title: Epiregulin (EREG) variation is associated with susceptibility to tuberculosis.
abstract: Although host genetics influences susceptibility to Mycobacterium tuberculosis, the human genes regulating pathogenesis remain largely unknown. We used M. tuberculosis-stimulated macrophage gene expression profiling in conjunction with a case-control genetic association study to discover epiregulin (EREG), as a novel candidate tuberculosis (TB) susceptibility gene. Using a genome-wide association study dataset, we found that among the 21 genes with greater than 50-fold induction, EREG had the most polymorphisms associated with TB. We genotyped haplotype-tagging polymorphisms in discovery (N = 337 cases, N = 380 controls) and validation (N = 332 cases) datasets and an EREG polymorphism (rs7675690) was associated with susceptibility to TB (genotypic comparison; corrected P = 0.00007). rs7675690 was also associated more strongly with infections caused by the Beijing lineage of M. tuberculosis when compared with non-Beijing strains (controls vs Beijing, OR 7.81, P = 8.7 × 10(-5); non-Beijing, OR 3.13, P = 0.074). Furthermore, EREG expression was induced in monocytes and peripheral blood mononuclear cells stimulated with M. tuberculosis as well as TLR4 and TLR2/1/6 ligands. In murine macrophages, EREG expression induced by M. tuberculosis was MYD88- and TLR2-dependent. Together, these data provide the first evidence for an important role for EREG as a susceptibility gene for human TB.
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: N T T
authors.initials: NT
authors.lastname: Thuong
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
authors.forename: T T H
authors.initials: TT
authors.lastname: Chau
authors.forename: N D
authors.initials: ND
authors.lastname: Bang
authors.forename: N T B
authors.initials: NT
authors.lastname: Yen
authors.forename: G E
authors.initials: GE
authors.lastname: Thwaites
authors.forename: Y Y
authors.initials: YY
authors.lastname: Teo
authors.forename: M
authors.initials: M
authors.lastname: Seielstad
authors.forename: M
authors.initials: M
authors.lastname: Hibberd
authors.forename: N T N
authors.initials: NT
authors.lastname: Lan
authors.forename: M
authors.initials: M
authors.lastname: Caws
authors.forename: J J
authors.initials: JJ
authors.lastname: Farrar
authors.forename: S J
authors.initials: SJ
authors.lastname: Dunstan
mesh_terms: D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000235:genetics*
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D004815:Epidermal Growth Factor