver Cell Lines

SLC35B4, solute receptor for UDP-N-acetylglucosamine and UDP-xylose, is associated with diabetes and predisposing conditions. This study investigated the localization of SLC35B4 and compared the differential expression between a knockdown of SLC35B4 and controls in HepG2. Responsiveness to glucose, expression, and localization were assayed using Western blot and immunostaining. Localization was confirmed using a proximity ligation assay. Two-dimensional (2D) gel electrophoresis and MALDI-TOF were used to identify differentially expressed proteins and pathway analysis was performed. SLC35B4 was increased by 60% upon glucose stimulation and localized in Golgi apparatus and endoplasmic reticulum. Presence of SLC35B4 in the Golgi apparatus suggests its involvement in the biosynthesis of glycoconjugate proteins. Four proteins were markedly under-expressed (Hsp60, HspA8, TUBA1A, and ENO1) and linked to the pathogenesis of diabetes or post-translationally modified by O-GlcNAc. Glucose levels activate SLC35B4 expression. This triggers a downstream effect via Hsp60 and other proteins. We hypothesize that the downstream effect on the proteins is mediated via altering the glycosylation pattern inside liver cells. The downstream cascade ultimately alters the ability of cultured liver cells to inhibit endogenous glucose production, and this could play a role in the association of the above-listed genes with the pathogenesis of diabetes.