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

Abstract

Background: The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear.

Methods: To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case-control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee.

Results: We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPs in MARCO (rs4491733, Mantel-Haenszel 2x2 χ2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 χ2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 χ2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 χ2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis.

Conclusions: These findings identify MARCO as a potentially important receptor in the host response to tuberculosis.

Figure 1

Haploview analysis of SNPs in MARCO [GeneID: 8685], located on chromosome 2q12. Linkage Disequilibrium (LD) in the African population is visualized across the MARCO locus, including upstream and downstream regions (chr2: 119414167–119468337). Polymorphisms are identified by their dbSNP rs numbers, and their position relative to the gene structure is marked. SNPs marked in bold were typed in this study. SNPs marked in green were included in the Wellcome Trust Case Control consortium [32] analysis and were used in validation studies. Empty squares indicate a high degree of LD (LD coefficient D' = 1) between pairs of markers. Numbers indicate the D' value expressed as a percentile. Black squares indicate pairs in strong LD with logarithm of odds (LOD) scores for LD ≥2; grey squares, D' < 1 with LOD ≥2; white squares, D' < 1.0 and LOD < 2.

Figure 2

TESS Analysis of potential transcription factor binding. The T variant allele creates potential for EFII and C/EBPalpha binding. A) The rs7559955 allele in intron 1 is found in a region of high conservation. Alignments of the homologous region from human, chimpanzee, macaque, mouse, rat, dog, and cow were performed, and the region of high conservation, and thus high regulatory potential as determined by ESPERR, is marked in blue. B) Transcription factor binding site analysis using TESS indicates that the presence of the T allele may confer the addition of EFII or C/EBPalpha transcription factor binding sites.