Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control.

TitleQuantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control.
Publication TypeJournal Article
Year of Publication2010
AuthorsFerreira MAR, Mangino M, Brumme CJ, Zhao ZZhen, Medland SE, Wright MJ, Nyholt DR, Gordon S, Campbell M, McEvoy BP, Henders A, Evans DM, Lanchbury JS, Pereyra F, Walker BD, Haas DW, Soranzo N, Spector TD, DE Bakker PIW, Frazer IH, Montgomery GW, Martin NG
Corporate AuthorsInternational HIV Controllers Study
JournalAm J Hum Genet
Volume86
Issue1
Pagination88-92
Date Published2010 Jan
ISSN1537-6605
KeywordsAdolescent, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Child, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Genetic Variation, Genotype, HIV Infections, HIV-1, Humans, Killer Cells, Natural, Lymphocyte Count, Quantitative Trait Loci, Risk
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 x 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 x 10(-14)). The MHC association with CD4:CD8 replicated convincingly (p = 1.4 x 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.

DOI10.1016/j.ajhg.2009.12.008
Alternate JournalAm. J. Hum. Genet.
PubMed ID20045101
PubMed Central IDPMC2801744
Grant ListAI068636 / AI / NIAID NIH HHS / United States
AI069415 / AI / NIAID NIH HHS / United States
AI069419 / AI / NIAID NIH HHS / United States
AI069423 / AI / NIAID NIH HHS / United States
AI069424 / AI / NIAID NIH HHS / United States
AI069428 / AI / NIAID NIH HHS / United States
AI069432 / AI / NIAID NIH HHS / United States
AI069434 / AI / NIAID NIH HHS / United States
AI069450 / AI / NIAID NIH HHS / United States
AI069452 / AI / NIAID NIH HHS / United States
AI069465 / AI / NIAID NIH HHS / United States
AI069471 / AI / NIAID NIH HHS / United States
AI069472 / AI / NIAID NIH HHS / United States
AI069474 / AI / NIAID NIH HHS / United States
AI069477 / AI / NIAID NIH HHS / United States
AI069484 / AI / NIAID NIH HHS / United States
AI069495 / AI / NIAID NIH HHS / United States
AI069501 / AI / NIAID NIH HHS / United States
AI069502 / AI / NIAID NIH HHS / United States
AI069511 / AI / NIAID NIH HHS / United States
AI069513 / AI / NIAID NIH HHS / United States
AI069532 / AI / NIAID NIH HHS / United States
AI069556 / AI / NIAID NIH HHS / United States
AI077505 / AI / NIAID NIH HHS / United States
AI25859 / AI / NIAID NIH HHS / United States
AI27661 / AI / NIAID NIH HHS / United States
AI34835 / AI / NIAID NIH HHS / United States
AI34853 / AI / NIAID NIH HHS / United States
AI38844 / AI / NIAID NIH HHS / United States
AI46370 / AI / NIAID NIH HHS / United States
AI69467 / AI / NIAID NIH HHS / United States
AL32782 / / PHS HHS / United States
G0600705 / / Medical Research Council / United Kingdom
G0800582 / / Medical Research Council / United Kingdom
MH071205 / MH / NIMH NIH HHS / United States
P30 AI050410 / AI / NIAID NIH HHS / United States
RR024975 / RR / NCRR NIH HHS / United States
U01 AI069423 / AI / NIAID NIH HHS / United States
/ / Wellcome Trust / United Kingdom