MO-1, Novel Obesity Gene: Genotype and Phenotype Characterization of Obese and Lean Arab Groups from Qatari and Palestinian Arab (QPA) origin

Dr. Adel Ahmad Shalata

Obesity is a common metabolic disorder that predisposes to dyslipidemia, hypertension, type 2 diabetes and cardiovascular disease. Over the last 20 years, the worldwide prevalence of obesity has increased to epidemic proportions. In the United States only four states had obesity prevalence rates of 15-19 percent in 1991 and no state had rates at or above 20 percent. In 2005, only 4 states had obesity prevalence rates less than 20 percent, while 17 states had prevalence rates equal to or greater than 25 percent, with 3 states having a prevalence rate greater than 30 percent.

Both genetic make-up and environmental factors, e.g. sedentary life style and overfeeding, contribute to the development of obesity. The estimated genetic contribution to body mass index (BMI) ranges from 60% to 84%. Although many trait loci have been found to be associated with obesity, only a few obesity genes have been identified, e.g. leptin, and their relationship to the development of obesity characterized.

Recently, we mapped and cloned a novel obesity gene, designated as the MO-1 gene (for morbid obesity-1 gene), in a large consanguineous Arab family (unpublished data), with an apparently autosomal recessive mode of inheritance. In this study we propose to expand our investigation and screen individuals from the Qatari and Palestinian Arab origin (QPA) for mutations and variants in the MO-1 gene. We also will identify polymorphic sites and SNPs in the MO-1 gene which correlates with clinical and metabolic measurements of obesity and insulin resistance. Subjects who carry these genetic variations in the MO-1 gene will receive detailed metabolic and genetic studies to identify the molecular and metabolic pathways which are regulated by the MO-1 gene and which are responsible for the development of obesity and insulin resistance.  We believe that the results of this study will lead to the identification of novel pathways which regulate cellular energy metabolism and provide new targets for the prevention and treatment of obesity and insulin resistance.
The QPA is going to be a large cohort that will be used in this proposal and in future plans as well for studying both obesity and type 2 diabetes.

Objectives of the study:

In this grant, we propose to study the MO-1 gene in a cohort of obese Arab families. We plan to recruit and study families with obesity and healthy leanness from Qatari and Palestinian Arab origin (QPA).
We plan to obtain and construct: a) comprehensive clinical and b) biochemical database of 300 obese and 300 lean subjects. And c) extract DNA and obtain a lymphoblast cell line from each one of the participants for further future studies.
The biochemical tests will include: SMA, total cholesterol, HDL, LDL, triglycerides, APO-A, APO-B, HbA1c, markers for atherosclerosis (VCAM-1, ICAM-1), inflammation markers (C-reactive protein, TNF-alpha, PAI-1, IL2, IL6, IL12, adeponectin, resistin, visfatin), oxidative stress markers (isoprostane and nitrotyrosines), leptin and cytokine studies.

Specific Objective:

1) To determine the genetic variation in a novel obesity gene, MO-1, in the QPA participants.
2) To examine the association between genetic variations in the MO-1 gene and obesity, energy expenditure, insulin resistance and glucose tolerance.

Secondary Objective:
The comprehensive families' clinical and biochemical database and the DNA samples with the lymphoblast cell lines will be a unique cohort that will use us for future research plans looking for new genes involved in obesity, diabetes mellitus type-2 and the Metabolic syndrome in the Arab population with the inter multidisciplinary cooperation involving other research PI's from Qatar research centers and from the TR&D center.