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dc.contributor.authorLipsitch, Marc
dc.contributor.authorBergstrom, Carl T
dc.contributor.authorAntia, Rustom
dc.date.accessioned2010-11-08T14:28:59Z
dc.date.issued2003
dc.identifier.citationLipsitch, Marc, Carl T. Bergstrom, and Rustom Antia. 2003. Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC Medical Genetics 4:2.en_US
dc.identifier.issn1471-2350en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4547513
dc.description.abstractBackground: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. Methods: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. Results: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. Conclusion: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi:10.1186/1471-2350-4-2en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC149356/pdf/en_US
dash.licenseLAA
dc.titleEffect of Human Leukocyte Antigen Heterozygosity on Infectious Disease Outcome: The Need for Allele-Specific Measuresen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalBMC Medical Geneticsen_US
dash.depositing.authorLipsitch, Marc
dc.date.available2010-11-08T14:28:59Z
dash.affiliation.otherSPH^Epidemiologyen_US
dc.identifier.doi10.1186/1471-2350-4-2*
dash.contributor.affiliatedLipsitch, Marc


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