B524 - Linkage of polymorphisms of PMCH with asthma and obesity - 08/07/2007

B number: 
Principal applicant name: 
Prof Tak Lee (King's College London, UK)
Dr David Cousins (Not used 0, Not used 0), Ms Hilary Sandig (Not used 0, Not used 0), Prof John Henderson (University of Bristol, UK), Dr Roger Newson (Imperial College London, UK), Prof Seif Shaheen (University of Bristol, UK), Prof John Holloway (University of Southampton, UK)
Title of project: 
Linkage of polymorphisms of PMCH with asthma and obesity
Proposal summary: 

Th1 and Th2 cells are the two main subsets of CD4+ T helper cell and are defined by their cytokine expression patterns. The subsets have different roles in the clearance of pathogens, and their unregulated activation leads to distinct immune pathologies. Th1 cells express IFNgamma and are crucial for the phagocytic immune response against intracellular pathogens such as M. tuberculosis, but their aberrant activation is implicated in autoimmunity. Human Th2 cells express IL-4, IL-5 and IL-13 and orchestrate an immune response characterized by eosinophilia and IgE class-switching, in order to fight extracellular pathogens. Th2 cell activation is also central to the pathogenesis of allergic diseases such as asthma, in which the Th2 cytokines play important roles.

PMCH encodes a pro-hormone, pro-melanin concentrating hormone (PMCH) of 165 amino acids which is proteolytically processed to form several peptides including the orexigenic peptide melanin concentrating hormone (MCH). PMCH was first implicated in the regulation of appetite by the finding that the gene is upregulated in obese, leptin deficient mice. Further studies demonstrated that intracerebroventricular administration of MCH into rats increases feeding, and weight gain occurs after chronic infusion of the peptide into the lateral ventricle, strongly suggesting that the peptide stimulates appetite. In addition, mice deficient in MCH are lean and hypophagic, and animals overexpressing the gene are obese. Several groups cloned the G-protein coupled receptor for MCH termed MCHR1, and MCHR1 deficient mice are resistant to diet induced obesity. A second receptor, MCHR2, was later identified in humans by its homology to MCHR1. MCHR2 is not present in the rodent genomes, but orthologues have been identified in ferret, dog and rhesus monkey, in addition to the human gene. PMCH therefore has an important role in increasing appetite, and a small molecule antagonist of MCHR1 has been shown to reduce feeding and weight gain in rats fed a high fat diet ad libitum.

The prevalence of both asthma and obesity are increasing in the western world, and a link between the two conditions has been proposed and debated. Epidemiological evidence from several studies suggests a positive association between body mass index (BMI) and asthma, especially in females (1). Mechanisms to explain the association are unknown.

Utilizing microarray analysis of in vitro differentiated Th1 and Th2 cells to identify secreted proteins selectively expressed by human Th2 cells, we found for the first time that activated Th2 cells expressed the gene PMCH. Activated Th2 cells secreted MCH-containing proteins, and ex vivo Th2 but not Th1 cells also expressed the gene.

PMCH gene is located on chromosome 12q23.1, a region consistently shown to have linkage to asthma. We hypothesize that expression of PMCH by Th2 cells in vivo in the asthmatic lung may provide a mechanistic link between allergic inflammation, asthma and obesity. Asthmatic individuals are not necessarily obese, however, therefore we wish to test whether there are genetic polymorphisms of PMCH that are associated with both asthma and obesity. As expected, a positive association between BMI and asthma in girls at 7 years of age has been confirmed in ALSPAC (AJ Henderson, unpublished data).

Date proposal received: 
Sunday, 8 July, 2007
Date proposal approved: 
Sunday, 8 July, 2007
Allergies, Genetics, Respiratory, Atopy
Primary keyword: