Sputum MUC5AC and MUC5B pQTL.

Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822–1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10–1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02–1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.

黏液过度分泌及（或）黏液高浓缩状态是多种阻塞性肺部疾病的核心特征，其中包括慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）。黏液本身由水、离子、盐类与蛋白质混合组成，其中凝胶形成型黏蛋白（gel-forming mucins）MUC5AC与MUC5B为含量最丰富的组分。近期已有研究将痰液中此类蛋白的浓度与COPD表型相关联，涵盖慢性支气管炎（chronic bronchitis, CB）与急性加重期（acute exacerbations, AE）。本研究旨在明确常见遗传变异是否会影响痰液黏蛋白浓度，且此类变异是否同样与COPD表型（尤其是慢性支气管炎与急性加重期）相关联。本研究依托COPD亚群与中间结局指标研究（Sub-Populations and InteRmediate Outcome Measures in COPD Study, SPIROMICS）队列开展全基因组关联分析（Genome-Wide Association Study, GWAS），以识别痰液黏蛋白浓度对应的蛋白质数量性状位点（protein quantitative trait loci, pQTL）；该队列中总黏蛋白分析样本量为708例，MUC5AC、MUC5B分析样本量为215例。随后，本研究采用回归模型（样本量822~1300例）分析黏蛋白pQTL与慢性支气管炎、急性加重期的关联。本研究进一步依托COPDGene队列（样本量5740例）与英国生物库（UK Biobank）数据开展重复验证分析。本研究共识别出1个与MUC5AC相关的全基因组显著性pQTL（rs75401036），以及2个与MUC5B相关的全基因组显著性pQTL（rs140324259、rs10001928）。位于11号染色体的rs140324259与MUC5B的关联最强，可解释痰液中MUC5B 14%的变异度。尽管rs140324259的C等位基因与较低的MUC5B水平相关，但该等位基因却会增加慢性支气管炎的发病风险（比值比（odds ratio, OR）=1.42；95%置信区间（confidence interval, CI）：1.10~1.80），同时也会增加为期3年随访期间急性加重期的发生风险（OR=1.41；95%CI：1.02~1.94）。rs140324259与慢性支气管炎、急性加重期的关联未能在COPDGene队列中得到重复验证。但在英国生物库中，rs140324259与慢性支气管炎的特征表型（即慢性排痰与咳嗽）存在关联，且同样表现为C等位基因会增加相关风险。综上，痰液中MUC5AC与MUC5B的浓度与常见遗传变异相关，而MUC5B的顶级关联位点可能会影响COPD表型，尤其是慢性支气管炎。