title: Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil.
abstract: Infection with the protozoan Leishmania infantum can lead to asymptomatic infection and protective immunity, or to the progressive and potentially fatal disease visceral leishmaniasis (VL). Published studies show host genetic background determines in part whether infected individuals will develop a symptomatic or asymptomatic outcome. The purpose of the current study was to fine map chromosome regions previously linked with risk for symptomatic (chromosome 9) or asymptomatic (chromosomes 15 and 19) manifestations of L. infantum infection. We conducted a family-based genetic study of VL and asymptomatic infection (detected by a DTH skin test) with a final post quality control sample of 961 individuals with full genotype and phenotype information from highly endemic neighborhoods of northeast Brazil. A total of 5485 SNPs under the linkage peaks on chromosomes 9, 15 and 19 were genotyped. No strong SNP associations were observed for the DTH phenotype. The most significant associations with the VL phenotype were with SNP rs1470217 (p=5.9e-05; pcorrected=0.057) on chromosome 9, and with SNP rs8107014 (p=1.4e-05; pcorrected=0.013) on chromosome 19. SNP rs1470217 is situated in a 180kb intergenic region between TMEM215 (Transmembrane protein 215) and APTX (Aprataxin). SNP rs8107014 lies in the intron between exons 26 and 27 of a 34 exon transcript (ENST00000204005) of LTBP4, (Latent transforming growth factor-beta-binding protein 4a). The latter supports growing evidence that the transforming growth factor-beta pathway is important in the immunopathogenesis of VL.
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA. Electronic address: jason-weirather@uiowa.edu.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Weirather
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: pduggal@jhsph.edu.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil; Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil. Electronic address: eltomaz@gmail.com.
authors.forename: Eliana L
authors.initials: EL
authors.lastname: Nascimento
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil. Electronic address: gloriag74@hotmail.com.
authors.forename: Gloria R
authors.initials: GR
authors.lastname: Monteiro
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil. Electronic address: daniellamartins@cb.ufrn.br.
authors.forename: Daniella R
authors.initials: DR
authors.lastname: Martins
authors.affiliation: Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil; Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil. Electronic address: heniolacerda@ufrnet.br.
authors.forename: Henio G
authors.initials: HG
authors.lastname: Lacerda
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK. Electronic address: mf300@cam.ac.uk.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fakiola
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK; Telethon Kids Institute, The University of Western Australia, Perth, Australia. Electronic address: jenefer.blackwell@telethonkids.org.au.
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil; Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN, Brazil; Institute of Science and Technology of Tropical Diseases, Brazil. Electronic address: smbj@cb.ufrn.br.
authors.forename: Selma M B
authors.initials: SM
authors.lastname: Jeronimo
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA; Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; Department of Microbiology, University of Iowa, Iowa City, IA, USA; Iowa City Veterans' Affairs Medical Center, Iowa City, IA, USA. Electronic address: mary-wilson@uiowa.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
mesh_terms: D001938:Brazil; D002874:Chromosome Mapping / Q000379:methods*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018314:Leishmania infantum / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins
keywords: Fine mapping; Genetic risk factors; Linkage regions; Tropical disease; Visceral leishmaniasis