Department of Respiratory and Critical Care Medicine, First People's Hospital of Kashi, Kashi, 844000, Xinjiang, People's Republic of China.
Clinical Research Center of Infectious Diseases (Pulmonary Tuberculosis), First People's Hospital of Kashi, Kashi, 844000, Xinjiang, People's Republic of China.
BMC Pulm Med. 2022 May 5;22(1):178. doi: 10.1186/s12890-022-01975-3.
Chronic obstructive pulmonary disease (COPD) is a complex, multifactorial, polygenic disease. The rate of occurrence of COPD in the Kashi population (Uyghur) is significantly higher than that observed nationwide. The identification of COPD-related genes in the Chinese Uyghur population could provide useful insights that could help us understand this phenomenon. Our previous whole-exome sequencing study of three Uyghur families with COPD demonstrated that 72 mutations in 55 genes might be associated with COPD; these included rs15783G > A in the anoctamin 3 (ANO3) gene/mucin 15 (MUC15) gene, rs1800517G > A in the collagen type IV alpha 4 chain (COL4A4) gene, rs11960G > A in the ribosome binding protein 1 (RRBP1) gene, and rs5516C > G in the kallikrein 1 (KLK1) gene. This case-control study aimed to further validate the association of the four mutations with COPD in the Chinese Uyghur population.
Sanger sequencing was used for the genotyping of four polymorphisms (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) in 541 unrelated Uyghur COPD patients and 534 Uyghur healthy controls. We then conducted stratified analyses based on the smoking status and airflow limitation severity, to explore the correlation between selected gene polymorphisms and COPD.
ANO3/MUC15 rs15783 and KLK1 rs5516 polymorphisms could significantly reduce COPD risk (p < 0.05), but COL4A4 rs1800517 and RRBP1 rs11960 polymorphisms were not correlated with COPD in the entire population. In a stratified analysis of smoking status, non-smokers with the ANO3/MUC15 rs15783G/G genotype (OR = 0.63, p = 0.032) or COL4A4 rs1800517 allele G (OR = 0.80, p = 0.023) had a reduced risk of COPD. Smokers with the RRBP1 rs11960A/G genotype had a lower risk of COPD (OR = 0.41, p = 0.025). The KLK1 rs5516G > C polymorphism was associated with a decreased risk of COPD (OR < 1, p < 0.05), irrespective of the smoking status of individuals. No significant association with COPD severity was observed in individuals with these four polymorphisms (p > 0.05).
We identified four previously unreported mutations (ANO3/MUC15 rs15783, COL4A4 rs1800517, RRBP1 rs11960, and KLK1 rs5516) that might decrease the COPD risk in individuals with different smoking statuses in the Chinese Uyghur population. Our findings provide new light for the genetic risk factors associated with the occurrence of COPD.
慢性阻塞性肺疾病（COPD）是一种复杂的、多因素的、多基因疾病。喀什地区（维吾尔族）的 COPD 发生率明显高于全国水平。在中国维吾尔族人群中识别 COPD 相关基因可能会提供有价值的见解，有助于我们理解这一现象。我们之前对三个患有 COPD 的维吾尔族家庭进行的全外显子组测序研究表明，55 个基因中的 72 个突变可能与 COPD 相关；其中包括ANO3/MUC15 基因中的 rs15783G>A、COL4A4 基因中的 rs1800517G>A、RRBP1 基因中的 rs11960G>A 和 KLK1 基因中的 rs5516C>G。本病例对照研究旨在进一步验证这四个突变与中国维吾尔族人群 COPD 的关联。
对 541 例维吾尔族 COPD 患者和 534 例维吾尔族健康对照者的 4 个多态性（ANO3/MUC15 rs15783、COL4A4 rs1800517、RRBP1 rs11960 和 KLK1 rs5516）进行 Sanger 测序。然后，我们根据吸烟状况和气流受限严重程度进行分层分析，以探讨选定基因多态性与 COPD 之间的关系。
ANO3/MUC15 rs15783 和 KLK1 rs5516 多态性可显著降低 COPD 风险（p<0.05），但 COL4A4 rs1800517 和 RRBP1 rs11960 多态性与全人群 COPD 无相关性。在吸烟状况的分层分析中，ANO3/MUC15 rs15783G/G 基因型的非吸烟者（OR=0.63，p=0.032）或 COL4A4 rs1800517 等位基因 G（OR=0.80，p=0.023）患 COPD 的风险降低。RRBP1 rs11960A/G 基因型的吸烟者患 COPD 的风险较低（OR=0.41，p=0.025）。KLK1 rs5516G>C 多态性与 COPD 风险降低（OR<1，p<0.05）相关，与个体的吸烟状态无关。这四个多态性与 COPD 严重程度无显著相关性（p>0.05）。
我们发现了四个以前未报道的突变（ANO3/MUC15 rs15783、COL4A4 rs1800517、RRBP1 rs11960 和 KLK1 rs5516），它们可能降低不同吸烟状态下中国维吾尔族人群 COPD 的风险。我们的发现为 COPD 发生的遗传危险因素提供了新的认识。
