Relationship Of The Lymphotoxin A Gene Polymorphism With Chronic Obstructive Pulmonary Disease

Background The context of chronic obstructive pulmonary disease (COPD) is characterized by limited airflow with chronic respiratory diseases. Chronic airway inflammation is the pathological basis of COPD, and inflammatory factors play important roles in the development and occurrence of COPD. Osteoporosis is a bone metabolic diseases of multi-gene regulation, also has a significant genetic predisposition. Recent researches have shown that, prevalence of osteoporosis in COPD patients was significantly higher than in the same age healthy people, which implys that there is a link between COPD and osteoporosis .Since genetic abnormal may involved in both diseases , it would be necessary to explore the genetic factors for patients with COPD complicated by osteoporosis. It is important to understand why the prevalence of osteoporosis in COPD patients was higher than that in healthy people for the individual treatment of COPD patients. Lymphotoxin A ( LTA) is an important for inflammatory mediator involved in regulating B, T lymphocytes in the immune regulation and local inflammatory response. It was showed that LTA were involved in the pathogenesis of both COPD and osteoporosis. In this study, LTA gene polymorphisms in northern China Han healthy individuals and COPD patients were explored. The aim of this study is to evaluate whether lymphotoxin A (LTA) gene polymorphisms are involved in the genetic susceptibility, clinical severity and secondary osteoporosis of COPD patients in a Han population of the northern China.Objective To evaluate whether Lymphotoxin A(LTA) gene polymorphisms are involoved in the genetic susceptibility , clinic severity and complication(OP)of COPD patients in the northern Han Chinese population. Materials and Methods1)163 AECOPD patients were randomly enrolled from pulmonary of 306th hospital as observe group. 163 healthy people as control group were enrolled from medical examination center of the same hospital. The two groups are well matched at the age and sex. 122 of 163 COPD patients measured the lung function and graded into I to IV grad according to the GOLD. In addition, 101 of 163 COPD patients measured bone density.2) DNA extraction: genomic DNA is extracted from peripheral blood by phenol - chloroform method.3) tSNP selection: 2 959bp reference sequence was obtained from the international haplotype project database. By using Tag SNP Picker program, rs2844482 (S1), rs2071590 (S2), rs2239704 (S3), rs2229094 (S5), rs1041981 (S6)were selected as the tSNP for genotyping. An known functional SNP rs909253 (S4) also enrolled for association analysis.4) Genotype analysis: genotyping were by PCR-sequencing meathod. Primers were designed by Primer 3 software. PCR products were sequenced. Sequence trace files were read by Codon Code Aligner software.The genotype is directly determined from the peaks map.5) Allele and genotype frequencies among cases and controls were compared with values predicted by Hardy-Weinberg equilibrium using X2 test. Relative risks of COPD associated with each genotype were calculated separately by non-conditional logistic regression anlysis, assuming an dominant,or recessive mode of inheritance. Because smoking,age,sex are known risks factors for COPD, matching by smoking status,age,sex improves the efficiency of the analysis to examine the possible association of gene variants tested and the clinical trait. All analyses were carried out by using SNP analyzer 6.0 package. For each odds ratio(OR), confidence intervals(CIs) were calculated. A two-tailed probability value of 0.05 was considered a statistically significant result.Results(1) Genotyping were successfully carried out for samples from COPD patients and control groups, and repeat typing results were all in line with the original results. Only a small number of samples were not successful typed. By chi-square test, LTA 6 SNPs genotype distribution in healthy control group were consistent with Hardy-Weinberg balance (p> 0.05). But 3 SNPs in patients (p < 0.05) were imbalances for Hardy-Weinberg test.(2) LTA 6 SNPs genotype frequency in the COPD patients group and the control group were all not significantly different.(3) According to the severity of pulmonary function, 122 patients in the COPD group have been divided into four sub-groups: mild, moderate , severe and very severe (including death). Comparing mild group with combined group (including moderate, severe and very severe group), distributing frequency of genotype and allele of rs2071590, rs2239704, rs909253, rs1041981 showed significant difference. Rs2071590 SNP showed significant association with severity of COPD under recessive model. Rs909253, rs1041981 SNP were under dominant model. Rs2239704 SNP was under co-dominant model.(4) LTA 6 SNPs genotype frequency between the osteoporosis group and normal bone mineral density group did not show significant difference.Conclusion(1) Our data indicated that Lymphotoxin A (LTA) showed gene polymorphism in COPD patients in a Han population of the northern China. LTA gene polymorphism is not associated with increased risk for COPD susceptibility.(2) Our data suggested that, comparing to common risk factors for COPD such as age.sex.smoking history, genetic factor plays key roles in determining whether COPD patients developing into moderate and severe grad from mild rapidly, Therefore, LTA may be one of the important factors that may affect COPD in the process.(3) From this study, LTA gene polymorphism has no significant correlation with the risk of COPD complicated osteoporosis.