Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control

Ferreira, Manuel A.R., Mangino, Massimo, Brumme, Chanson J., Zhao, Zhen Zhen, Medland, Sarah E., Wright, Margaret J., Nyholt, Dale R., Gordon, Scott, Campbell, Megan, McEvoy, Brian P., Henders, Anjali, Evans, David M., Lanchbury, Jerry S., Pereyra, Florencia, Walker, Bruce D., Haas, David W., Soranzo, Nicole, Spector, Tim D., de Bakker, Paul I.W., Frazer, Ian H., Montgomery, Grant W., & Martin, Nicholas G. (2010) Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control. American Journal of Human Genetics, 86(1), pp. 88-92.

View at publisher

Abstract

Abnormal expansion or depletion of particular lymphocyte subsets is associated with clinical manifestations such as HIV progression to AIDS and autoimmune disease. We sought to identify genetic predictors of lymphocyte levels and reasoned that these may play a role in immune-related diseases. We tested 2.3 million variants for association with five lymphocyte subsets, measured in 2538 individuals from the general population, including CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells, and the derived measure CD4:CD8 ratio. We identified two regions of strong association. The first was located in the major histocompatibility complex (MHC), with multiple SNPs strongly associated with CD4:CD8 ratio (rs2524054, p = 2.1 × 10−28). The second region was centered within a cluster of genes from the Schlafen family and was associated with NK cell levels (rs1838149, p = 6.1 × 10−14). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 × 10−9) in an independent panel of 988 individuals. Conditional analyses indicate that there are two major independent quantitative trait loci (QTL) in the MHC region that regulate CD4:CD8 ratio: one is located in the class I cluster and influences CD8 levels, whereas the second is located in the class II cluster and regulates CD4 levels. Jointly, both QTL explained 8% of the variance in CD4:CD8 ratio. The class I variants are also strongly associated with durable host control of HIV, and class II variants are associated with type-1 diabetes, suggesting that genetic variation at the MHC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

Impact and interest:

44 citations in Scopus
Search Google Scholar™
43 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 92025
Item Type: Journal Article
Refereed: Yes
DOI: 10.1016/j.ajhg.2009.12.008
ISSN: 0002-9297
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 18 Jan 2016 23:00
Last Modified: 15 Feb 2016 00:02

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page