Ebook COPD - Heterogeneity and personalized treatment: Part 2
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Ebook COPD - Heterogeneity and personalized treatment: Part 2
Genetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2 of COPD. genetic risk factors are also important [1 ]. In addition, an interaction between genetics and environment is believed to drive the development of COPD.Pathways that play a role in COPD pathogenesis include the response to oxidative stress, the protease-antiprotease imbalance, cell death, Ebook COPD - Heterogeneity and personalized treatment: Part 2and inflammation [2-5]. Genetic studies have been performed to identify genetic risk factors and to understand the pathogenesis of COPD. Familybased sEbook COPD - Heterogeneity and personalized treatment: Part 2
tudies and candidate gene association studies have found associations for many genes and loci. However, alpha-1 antitrypsin deficiency caused by mutatGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2aracterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes’ transcriptional and post-transcriptional regulatory mechanisms |7|.W.J. KimDepartment of Internal Medicine and EnvironmentalHealth Center. Kangwon National University.Chuneheon. So Ebook COPD - Heterogeneity and personalized treatment: Part 2uth Koreae-mail: puhno2íộ'kangwon.ac.krHistory of Genetic Studies for COPDFamily studies have supported genetic factors to play an important role in tEbook COPD - Heterogeneity and personalized treatment: Part 2
he development of COPE) [8]. Twin studies have reported heatability of lung function between 30 and 50% |9|. Recently, heritability of COPD was estimaGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2h lung function that is the most important phenotype of COPD [ 111.Candidate gene strategies were used to test hypothesis of genetic associations with COPD. However, there were few genetic associations that were consistently significant, and this strategy has limitation in identifying novel mechanis Ebook COPD - Heterogeneity and personalized treatment: Part 2ms of COPE).Genome-Wide Association StudyAlthough whole-genome and exome sequencing may be the next tools used for the genetic study of COPD. genome-wEbook COPD - Heterogeneity and personalized treatment: Part 2
ide association study (GWAS) is currently the most widely used method for the discovery of candidate genes [ 121. Several GWASs have discovered novel Genetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2the general population. Some of these lung function genes are also associated w ith COPD susceptibility. The genetic basis of different© Springer-Verlag Berlin Heidelberg 2017S.-D. Lee (cd.). COPD. DOI 10. ItIO7/978-3-662-471784-11169170WJ. KimCOPD-related phenotypes, including emphysema and chronic Ebook COPD - Heterogeneity and personalized treatment: Part 2 bronchitis, also overlaps with that of COPD susceptibility. After being implicated in disease pathogenesis, these genes can be used as potential drugEbook COPD - Heterogeneity and personalized treatment: Part 2
targets or as biomarkers that can influence diagnosis and personalized treatment.Currently, the most well-known candidate genes for COPD are CHRNA3/5Genetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2ce similarity 13. member A), and AGER (advanced glycosylation end product-specific receptor). They have been replicated in multiple populations. None of them are targeted by treatments for COPD yet, and the mechanisms by which they alter COPD risk are still largely unknown. There is some emerging ev Ebook COPD - Heterogeneity and personalized treatment: Part 2idence that they may be good targets for treatments or useful as biomarkers. However, more study is required to understand the functional roles of theEbook COPD - Heterogeneity and personalized treatment: Part 2
se candidate genes.CHRNA3, CHRNA5, and IREB2There are several genes at chromosome 15q25 that have been identified by GWAS for affecting COPD risk, incGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2he NETT (National Emphysema Treatment Trial )/NAS (normative aging study) cohorts, the Boston early onset COPD cohort, and the COPDGene study cohort. The association between CHRNA3/5 and COPD has been replicated in multiple ethnic populations by direct genotyping 116-18). The CHRNA3/5 region is also Ebook COPD - Heterogeneity and personalized treatment: Part 2 associated with lung cancer and nicotine addiction. It has been debated w hether this common susceptibility region is the result of a common pathogenEbook COPD - Heterogeneity and personalized treatment: Part 2
ic pathway for lung cancer and COPD. or if it is simply associated with nicotine addiction, a risk factor for both diseases. In addition, the causal vGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2thogenesis of COPD and smoking behavior 119).CHRNA3/5 and CHRNB4 are subunits of the nicotine cholinergic receptor, and the cholinergic system is active not only in cholinergic neuronal cells, but also in bronchial epithelial cells and airway inflammatory cells. The proteins are responsive to nicoti Ebook COPD - Heterogeneity and personalized treatment: Part 2ne and are upregulilted during chronic tobacco exposure. A recent study integrating GWAS results with expression quantitative trait loci (eỌTL) studyEbook COPD - Heterogeneity and personalized treatment: Part 2
results found that SNPs in the 15q25 region were associated w ith the expression of IREB2 and CHRNA3 in blood and sputum samples [20). CHRNA3/5 and IRGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2between COPD patients and controls, and genotyping the SNPs within the candidate regions 121). IREB2 is a protein that binds iron-responsive elements (IREs). maintains cellular iron metabolism. and is regulated in response to oxygen and iron supply. ỊREB2 expression is higher in the lung tissue of C Ebook COPD - Heterogeneity and personalized treatment: Part 2OPD cases. The Ireb2 knockout mouse has abnormal iron metabolism in the brain, which causes cellular dysfunction |22). However, the role of ÍREB2 in CEbook COPD - Heterogeneity and personalized treatment: Part 2
OPD pathogenesis is still not known. A GWAS of the pulmonary artery measurement obtained by computed tomography (CT) in cohorts from the COPDGene StudGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2IREB2 123). This suggests a role for 1REB2 in the pathogenesis of pulmonary hypertension in COPD. particularly in the vascular subtype.HHIPMany recently identified COPD-associated variants are located at chromosome 4q3l. upstream of HHỈP. This intergenic region has associated with COPD susceptibilit Ebook COPD - Heterogeneity and personalized treatment: Part 2y in several GWASs [13. 14. 24), and has consistently replicated in multiple ethnicities [25-28). This region is also associated with lung function inEbook COPD - Heterogeneity and personalized treatment: Part 2
the general population [29-31). HHIP is also associated with adult height in11 Genetics of COPD171the general population 132). Considering that the FGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2t the HHIP gene interacted with environmental tobacco smoke in utero, suggesting that this gene is involved in the lung response to smoke exposure in early life 133).HHIP encodes a membrane glycoprotein that is an endogenous antagonist for the Hedgehog pathway. Hedgehog signaling is important for th Ebook COPD - Heterogeneity and personalized treatment: Part 2e morphogenesis of the lung and other organs [34]. Although the role of HHIP in COPD is not fully understood, several studies have validated the functEbook COPD - Heterogeneity and personalized treatment: Part 2
ion of this gene in COPD pathogenesis. The associated SNPs are located upstream of HHIP. suggesting that they may affect promoter activity. A lung eỌTGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2l. reported that HHỈP expression is reduced in COPD lung tissues and the genomic region upstream of HHIP interacts with the HHIP promoter. The risk allele of a variant in the HHỈP enhancer region reduces promoter activity via a differential binding affinity to transcription factors 136).These studie Ebook COPD - Heterogeneity and personalized treatment: Part 2s suggest that the genetic variation of the HHIP region affects the risk of COPD by affecting HHIP expression in lung tissues. HH1P silencing in an aiEbook COPD - Heterogeneity and personalized treatment: Part 2
rway epithelial cell line leads to a change in gene expression, and these differentially expressed genes are enriched in pathways related to the extraGenetics of COPDWoo Jin KimIntroductionAlthough environmental factors, including cigarette smoking and biomass smoke exposure, are major risk factors Ebook COPD - Heterogeneity and personalized treatment: Part 2ave increased airspace size after cigarette smoke exposure, increased lung compliance, and increased numbers of lymphoid aggregates. The functions of the genes with altered expression in Hhip*~ mice exposed to cigarette smoke were enriched in the pathway of lymphocyte activation 138). They used hapl Ebook COPD - Heterogeneity and personalized treatment: Part 2oinsufticient mice because Hhip~l~ mice die shortly after birth due to lung branching morphogenesis failure.HHIP was also found to be associated withEbook COPD - Heterogeneity and personalized treatment: Part 2
lung cancer by a candidate gene study [39). TheGọi ngay
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