Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures

ResearchWorks/Manakin Repository

Search ResearchWorks


Advanced Search

Browse

My Account

Statistics

Related Information

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures

Show simple item record

dc.contributor.author Lipstitch, Marc en_US
dc.contributor.author Bergstrom, Carl T. en_US
dc.contributor.author Antia, Rustom en_US
dc.date.accessioned 2010-04-21T15:47:12Z
dc.date.available 2010-04-21T15:47:12Z
dc.date.issued 2003 en_US
dc.identifier.citation Lipsitch M, Bergstrom C, Antia R. Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures. BMC Medical Genetics. 2003;4(1):2. en_US
dc.identifier.other 10.1186/1471-2350-4-2 en_US
dc.identifier.uri http://www.biomedcentral.com/1471-2350/4/2 en_US
dc.identifier.uri http://hdl.handle.net/1773/15707
dc.description.abstract Background: 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.description.sponsorship This work was supported in part by National Insitutes of Health grants R01AI48935 to ML and R29GM54268 to RA. en_US
dc.language.iso en_US en_US
dc.title Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures en_US
dc.type Article en_US


Files in this item

Files Size Format View
1471-2350-4-2.pdf 290.2Kb PDF View/Open

This item appears in the following Collection(s)

Show simple item record