Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Abstract

Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. Objectives: To identify a gene for BHR on chromosome 5q31-q33. Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.

Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline

“…4,15 However, along with conflicting results for the associations between polymorphisms of genes in leukotriene and COX pathways [16][17][18] genes on other pathways including bronchial hyperresponsiveness by MHC or structural genes have provided new insights for AERD pathogenesis. 5,19 Therefore, although further replications and functional evaluations are required, our findings on the associations of TAP2 with AERD-related symptoms, particularly with FEV1 decline by aspirin provocation, might provide evidences for the role of the gene in respiratory deficiencies. Abbreviations: SNP, single-nucleotide polymorphism; UTR, untranslated region.…”

“…Although pathophysiology of AERD has been closely linked to the overproduction of cysteinyl-leukotrienes (CysLTs), 4 recent studies have also reported that genes on other pathways, such as the structural gene protocadherin-1 (PCDH1) and the transporter gene solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12), could be involved in the development of aspirin hypersensitivity in asthmatics. 5,6 Both transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/ TAP) (TAP1 and TAP2), also referred as transporter associated with antigen processing, are located within the major histocompatibility complex (MHC) class II region of the leukocyte antigen (HLA) locus on human chromosome 6. TAP complex is a heterodimer consisted of two subunits encoded by TAP1 and TAP2.…”

Ethiopathogenic mechanisms of bronchial asthma

“…Some 30 locus on various chromosomes have been linked on the one hand with the function of the airways and another on the production of IgE [4,5]. Chromosome 5 (5q31-q33) contains the genes that modulate the production of interleukins secreted by Th2 lymphocytes, such as IL-4 and IL-13 responsible for the atopic response when involved in the secretion of IgE by B lymphocytes (plasma cells), as well as other interleukins (IL-3, IL-5, IL-9) which also intervene In addition, in the same gene has been identified the protocadherin-1 (PCDH1) that could alter the integrity of the bronchial epithelium, the first line of defense against inhalation of environmental substances [6]. On the other hand, the onset of asthma in the pediatric age has linked to chromosome 17q21 the main genetic determinant of the ORMDL3 gene that encodes endoplasmic reticulum proteins and has also been associated with poor outcome in children exposed to environmental irritants, especially tobacco smoke [7,8].…”

Fast preparation of a polyclonal antibody against chicken protocadherin 1

“…Abnormalities in delta-pcdhs genes may be responsible for the pathogenesis of several neurological disorders and carcinogenesis. For instance, Koppelman et al (2009) found that pcdh1 was a susceptibility gene for bronchial hyperresponsiveness, and Koning et al (2012) found that pcdh1 was a novel susceptibility gene for asthma that is expressed in airway epithelium. Philibert et al (2012) found that the deficiency of pcdh12 led to modifications in the structure and function of arteries.…”