||Slightly increased risk for pulmonary fibrosis (and decreased DSP expression)
||One copy of the risk allele (G), slightly increased risk for pulmonary fibrosis
||common/normal (higher levels of DSP expression)
The SNP rs2076295 on chromosome 6p24 is located within the intronic region of the DSP gene, which encodes the protein desmoplakin. Desmoplakin is a component of the desmosome, and is an adhesive intercellular molecule that tightly links adjacent cells for cell-cell adhesion. It is part of a dynamic structure that involves other proteins, such as plakoglobin and plakophilins, which tether the cytoskeleton to the cell membrane [PMID 20066089]. The minor allele rs2076295(G) is reported by dbSNP to have an allele frequency (MAF) of 0.454.
A recent case-control genome-wide association study (GWAS) involving 1,616 cases and 4,683 controls (and a replication study with 876 cases and 1,890 controls) was performed on non- Hispanic white individuals with fibrotic idiopathic interstitial pneumonia (IIP) [PMID 23583980]; note the correction posted online 1 Oct 2013. The most common and severe form of IIP is idiopathic pulmonary fibrosis (IFP), and all forms of IIP (including IFP) were included in this study, in which a total of 439,828 SNPs were studied. Using an additive model for the minor allele at each SNP, a total of 19 SNPs, representing 7 chromosome locations, with genome-wide significant associations (P < 5 x 10-8) were identified in the GWAS discovery process.
Apart from SNPs that have been previously associated with IIP in the MUC5B, TERT, and TERC genes [PMID 21506741][PMID 21506748][PMID 23321605][PMID 17392301][PMID 17460043][PMID 18835860], many of the other genome-wide significant SNPs reported in this study were newly discovered risk loci for IIP. Among them is rs2076295 (minor allele = G; Pmeta = 1.1 x 10-19), which is in the intronic region of the DSP gene, with an odds ratio (OR) of 1.43 for IIP (discovery GWAS). A related lung tissue gene expression study (100 IPF cases, 94 controls) showed that DSP expression was down-regulated in cases when compared to controls (P = 0.0002), and the expression level was genotype-dependent on the SNP (P = 0.002) – relative expression of DSP decreased with the number of copies of the putative risk allele, with GG alleles having the lowest level of expression, and TT the highest. This is consistent with the additive model used in the discovery GWAS.
IIP represents a group of lung diseases that are often characterized by pulmonary fibrosis or progressive scarring of the alveolar interstitium, which can eventually lead to hypoxemic respiratory insufficiency and death [PMID 11790668]. Some forms are known to be associated with environmental exposures (e.g. asbestos), drug toxicity, radiation exposure, or collagen vascular diseases (e.g. scleroderma). Previous studies have focused on the association between IIP and the MUC5B, TERT, and TERC genes. MUC5B encodes mucin 5B, expressed in mucus-producing cells in the distal airways of the lung. Lung tissue from individuals with IIP has higher concentrations of MUC5B than controls. TERT and TERC are involved in the maintenance of telomere lengths, and mutations in these genes are associated with shortened telomeres in the alveolar epithelia.
The recently discovered association with the DSP locus suggests that changes in cell-cell adhesion may also play a role in IIP. Desmosomes (and desmoplakin) are important in maintaining the integrity of tissues that experience mechanical stress (such as the peripheral portions of the lung), and there is strong evidence that perturbation of the desmosome disrupts epithelial homeostasis [PMID 20066089]. Mutations in DSP have also been associated with other diseases that involve loss of tissue integrity, such as in arrhythmogenic right ventricular dysplasia [PMID 18382419], keratodermas [PMID 9887343][PMID 10594734], and alopecia [PMID 11841538][PMID 20738328].
[PMID 30207747] A Novel Variant of Desmoplakin Is Potentially Associated with Silicosis Risk.
[PMID 33076992] Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study.