Chr15q25 Genetic Variant rs16969968 Alters Cell Differentiation in Respiratory Epithelia

Abstract

The gene cluster region, CHRNA3/CHRNA5/CHRNB4, encoding for nicotinic acetylcholine receptor (nAChR) subunits, contains several genetic variants linked to nicotine addiction and brain disorders. The CHRNA5 single-nucleotide polymorphism (SNP) rs16969968 is strongly associated with nicotine dependence and lung diseases. Using immunostaining studies on tissue sections and air-liquid interface airway epithelial cell cultures, in situ hybridisation, transcriptomic and cytokines detection, we analysed rs16969968 contribution to respiratory airway epithelial remodelling and modulation of inflammation. We provide cellular and molecular analyses which support the genetic association of this polymorphism with impaired ciliogenesis and the altered production of inflammatory mediators. This suggests its role in lung disease development.

PLEK2 mediates metastasis and invasion via α5‐nAChR activation in nicotine‐induced lung adenocarcinoma

“…nAChR is a nicotine‐dependent receptor, and its expression level plays an important role in the development of smoking‐related diseases, especially respiratory diseases, 9 such as chronic obstructive pulmonary disease (COPD) and lung cancer. Genome‐wide association studies have shown that CHRNA5 gene (encoding α5‐nAChRs [α5‐nAChR]) polymorphisms are significantly related to the occurrence and development of cancer, especially lung cancer 10,11 ; it is highly expressed in esophageal cancer, gastric cancer and lung cancer and plays an important role in tumor cell proliferation, invasion and metastasis 12 . Our previous studies have shown that α5‐nAChR mediates the development and progression of nicotine‐induced lung cancer, activates Hif‐1α/VEGF, JAK2/STAT3, and Jab/Csn5 signaling, and promotes the proliferation and migration of lung cancer cells 13–15 .…”

Molecular Effects of Mutations in Human Genetic Diseases

“…The eight papers published in this SI described case studies that may provide a useful framework for understanding the general molecular defects underlying a broad and diverse spectrum of human diseases. These included multifactorial or polygenic disorders, such as lung cancer (OMIM*612052) and osteoporosis (OMIM*166710) [ 1 , 2 ], or monogenic disorders, such as Long QT Syndrome 1 (LQT; OMIM*192500), Hyaline fibromatosis syndrome (OMIM*228600), Dystrophic epidermolysis bullosa (RDEB; OMIM*226600), Xeroderma Pigmentosum C Phenotype (XP-C; OMIM*278720), and MTHFR deficiency (OMIM*236250) [ 3 , 4 , 5 , 6 , 7 ].…”

“…Two of the SI-published works investigated the role of novel genetic variants in the ANTXR2 and LRP5 genes identified by NGS of affected individuals from selected cohorts [ 2 , 4 ]. Diabasana et al studied the molecular effects of a small nucleotide polymorphism (SNP) of CHRNA5 gene, known to confer susceptibility for lung disease [ 1 ]. Beilin et al investigated the correlation between specific mutations, selected among hundreds of COL7A1 reported variants, and the varying severity of cutaneous manifestation [ 5 ].…”

“…Direct inspection of patient-derived tissues can be used to identify abnormal molecular and morphological features in the patients compared to healthy individuals. In the work of Diabasane et al, lung tissue sections from patients carrying the CHRNA5 SNP (rs16969968) were used to assess its impact on epithelial remodelling in human lungs [ 1 ]. The significant decrease in multiciliated cells in bronchial epithelia of SNP patients compared to WT patients suggested a SNP-associated alteration of ciliogenesis [ 1 ].…”

“…In the work of Diabasane et al, lung tissue sections from patients carrying the CHRNA5 SNP (rs16969968) were used to assess its impact on epithelial remodelling in human lungs [ 1 ]. The significant decrease in multiciliated cells in bronchial epithelia of SNP patients compared to WT patients suggested a SNP-associated alteration of ciliogenesis [ 1 ]. In another SI work, Jorik M. van Rijn et al used second harmonic generation (SHG) imaging, which visualises non-labelled fibrillar proteins such as collagen, and electron microscopy inspection of duodenum and skin sections from ANTXR2-deficient patients [ 4 ].…”