Supplementary Material for: Genetic Variation in the Scavenger Receptor MARCO and Its Association with Chronic Obstructive Pulmonary Disease and Lung Infection in 10,604 Individuals

<b><i>Background:</i></b> MARCO (macrophage receptor with collagenous structure) is a dominant receptor for unopsonized particles and bacteria in the lungs. Reduced function of this receptor due to genetic variation may be associated with susceptibility to chronic obstructive pulmonary disease (COPD) and lung infection. <b><i>Objectives:</i></b> To identify novel genetic variants in <i>MARCO</i> that are associated with reduced lung function, or increased risk of COPD or lung infection. <b><i>Methods:</i></b> We first screened 760 individuals with extreme lung phenotypes in a large general population study to identify novel variants in the <i>MARCO</i> gene. We next genotyped the entire cohort consisting of 10,604 individuals to assess the clinical relevance of these variants. <b><i>Results:</i></b> We identified 4 novel (R124H, K201N, P303L and G340W) and 5 previously described (H101Q, F282S, G319V, K387Q and E511D) non-synonymous variants. When screening the entire cohort for these variants, we found low minor allele frequencies ranging from 0.005 to 5%. None of the individual <i>MARCO</i> genotypes were associated with reduced lung function, or risk of COPD or lung infection. H101Q heterozygotes had an increased odds ratio for sepsis of 2.2 (95% CI: 1.1–4.4) compared to non-carriers, but none of the other <i>MARCO</i> genotypes were associated with the risk of sepsis. <b><i>Conclusions:</i></b> We identified 9 non-synonymous variants in the <i>MARCO</i> gene and showed that these variants are not major risk factors for COPD or lung infection in the Danish population. H101Q heterozygotes had increased sepsis risk, but further research is required to confirm this finding. This study is the first to examine genetic variants in <i>MARCO</i> and the risk of COPD and infections in humans.

<b><i>背景：</i></b> MARCO（含胶原结构的巨噬细胞受体，macrophage receptor with collagenous structure）是肺部中识别未调理化颗粒（unopsonized particles）与细菌的主要受体。该受体因遗传变异导致功能降低，可能与慢性阻塞性肺疾病（COPD，chronic obstructive pulmonary disease）易感性以及肺部感染相关。<b><i>研究目的：</i></b> 鉴定MARCO基因中与肺功能降低、COPD或肺部感染风险升高相关的新型遗传变异。<b><i>研究方法：</i></b> 本研究首先在一项大型普通人群研究中筛选760名具有极端肺表型（extreme lung phenotypes）的个体，以鉴定MARCO基因的新型变异。随后对包含10604名个体的全部队列（cohort）进行基因分型，以评估上述变异的临床相关性。<b><i>研究结果：</i></b> 本研究共鉴定出4个新型错义变异（non-synonymous variants）（R124H、K201N、P303L及G340W）以及5个已报道的错义变异（H101Q、F282S、G319V、K387Q及E511D）。在对全部队列进行上述变异筛查时，发现其次要等位基因频率（minor allele frequency, MAF）介于0.005%至5%之间。未发现单个MARCO基因型与肺功能降低、COPD或肺部感染风险存在显著关联。与非携带者相比，H101Q杂合子的脓毒症（sepsis）优势比（odds ratio, OR）为2.2（95%置信区间（confidence interval, CI）：1.1~4.4），但其余MARCO基因型均与脓毒症风险无显著关联。<b><i>研究结论：</i></b> 本研究在MARCO基因中鉴定出9个错义变异，并证实该类变异在丹麦人群中并非COPD或肺部感染的主要危险因素。H101Q杂合子的脓毒症风险升高，但仍需开展进一步研究以验证该发现。本研究是首个针对人类MARCO基因变异与COPD及感染风险相关性的研究。