Family With Sequence Similarity 13 Member A Research Articles

SNPs in FAM13A and IL2RB genes are associated with FeNO in adult subjects with asthma

Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008–2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming an a priori genetic model: step (1) a machine learning technique [gradient boosting machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step (2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A (FAM13A) and SNP rs3218258 in interleukin 2 receptor subunit beta (IL2RB) gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses (FAM13A), or in immune response processes (IL2RB). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation.

AKT Phosphorylates FAM13A and Promotes Its Degradation via CUL4A/DDB1/DCAF1 E3 Complex.

SNPs within FAM13A (family with sequence similarity 13 member A) gene are significantly associated with chronic obstructive pulmonary disease and lung function in genome-wide association studies (GWAS). However, how FAM13A protein is regulated under physiological and pathological conditions remains largely elusive. Herein, we report that FAM13A is phosphorylated at the serine 312 residue by AKT kinase after cigarette smoke extract treatment and thereby recognized by the CULLIN4A/DCAF1 (DDB1 and CUL4 associated factor 1) E3 ligase complex, rendering the ubiquitination-mediated degradation of FAM13A. More broadly, downregulation of FAM13A protein upon AKT activation, as a general cellular response to acute stress, was also detected in influenza- or naphthalene-injured lungs in mice. Functionally, reduced protein levels of FAM13A lead to accelerated epithelial cell proliferation in murine lungs during the recovery phase after injury. In summary, we characterized a novel molecular mechanism that regulates the stability of FAM13A protein, which enables the fine-tuning of lung epithelial repair after injury. These significant findings will expand our molecular understanding of the regulation of protein stability, which may modulate lung epithelial repair implicated in the development of chronic obstructive pulmonary disease and other lung diseases.

Family with sequence similarity 13 member A mediates TGF-\u03b21-induced EMT in small airway epithelium of patients with chronic obstructive pulmonary disease

BackgroundTo explore the role of family with sequence similarity 13 member A (FAM13A) in TGF-β1-induced EMT in the small airway epithelium of patients with chronic obstructive pulmonary disease (COPD).MethodsSmall airway wall thickness and protein levels of airway remodeling markers, EMT markers, TGF-β1, and FAM13A were measured in lung tissue samples from COPD and non-COPD patients. The correlations of FAM13A expression with COPD severity and EMT marker expression were evaluated. Gain- and loss-of-function assays were performed to explore the functions of FAM13A in cell proliferation, motility, and TGF-β1-induced EMT marker alterations in human bronchial epithelial cell line BEAS-2B.ResultsIndependent of smoking status, lung tissue samples from COPD patients exhibited significantly increased small airway thickness and collagen fiber deposition, along with enhanced protein levels of remodeling markers (collagen I, fibronectin, and MMP-9), mesenchymal markers (α-SMA, vimentin, and N-cadherin), TGF-β1, and FAM13A, compared with those from non-COPD patients. FAM13A expression negatively correlated with FEV1% and PO2 in COPD patients. In small airway epithelium, FAM13A expression negatively correlated with E-cadherin protein levels and positively correlated with vimentin protein levels. In BEAS-2B cells, TGF-β1 dose-dependently upregulated FAM13A protein levels. FAM13A overexpression significantly promoted cell proliferation and motility in BEAS-2B cells, whereas FAM13A silencing showed contrasting results. Furthermore, FAM13A knockdown partially reversed TGF-β1-induced EMT marker protein alterations in BEAS-2B cells.ConclusionsFAM13A upregulation is associated with TGF-β1-induced EMT in the small airway epithelium of COPD patients independent of smoking status, serving as a potential therapeutic target for anti-EMT therapy in COPD.

Connecting COPD GWAS Genes: FAM13A Controls TGFβ2 Secretion by Modulating AP-3 Transport.

Chronic obstructive pulmonary disease (COPD) is a common, complex disease and a major cause of morbidity and mortality. Although multiple genetic determinants of COPD have been implicated by genome-wide association studies (GWASs), the pathophysiological significance of these associations remains largely unknown. From a COPD protein-protein interaction network module, we selected a network path between two COPD GWAS genes for validation studies: FAM13A (family with sequence similarity 13 member A)-AP3D1-CTGF- TGFβ2. We find that TGFβ2, FAM13A, and AP3D1 (but not CTGF) form a cellular protein complex. Functional characterization suggests that this complex mediates the secretion of TGFβ2 through an AP-3 (adaptor protein 3)-dependent pathway, with FAM13A acting as a negative regulator by targeting a late stage of this transport that involves the dissociation of coat-cargo interaction. Moreover, we find that TGFβ2 is a transmembrane protein that engages the AP-3 complex for delivery to the late endosomal compartments for subsequent secretion through exosomes. These results identify a pathophysiological context that unifies the biological network role of two COPD GWAS proteins and reveal novel mechanisms of cargo transport through an intracellular pathway.

FAM13A Regulates KLRG1 Expression and Interferon Gamma Production of Natural Killer Cells

Abstract The polymorphism of the gene FAM13A (family with sequence similarity 13, member A) is strongly linked to the risk of lung cancer and chronic obstructive pulmonary disease, which are among the leading causes of mortality and morbidity in lung-related diseases worldwide. However, the underlying molecular and cellular mechanisms through which FAM13A contributes to the pathogenesis of these diseases largely remain unclear. Here, using a Fam13a knock out (KO) mouse model, we showed that Fam13a depletion upregulated the expression of the terminal differentiation and inhibitory marker, KLRG1 (killer cell lectin-like receptor G1) in natural killer (NK) cells. NK cells from Fam13a-deficient mice showed impaired IFN-γ production either against target tumor cells or following various cytokine cocktail stimulations. Furthermore, the number of lung metastases induced by B16F10 melanoma cells was increased in Fam13a-KO mice. Collectively, our data suggest a key role of FAM13A in regulating NK cell functions, indicating that the key lung-disease risk gene FAM13A might contribute to the pathogenesis of several lung diseases via regulating NK cells.

FAM13A promotes proliferation of bovine preadipocytes by targeting Hypoxia-Inducible factor-1 signaling pathway

ABSTRACT The family with sequence similarity 13 member A (FAM13A) gene has been discovered in recent years and is related to metabolism. In this study, the function of FAM13A in precursor adipocyte proliferation in Qinchuan cattle was investigated using fluorescence quantitative polymerase chain reaction (PCR), western blotting, 5-ethynyl-2′-deoxyuridine staining, and other tests. FAM13A promoted precursor adipocyte proliferation. To determine the pathway FAM13A was involved in, transcriptome sequencing, fluorescence quantitative PCR, western blotting, and other tests were used, which identified the hypoxia inducible factor-1 (HIF-1) signalling pathway. Finally, cobalt chloride, a chemical mimic of hypoxia, was used to treat precursor adipocytes. mRNA and protein levels of FAM13A were significantly increased after hypoxia. Thus, FAM13A promoted bovine precursor adipocyte proliferation by inhibiting the HIF-1 signalling pathway, whereas chemically induced hypoxia negatively regulated FAM13A expression, regulating cell proliferation.

Effect of family with sequence similarity 13 member A gene interference on apoptosis and proliferation of human airway epithelial cells and its relationship with small airway remodeling in patients with chronic obstructive pulmonary disease

Objective: To explore the relationship between family with sequence similarity 13 member A (FAM13A) gene and small airway remodeling in chronic obstructive pulmonary disease (COPD), and the effect of interference with FAM13A gene expression on the apoptosis and proliferation phenotype of human airway epithelial cells (16HBE). Methods: From January 2018 to January 2020, 74 patients in the Department of Thoracic Surgery of General Hospital of Ningxia Medical University were treated by surgery for lung tumors or pulmonary bullae. According to the lung function and smoking history, the 74 patients were divided into four groups: non-smoking group with normal lung function (normal group, 23 patients), smoking group with normal lung function (smoking group, 24 patients), non-smoking group with COPD (11 patients) and smoking group with COPD (16 patients). The expression of FAM13A in small airway of each group was detected by immunohistochemistry, and the correlation between FAM13A and the airflow restriction indexes by pulmonary function was analyzed. The shRNA fragment of FAM13A gene was designed, and the shRNA lentivirus vector of FAM13A gene was constructed and packaged. The expression level of FAM13A gene was detected by real-time fluorescent quantitative PCR (qRT-PCR) and Western blot, and the best shRNA sequence was screened. Flow cytometry was used to detect apoptosis rate and the fluorescence intensity of proliferation marker Ki-67 in 16HBE cells. Results: FAM13A was mainly expressed in the cytoplasm of small airway epithelial cells. The levels of FAM13A absorbance (A) of small airway epithelial cells in non-smoking group and smoking group with COPD were higher than those in normal group and smoking group (0.365±0.026, 0.412±0.053 to 0.113±0.018, 0.105±0.009, all P<0.05), and they were negatively correlated with forced expiratory volume in 1s/forced vital capacity (FEV(1)/FVC) and FEV(1)% pre (r=-0.48 and r=-0.40, all P<0.05). The FAM13A shRNA lentiviral vector was successfully constructed, and FAM13A interference was successfully achieved in the 16HBE cell line. After infection of 16HBE cells, the results of qRT-PCR and Western blot showed that the expression of FAM13A in shRNA-target-2 group decreased (all P<0.01). Compared with the negative control group (shRNA-NC), the apoptosis rate of FAM13A shRNA group decreased (P=0.023), and the fluorescence intensity of Ki-67 also decreased (P=0.042). Conclusions: FAM13A gene expression is increased in COPD small airway epithelial cells, and it is related to COPD airflow limitation. FAM13A gene may participate in the process of COPD remodeling by affecting the apoptosis and proliferation of human airway epithelial cells.

FAM13A affects body fat distribution and adipocyte function

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

The Molecular Characteristics of the FAM13A Gene and the Role of Transcription Factors ACSL1 and ASCL2 in Its Core Promoter Region.

The gene family with sequence similarity 13 member A (FAM13A) has recently been identified as a marker gene in insulin sensitivity and lipolysis. In this study, we first analyzed the expression patterns of this gene in different tissues of adult cattle and then constructed a phylogenetic tree based on the FAM13A amino acid sequence. This showed that subcutaneous adipose tissue had the highest expression in all tissues except lung tissue. Then we summarized the gene structure. The promoter region sequence of the gene was successfully amplified, and the −241/+54 region has been identified as the core promoter region. The core promoter region was determined by the unidirectional deletion of the 5’ flanking promoter region of the FAM13A gene. Based on the bioinformatics analysis, we examined the dual luciferase activity of the vector constructed by the mutation site, and the transcription factors ACSL1 and ASCL2 were found as transcriptional regulators of FAM13A. Moreover, electrophoretic mobility shift assay (EMSA) further validated the regulatory role of ACSL1 and ASCL2 in the regulation of FAM13A. ACSL1 and ASCL2 were finally identified as activating transcription factors. Our results provide a basis for the function of the FAM13A gene in bovine adipocytes in order to improve the deposition of fat deposition in beef cattle muscle.

High expression of FAM13A was associated with increasing the liver cirrhosis risk.

AimLiver cirrhosis is a consequence of chronic liver disease, and it may be caused by multiple influences of both genetic and environmental factors. Family with sequence similarity 13 member A (FAM13A) has been previously associated with lung function in several lung diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary fibrosis. The aim of this study was to explore whether FAM13A polymorphisms confer susceptibility to liver cirrhosis.Methods FAM13A expression was evaluated in liver cirrhosis tissues by immunohistochemistry staining. The relationship between FAM13A gene polymorphism and liver cirrhosis was determined by association analysis. The genotypes were assessed in the Agena MassARRAY platform. Statistical analysis was performed using chi‐squared test/Fisher's exact test, genetic model analysis, and haplotype analysis.ResultsThe results showed that the expression of FAM13A is obvious higher in the liver cirrhosis tissue cells than in the normal liver tissue cells. Moreover, association analysis results indicated that the minor allele “A” of rs3017895 was positively associated with high risk of liver cirrhosis in the allele model by the chi‐squared test (OR = 1.32, 95%CI = 1.03–1.68, p = 0.028). Logistic regression analyses revealed that the risk of liver cirrhosis was significantly higher in subjects with the G/A‐G/G genotype of rs3017895 than those with A/A genotype under the dominant model and log additive model, and the T/A‐A/A genotype of rs1059122 was positively associated with higher liver cirrhosis than T/T genotype based on dominant model respectively. In addition, haplotype analysis showed that the G‐A haplotype of rs3017895‐rs1059122 of the FAM13A gene significantly increased the risk of liver cirrhosis.ConclusionOur findings demonstrated that the high expression of FAM13A may be associated with an increased risk of liver cirrhosis.

Progresses in human FAM13A gene

Variants in FAM13A(family with sequence similarity 13 member A) have been found in genome-wide association studies(GWAS) to associate with lung function in several common chronic lung diseases(CLD) such as asthma, chronic obstructive pulmonary disease(COPD), as well as in idiopathic interstitial pneumonias(IIP). This gene was cloned in 2004, yet the function of encoded protein is unknown.Its genetic contribution in CLD suggests a major function of this gene both in lung physiology and CLD.This review provides a brief summary of the current research of FAM13A, and demonstrates the necessity to study its biological function besides its well accepted genetic contribution.Further interpretations of FAM13A variants may help in understanding of CLD mechanisms and offer opportunity for intervention. Key words: FAM13A gene; Asthma; Chronic obstructive pulmonary disease

FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition

BackgroundCystic fibrosis (CF) lung disease severity is highly variable and dependent on several factors including genetic modifiers. Family with sequence similarity 13 member A (FAM13A) has been previously associated with lung function in the general population as well as in several chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), we examined whether FAM13A is a modifier gene of CF lung phenotype. We also studied how FAM13A may contribute to the physiopathological mechanisms associated with CF. MethodsWe investigated the association of FAM13A with lung function in CF French patients (n=1222) by SNP-wise analysis and Versatile Gene Based Association Study. We also analyzed the consequences of FAM13A knockdown in A549 cells and primary bronchial epithelial cells from CF patients. ResultsWe found that FAM13A is associated with lung function in CF patients. Utilizing lung epithelial A549 cells and primary human bronchial epithelial cells from CF patients we observed that IL-1β and TGFβ reduced FAM13A expression. Knockdown of FAM13A was associated with increased RhoA activity, induction of F-actin stress fibers and regulation of epithelial-mesenchymal transition markers such as E-cadherin, α-smooth muscle actin and vimentin. ConclusionOur data show that FAM13A is a modifier gene of CF lung phenotype regulating RhoA activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition.

Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A

Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively. The aim of this study was to identify common genetic variants associated with FEV1 and its ratio to forced vital capacity (FVC) in never-smokers. Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results (P<10-5) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n=1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses. We identified associations between the FEV1/FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein (HHIP) and family with sequence similarity 13 member A(FAM13A) were shown to have an additive effect on FEV1/FVC levels in the genetic risk score analysis; were associated with gene expression of HHIP and FAM13A in lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts (P<2.19×10-7). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV1 identification analysis were not replicated. The genes HHIP and FAM13A confer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.

Candidate genes for COPD: current evidence and research.

COPD is a common complex disease characterized by progressive airflow limitation. Several genome-wide association studies (GWASs) have discovered genes that are associated with COPD. Recently, candidate genes for COPD identified by GWASs include CHRNA3/5 (cholinergic nicotine receptor alpha 3/5), IREB2 (iron regulatory binding protein 2), HHIP (hedgehog-interacting protein), FAM13A (family with sequence similarity 13, member A), and AGER (advanced glycosylation end product–specific receptor). Their association with COPD susceptibility has been replicated in multiple populations. Since these candidate genes have not been considered in COPD, their pathological roles are still largely unknown. Herein, we review some evidences that they can be effective drug targets or serve as biomarkers for diagnosis or subtyping. However, more study is required to understand the functional roles of these candidate genes. Future research is needed to characterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes’ transcriptional and posttranscriptional regulatory mechanisms.

Family with sequence similarity 13 member A (FAM13A)

Family with sequence similarity 13 member A (FAM13A)