Association between PTCH1 Gene Polymorphisms and Chronic Obstructive Pulmonary Disease Susceptibility in a Chinese Han Population: A Case-Control Study
Chronic obstructive pulmonary disease (COPD) is a major chronic respiratory disease characterized by incompletely reversible airflow obstruction, airway mucus accumulation, chronic inflammation, and airway remodeling. It is a leading cause of morbidity and mortality worldwide, with projections indicating that it could become the fifth leading cause of morbidity and the third leading cause of mortality globally in the near future. Tobacco smoking is the primary risk factor for COPD, with approximately 10% to 20% of smokers developing the disease. However, individual variation in response to the same risk factor suggests a role of genetic predisposition in the development and progression of COPD. Identifying genetic factors associated with COPD could aid in its diagnosis and treatment.
The Hedgehog (Hh) signaling pathway plays a crucial role in lung branching morphogenesis and embryonic development. Patched 1 (PTCH1) is a 12-pass transmembrane receptor for the Hh protein, and its binding to Hh protein relieves the inhibition of Smoothened, resulting in the induction of downstream signaling and transcriptional changes in target genes. PTCH1, encoded by the PTCH1 gene located on chromosome 9q22, participates in multiple signaling mechanisms, including lung organogenesis and response to injury. Mutations in PTCH1 have been previously associated with the risk of COPD in populations of European descent. However, given the significant differences in genetic backgrounds between European and Asian populations, studies on PTCH1 single-nucleotide polymorphisms (SNPs) in Asian populations are essential.
This case-control study aimed to investigate the association between PTCH1 polymorphisms and COPD susceptibility in a Chinese Han population. The study included 296 patients with COPD and 300 healthy individuals. All participants were of Han ethnicity and lived in Hunan Province, China. Patients diagnosed with stable COPD at the Second Xiangya Hospital of Central South University between May 2012 and May 2016 were consecutively recruited. The control group consisted of healthy volunteers with normal lung function and no lung-related or chronic diseases. The diagnosis of COPD was confirmed according to the criteria of the Global Initiative for Chronic Obstructive Lung Disease. All subjects provided written informed consent, and the study protocol was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University.
Genomic DNA was extracted from peripheral blood samples of all participants using the DNeasy Blood and Tissue Kit. SNPs in the PTCH1 gene were identified and genotyped based on linkage disequilibrium (LD) analysis. The tag SNPs were selected using the tagger program in Haploview 4.2 based on the 1000 Genomes database. Genotyping was performed using the SNPseq assay, an efficient multiple gene region enrichment/next-generation sequencing-based assay. The call rate of all SNPs was above 97%, and all SNPs in the control group were in Hardy-Weinberg equilibrium.
The study identified 28 SNPs in the PTCH1 gene. Among them, the “A” allele of rs28491365 (OR: 1.388, 95% CI: 1.055–1.827, P = 0.018), and the “G” alleles of rs10512248 (OR: 1.299, 95% CI: 1.021–1.653, P = 0.033) and rs28705285 (OR: 1.359, 95% CI: 1.024–1.803, P = 0.033) were significantly associated with an increased risk of COPD. Genetic model analysis revealed that the “T/T” genotype of rs34695652 was associated with a decreased COPD risk under the recessive model (OR: 0.490, 95% CI: 0.270–0.880, P = 0.010). Additionally, the rs28504650/rs10512248 haplotype CG was significantly associated with an increased COPD risk after adjustment for age, gender, and smoking status (OR: 6.364, 95% CI: 1.220–33.292, P = 0.028).
The study population included 296 cases (244 males) and 300 controls (251 males). There were no significant differences in gender, body mass index (BMI), predicted percentage of forced expiratory volume in 1 second (FEV1% predicted), and smoking status between the COPD and control groups. However, patients with COPD were significantly older than controls (67.1 ± 8.8 vs. 54.9 ± 9.6 years, P < 0.001).
In the allele analysis, the “A” allele of rs28491365, and the “G” alleles of rs10512248 and rs28705285 were significantly associated with an increased risk of COPD. The “T/T” genotype of rs34695652 was associated with a decreased COPD risk under the recessive model. Crude analysis under the dominant model showed that T/G-G/G genotype of rs10512248 (OR: 1.450, 95% CI: 1.040–2.010, P = 0.020), T/A-A/A genotype of rs28491365 (OR: 1.470, 95% CI: 1.060–2.050, P = 0.020), A/C-C/C genotype of rs28469297 (OR: 1.400, 95% CI: 1.010–1.940, P = 0.040), and T/G-G/G genotype of rs28705285 (OR: 1.420, 95% CI: 1.020–1.990, P = 0.030) were significantly associated with an increased risk of COPD. However, after adjustment for age, gender, and smoking status, no correlations between these SNPs and COPD were revealed by logistic regression analysis.
Haplotype and LD association analysis identified seven LD blocks including 19 SNPs with D’ = 1. The rs28504650/rs10512248 haplotype CG was significantly associated with an increased risk of COPD after adjustment for age, gender, and smoking status (OR: 6.364, 95% CI: 1.220–33.292, P = 0.028). Another pair of SNPs, rs113154802 and rs28705285, formed three haplotypes: CG, CT, and TT. The CG haplotype was significantly associated with the COPD risk by crude analysis (OR: 1.335, 95% CI: 1.010–1.770, P = 0.044), but the association was not confirmed after adjustment for age, gender, and smoking status (OR: 1.354, 95% CI: 0.956–1.918, P = 0.087).
The findings of this study provide new insights into the role of PTCH1 polymorphisms in the susceptibility to COPD in the Chinese Han population. The Hh signaling pathway, in which PTCH1 is a key component, is implicated in the development of COPD. Previous genome-wide association studies have shown that SNPs in the PTCH1 gene are associated with pulmonary function in European populations. The rs10512248 SNP, identified in this study, has been previously correlated with FEV1 and forced vital capacity. The increased expression of PTCH1 protein in the airway epithelium of patients with COPD further supports the involvement of PTCH1 in COPD pathogenesis.
The SNPs rs10512248 and rs28491365 are located in intronic regions, which are often considered “junk DNA.” However, introns can participate in gene expression at multiple levels, and regulatory elements in the intron region can directly affect transcription. The SNPs rs28705285 and rs34695652 are located in the 5′ flanking region, with rs28705285 associated with an increased risk of COPD and rs34695652 associated with a decreased risk. These findings suggest that PTCH1 polymorphisms may influence COPD susceptibility through regulation of gene expression.
This study has several limitations. First, the interaction between genetic polymorphisms and environmental risk factors such as tobacco smoking could not be confirmed due to the limited sample size. Future studies involving a larger number of participants are needed to explore this association. Second, the molecular mechanism underlying the association of COPD with PTCH1 polymorphisms was not clarified. After statistical adjustment, the significance of the association was not confirmed for some SNPs. Analysis of a higher number of loci is needed to verify the results of this study. Additionally, the age difference between the two groups was statistically significant, but age-stratified analysis was not performed due to the limited sample size.
In summary, this study identified three loci (rs10512248, rs28491365, and rs28705285) positively associated and one locus (rs34695652) negatively associated with COPD susceptibility in a Chinese Han population. These findings contribute to the understanding of COPD pathogenesis and provide a foundation for further research into the correlation between the PTCH1 gene and COPD risk in different populations, potentially leading to the development of new therapeutic strategies for this disease.
doi.org/10.1097/CM9.0000000000000858
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