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

• Type of Material: Article
• Authors: Marc Marc, Harvard School of Public Health; Carl T Bergstrom, University of Washington; Rustom Antia, Emory University
• Language: English
• Date: 2003
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2003 Lipsitch et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
• Final Published Version (URL): http://www.biomedcentral.com/1471-2350/4/2
• Title of Journal or Parent Work: BMC Medical Genetics
• ISSN: 1471-2350
• Volume: 4
• Issue: 2
• Grant/Funding Information: This work was supported in part by National Insitutes of Health grants R01AI48935 to ML and R29GM54268 to RA. The authors thank the Helen Riaboff Whiteley Center at Friday Harbor for providing a beautiful and conducive environment for beginning this work.
• Research Categories: Health Sciences, Public Health; Biology, Virology; Biology, General

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.