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Original Article Association of EGLN1 and EGLN3 Single-Nucleotide Polymorphisms with Chronic Obstructive Pulmonary Disease Risk in a Chinese Population

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Original Article Association of EGLN1 and EGLN3 Single-Nucleotide Polymorphisms with Chronic Obstructive Pulmonary Disease Risk in a Chinese Population Int J Clin Exp Med 2017;10(7):10866-10873 www.ijcem.com /ISSN:1940-5901/IJCEM0046332 Original Article Association of EGLN1 and EGLN3 single-nucleotide polymorphisms with chronic obstructive pulmonary disease risk in a Chinese population Si Fang*, Jinfan Qiu*, Huapeng Yu, Huizhen Fan, Xiping Wu, Zekui Fang, Qixiao Shen, Shuyu Chen Department of Respiration, Zhujiang Hospital, Southern Medical University, Guangzhou, China. *Equal contribu- tors. Received December 11, 2016; Accepted March 31, 2017; Epub July 15, 2017; Published July 30, 2017 Abstract: Hypoxia is implicated in the process of chronic inflammation, which is the characteristic pathogenesis of COPD (chronic obstructive pulmonary disease). EGLNs (EglN prolyl hydroxylase) that connect oxygen sensing to the activation of HIF-1 (hypoxia inducible factor-1) have been proven to play a role in the development of COPD. The ob- jective of this study was to explore the role of EGLN1 and EGLN3 SNPs (single-nucleotide polymorphisms) in suscep- tibility and development of COPD in a Chinese cohort. Seven SNPs were chosen from two genes (EGLN1 and EGLN3) in 217 cases and 447 controls. The relationship between SNPs and COPD risk was analyzed by using genetic model analysis. Among the seven SNPs, rs11156819 in EGLN3 exhibited a significant association with COPD risk with an OR of 1.392 (95% CI=1.085-1.787, P=0.009). In the log-additive model, the minor allele T of rs11156819 in EGLN3 significantly increased the risk of COPD (OR=1.58, 95% CI=1.14-2.19,P =0.006) after adjusting for gender, age and smoking status. Furthermore, the haplotypes TC (rs11156819-rs900358) was associated with increased COPD risk (OR=1.49, 95% CI=1.10-2.03, P=0.011). This study suggests that rs11156819 in EGLN3 gene has a significant as- sociation with COPD susceptibility among the Chinese population. Keywords: EGLN1, EGLN3, single-nucleotide polymorphisms, COPD, case-control study Introduction lase (EGLNs), both of which mediate the main response to hypoxia. HIF-1 is a pivotal player Chronic obstructive pulmonary disease (CO- in mobilizing the cellular adaptation to low oxy- PD) has been one of the diseases with the high- gen availability [4]. It consists of two subunits: est morbidity and mortality all over the world, HIF-1α and HIF-1β [5]. In normoxia, HIF-1α is resulting in increasing economic and social bur- rapidly degraded by hydroxylation pathway [6, den [1]. The pathogenesis character of COPD is 7]. However, theoxygen-dependent hydroxyl- the parenchymal tissues destruction and irre- ation of HIF-1α is mediated by a family of EglN versible airflow limitation, which is induced by prolyl hydroxylase (EGLNs). There are three the chronic inflammatory response [2]. With EGLN family members (EGLN1, EGLN2, EGLN3) pulmonary function deterioration and the dis- in human and mice [8]. Under hypoxia con- ease progression, the alveolar hypoxia and ditions, EGLNs lose their activity and fail to hypoxemia are increasingly severe. In addition, hydroxylate HIF-1α, which leads to HIF-1α sta- it seems that tissue hypoxia plays a vital role in bilization [9, 10]. As a consequence, HIF-1α progression and comorbidities of COPD, includ- speeds up the adaptive changes in cellular ing cardiovascular disease, lung cancer and metabolism, along with the production of sev- pulmonary hypertension [3]. eral pro-inflammatory factors after hypoxia [10]. In fact, hypoxia has been proven to partici- Chronic hypoxemia can stimulate the expres- pate in the process of chronic inflammation[11] sions of hypoxia inducible factor-1 (HIF-1) and and HIF-1 favors the development of inflam- a family of oxygen-dependent HIF hydroxylat- mation [12, 13]. EGLNs which provide a link ing dioxygenases termed EglN prolyl hydroxy- between sensing the concentration of intracel- Association of EGLN1/EGLN3 SNPs with COPD risk lular oxygen and the activation of HIF-1α are by the Ethics Committee of Zhujiang Hospital, supposed to involve in the process of chronic Southern Medical University. inflammation and COPD. SNPs selection and genotyping Cigarette smoking is the most commonly reco- gnized environmental risk factor for COPD [14]. Seven tag SNPs (rs2009873, rs11156819, However, not all smokers develop into COPD rs1680709, rs1680710, rs1750708, rs176- despite the similar smoking history. Therefore, 9601, rs900358) from EGLN1 and EGLN3, there are some potential genetic factors which with minor allele frequencies >5% in the Hap- would contribute to the development and se- Map Chinese Han Beijing population, were verity of COPD [15]. In order to illuminate the selected in this study. According to the previous pathogenesis of COPD, researchershave con- studies, 5 ml of peripheral blood were collected ducted many candidate genes over the past from each subject and stored at -80°C [20]. few decades. Several novel loci at CHRNA3/ According to the manufacturer’s instructions, CHRNA5/IREB2 [16] and HHIP [17] have been genomic DNA was extracted from whole blood proven to be the risk loci for COPD by GW- samples using the FlexGene DNA purification AS; additional loci have also been identified kit (Xibao Biotech Co, Shanghai, china). through larger study at RAB4B, EGLN2, MIA SNPscanTM (Center for Human Genetics Re- and CYP2A6 [18]. In addition, increasing stu- search, Shanghai Genesky Bio-Tech Co, Ltd) dies performed on Chinese people have con- was used to test the loci information of sam- firmed several susceptible loci associated ples. The technical personnel of genotyping with COPD such as HHIP [19], RNF150/EGLN2 were blind to the case or control status of [20], CDH13 [21]. samples. Numerous studies have found that some su- Statistical analysis sceptible loci in EGLN2 increased the risk of COPD [20, 22]. However, few studies have Statistical analyses were conducted in SPSS explored the relationship between EGLN1 and 20.0 (IBM Corporation, Armonk, NY, USA). EGLN3 and the risk of COPD. Therefore, we con- ducted a case-control study to evaluate the Continuous variables were presented as association between seven single-nucleotide mean ± SD and analyzed by Student’s t-test. polymorphisms (SNPs) in EGLN1 and EGLN3 Then, categorical variables were analyzed by genes and COPD in Chinese population. χ2 test. Each SNP was tested for deviation from Hardy-Weinberg equilibrium (HWE) using Materials and methods the x2 test to compare the observed and ex- Study subjects pected genotype frequencies among the con- trols. In this study, 217 patients from Zhujiang Furthermore, the association between all Hospital were enrolled. Inclusion criteria for participants with COPD were: age ≥40 years, SNPs and the risk of COPD under different forced expiratory volume in 1 second (FEV1)/ genetic models (codominant, dominant, reces- forced vital capacity (FVC) <0.7. The severity of sive, over-dominant and log-additive) was cal- COPD was identified with the guidelines of WHO culated by SNP stats software [23]. Multivariate Global initiative for Chronic Obstructive Lung logistic regression analysis was used to as- Disease (GOLD) [1]. Exclusion criteria were sess the relationship between each SNPs and bronchial asthma, lung cancer, pulmonary different group of COPD (mild/moderate and tuberculosis, bronchiectasis and other pulmo- severe/very severe), and confounders (age, nary diseases. Meanwhile, 447 control sub- gender and smoking status). jects without established diagnosis of medical illness and COPD family history were randomly The association between SNPs and COPD phe- enrolled from the health centers of Zhujiang notypes (FEV1, FEV1/FVC) was analyzed by Hospital during the same period. All of the par- liner regression analysis. Haploview software ticipants signed informed consent forms at the (version 4.2) was used to analyze linkage dis- beginning of the study. This study was approved equilibrium (LD) and haplotype [24]. In all sta- 10867 Int J Clin Exp Med 2017;10(7):10866-10873 Association of EGLN1/EGLN3 SNPs with COPD risk Table 1. Demographic characteristics of patients and control Then the association between se- participants lected SNPs and the COPD risk was Variables Cases (N %) Controls (N %) P-Value explored by genetic models (con- dominant, dominant, recessive, over- Sex 0.083a dominant and log-additive). Our re- Female 23 (10.6) 30 (6.7) sults showed that the minor allele T Male 194 (89.4) 417 (93.3) of rs11156819 in EGLN3 (Table 4) b Age (year) <0.001 was noticeably associated with an Mean ± SD 70.13±7.88 65.14±9.46 increased risk of COPD in the con- BMI <0.001b dominant (TC vs CC; TT vs CC) before Mean ± SD 21.79±4.15 23.67±3.15 (OR=1.48, 95% CI=1.05-2.09; OR= Smoking status <0.001a 1.75, 95% CI=0.99-3.488, P= Nonsmoker 51 (23.5) 365 (81.7) 0.033, respectively) and after (OR= Smoker 166 (76.5) 82 (18.3) 1.80, 95% CI=1.14-2.84; OR=2.14, Lungfunction (mean ± SD) <0.001b 95% CI=1.01-4.54, P=0.016, res- FEV1 47.21±21.81 99.01±15.58 pectively) adjustment. Simultaneou- FEV1/FVC 44.90±13.35 76.85±5.75 sly, in the dominant model (T/C-T/T vs C/C), the T/C-T/T genotype was Clinical stages <0.001b associated with an increased risk of Stage I 20 (9.2) developing COPD before (OR=1.53, Stage II 65 (30.0) 95% CI=1.10-2.12; OR=1.86, 95% Stage III 73 (33.6) CI=1.21-2.87, P=0.005, respective- Stage IV 59 (27.2) ly) correcting for age, gender and Pa: P-values were calculated from two-side chi-square test. Pb: P-values smoking status. The genotype “T/C” were calculated by Student t-tests. BMI: body mass index; FEV1: forced in the over-dominant model, in- expiratory volume in one second; FVC: forcedexpiratory volume.
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