Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis.

Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis.

Publication date: Nov 06, 2019

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual allele effects, has the potential to delineate molecular interactions that are important in SSc-related lung pathology. However, detecting genetic interactions, or epistasis, in human cohorts is challenging. Large numbers of variants with low minor allele frequencies, paired with heterogeneous disease presentation, reduce power to detect epistasis. Here we present an analysis that increases power to detect epistasis in human genome-wide association studies (GWAS). We tested for genetic interactions influencing lung function and autoantibody status in a cohort of 416 SSc patients. Using Matrix Epistasis to filter SNPs followed by the Combined Analysis of Pleiotropy and Epistasis (CAPE), we identified a network of interacting alleles influencing lung function in patients with SSc. In particular, we identified a three-gene network comprising WNT5A, RBMS3, and MSI2, which in combination influenced multiple pulmonary pathology measures. The associations of these genes with lung outcomes in SSc are novel and high-confidence. Furthermore, gene coexpression analysis suggested that the interactions we identified are tissue-specific, thus differentiating SSc-related pathogenic processes in lung from those in skin.

Tyler, A., Mahoney, J.M., and Carter, G.W. Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis. 19431. 2019 G3 (Bethesda).

Concepts Keywords
Allele Gene network
Allele Frequencies Progressive fibrosis
Alleles Lung disease
Autoantibody Systemic Sclerosis Scleroderma
Autoimmune Branches of biology
Bethesda Organ systems
CAPE Autoimmune diseases
Cohort Connective tissue diseases
Epistasis Classical genetics
Fibrosis Epistasis
Gene Sjögren syndrome
Genetic Interactions Systemic scleroderma
Genome Lung cancer
Interact Pleiotropy
Lung
Lung Disease
Pathogenesis
Pathogenic
Pathology
Pleiotropy
Progressive
Scleroderma
SNPs
Systemic Sclerosis
Targeted Treatments

Semantics

Type Source Name
disease MESH Systemic Sclerosis
disease DOID Systemic Sclerosis
disease MESH autoimmune disease
disease DOID autoimmune disease
disease MESH fibrosis
disease MESH cause of death
disease MESH lung disease
disease DOID lung disease
gene UNIPROT LARGE1
gene UNIPROT NR4A3
gene UNIPROT SMC2
gene UNIPROT WNT5A
gene UNIPROT RBMS3
gene UNIPROT MSI2
pathway BSID Wnt signaling
pathway BSID Wnt Signaling

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