Novel Gentic Variations Contributing to Asthma Susceptability in Saudi Arabia
Research Problem Asthma is one of the most common chronic diseases in the world that affects approximately 300 million individuals worldwide. It is characterized by airway inflammation and bronchoconstriction leading to airflow obstruction, however, the triggering factors behind asthma development remains to be elucidated. Genetic risk factors have been suggested to play a central role in asthma development. Twin studies supported a strong genetic component to asthma, especially childhood asthma, with heritability estimates suggesting that 48-70% of asthma risk is attributed to genetic risk factors. Suggestive susceptibility genes have been identified in European and American populations but not yet in the Middle East including Saudi Arabia. Identified genes whether they are polymorphic variants of genes encoding known pathophysiological molecules or novel genes identified by linkage or genome-wide association studies (GWAS) are inconsistent in different populations thereby adding to the need to undertake genetic studies on different ethnic populations and in different countries. Here, the investigators hypothesize that polymorphic variation of novel susceptibility genes form a major risk factor for asthma development, response to treatment and progression in the Saudi population with strong diagnostic, prognostic and therapeutic implications.
Research Significance Since the manifestation of complex inflammatory disorders with strong heritability is complex involving genetic and environmental interaction, each ethnically distinct population must be examined to know whether gene-disease association exists in that population. The objectives of this proposal are to discover novel asthma susceptibility genes in the Saudi population. A better understanding of the genetic mechanisms of asthma will enhance our knowledge of its pathophysiology. Asthmatic patients with distinct genotypes respond differently to asthma medications. Therefore, improvements in diagnostics and pharmacogenetics may be the first clinical developments of these extensive studies. This embraces the concept of asthma subphenotypes and stratified medicine where interventions are targeted at those individuals who will best benefit from them with minimal side effects. Physicians looking after asthmatic patients will be able to provide better medical service tailored to those patients, as well as to identify Saudi people at high risk for the development of asthma, especially the more severe forms of the disease.
Research Objectives The main objective of our proposal is to identify known and novel asthma susceptibility genes in the Saudi population and to investigate their interaction with clinical, environmental, and inflammatory factors contributing to asthma pathophysiology.
Research Methodology In this proposal, the investigators will investigate the genetic factors contributing to asthma susceptibility by determining in Saudi population, the presence of single nucleotide polymorphisms (SNPs) that have been previously reported from linkage and GWAS in other populations. Whole genome DNA will also be scanned for novel SNPs of selected "asthma genes" using microarrays. This will enable us to identify new SNPs that contribute to the risk of asthma specifically in the Saudi population. In addition, the investigators will cross-reference all genetic and immunological parameters with the corresponding clinical data in order to elucidate the impact of certain genes, or their products (e.g. cytokines), on the clinical manifestation of asthma.
Collection of Clinical Data That Will be Used in This Study and Will Form a Data Bank for Asthma in Saudi Arabia
Identify Known and NOVEL Genetic Risk Factors Contributing to Asthma Susceptibility
Study the Mechanistic Roles of the Genetic Variants Within Major Asthma Susceptibility Genes
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Novel Gentic Variations Contributing to Asthma Susceptability in Saudi Arabia|
- IL-4 receptor alpha and STAT6 single nucleotide polymorphisms are associated with increased risk of asthma in a Saudi Arabian population. [ Time Frame: 2 years ] [ Designated as safety issue: No ]IL-4Rα rs1805010 and rs1801275 SNPs have been found to be significantly associated with asthma susceptibility in different ethnic groups; some STAT6 SNPs, including rs324011 and rs324015, have also been associated with asthma predisposition and/or IgE levels. Risk evaluations of IL-4Rα and STAT6 SNPs in association with asthma have never been evaluated in Saudi Arabian populations. Methods: Saudi Arabian patients with documented history of severe asthma (n=190) and healthy subjects (n=194) were recruited. Allelic and genotype association to asthma was assessed for IL-4Rα and STAT6 polymorphisms using nucleotide sequencing. Results: The IL4Rα rs1801275 SNP A/G-G/G genotypes, but not the A/A genotype, were significantly associated with asthma predisposition (OR=0.47; 95% CI=0.31-0.72; P<0.001*; dominant model); Similarly, for STAT6 rs324011, odds were significantly higher that homozygous T/T genotype could be associated with asthma.
|Study Start Date:||October 2010|
|Study Completion Date:||September 2013|
|Primary Completion Date:||September 2013 (Final data collection date for primary outcome measure)|
|Asthmatic sporadic and familial|
|Control subjects spradic and familial|