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

Abstract

Background: 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. Objectives: To identify novel genetic variants in MARCO that are associated with reduced lung function, or increased risk of COPD or lung infection. Methods: We first screened 760 individuals with extreme lung phenotypes in a large general population study to identify novel variants in the MARCO gene. We next genotyped the entire cohort consisting of 10,604 individuals to assess the clinical relevance of these variants. Results: 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 MARCO 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 MARCO genotypes were associated with the risk of sepsis. Conclusions: We identified 9 non-synonymous variants in the MARCO 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 MARCO and the risk of COPD and infections in humans.

Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants

“…The MARCO promoter SNP increased the risk for severe RSV disease by approximately 62%. A previous investigation tested whether 9 non-synonymous coding variants or tag SNPs in MARCO associated with chronic obstructive pulmonary disease and found no association, although one of the SNPs (rs41279766) associated with the risk of sepsis ( Thomsen et al, 2013 ). Another study found tag SNPs associated with increased risk of pulmonary tuberculosis, while another was associated with resistance ( Bowdish et al, 2013 ), thus the role of MARCO in this disease is not clear.…”

Genetic variants of MARCO are associated with susceptibility to pulmonary tuberculosis in a Gambian population

“…Although animal models using MARCO knockout mice strongly associate MARCO with many pulmonary infections, such as pneumonia and influenza [38-41], whether polymorphisms in MARCO are associated with susceptibility to infection in humans remains to be determined. A recent Danish study found that non-synonymous SNPs within MARCO were found at very low frequency (0.005-5%) within a Danish population, and in a study investigating whether MARCO was associated with chronic obstructive pulmonary disease (COPD) and lung infection in COPD patients, only one of these was associated with an increased risk of sepsis and none with pneumonia or COPD itself [42]. Unfortunately, the intronic SNPs identified in our study and in the Chinese Han population [23] were not investigated.…”

Scavenger Receptors

“…Most studies have been centered on the role of MARCO in the host defense against respiratory tract infections and pneumoconiosis induced by crystalline silica or cigarette smoke (Thakur, Hamilton, & Holian, 2008; Thomsen, Nordestgaard, Kobzik, & Dahl, 2013). However, several lines of evidence recently implicated MARCO as a regulator of DC function and antitumor immunity.…”