title: Reduced lentivirus susceptibility in sheep with TMEM154 mutations.
abstract: Visna/Maedi, or ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify ovine genetic risk factors for lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10(-9)). Sanger sequencing of the ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5-1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36-3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in ovine lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.
authors.affiliation: U.S. Meat Animal Research Center, Agriculture Research Service, United States Department of Agriculture, Clay Center, Nebraska, USA. mike.heaton@ars.usda.gov
authors.forename: Michael P
authors.initials: MP
authors.lastname: Heaton
authors.forename: Michael L
authors.initials: ML
authors.lastname: Clawson
authors.forename: Carol G
authors.initials: CG
authors.lastname: Chitko-Mckown
authors.forename: Kreg A
authors.initials: KA
authors.lastname: Leymaster
authors.forename: Timothy P L
authors.initials: TP
authors.lastname: Smith
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Harhay
authors.forename: Stephen N
authors.initials: SN
authors.lastname: White
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Herrmann-Hoesing
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mousel
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Lewis
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Kalbfleisch
authors.forename: James E
authors.initials: JE
authors.lastname: Keen
authors.forename: William W
authors.initials: WW
authors.lastname: Laegreid
mesh_terms: D000818:Animals; D001947:Breeding; D016022:Case-Control Studies; D004198:Disease Susceptibility; D016368:Frameshift Mutation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D011021:Pneumonia, Progressive Interstitial, of Sheep / Q000235:genetics* / Q000821:virology; D012756:Sheep; D034561:Sheep, Domestic / Q000235:genetics* / Q000821:virology; D016182:Visna / Q000235:genetics* / Q000821:virology; D014790:Visna-maedi virus / Q000235:genetics / Q000472:pathogenicity*
chemical_list: D008565:Membrane Proteins