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

被引：75

作者：

Ferreira, Manuel A. R. ^{[1
]}

Mangino, Massimo ^{[2
]}

Brumme, Chanson J. ^{[3
,4
,5
,6
]}

Zhao, Zhen Zhen ^{[1
]}

Medland, Sarah E. ^{[1
]}

Wright, Margaret J. ^{[1
]}

Nyholt, Dale R. ^{[1
]}

Gordon, Scott ^{[1
]}

Campbell, Megan ^{[1
]}

McEvoy, Brian P. ^{[1
]}

Henders, Anjali ^{[1
]}

Evans, David M. ^{[1
]}

Lanchbury, Jerry S. ^{[2
]}

Pereyra, Florencia ^{[3
,4
,7
]}

Walker, Bruce D. ^{[3
,4
,8
]}

Haas, David W. ^{[9
]}

Soranzo, Nicole ^{[2
]}

Spector, Tim D. ^{[2
]}

de Bakker, Paul I. W. ^{[5
,6
,10
]}

Frazer, Ian H. ^{[11
]}

Montgomery, Grant W. ^{[1
]}

Martin, Nicholas G. ^{[1
]}

机构：

[1] Queensland Inst Med Res, Brisbane, Qld 4029, Australia

[2] Kings Coll London, St Thomas Hosp, Twin Res & Genet Epidemiol Dept, London SE1 7EH, England

[3] MIT, Ragon Inst MGH, Charlestown, MA 02129 USA

[4] Harvard Univ, Charlestown, MA 02129 USA

[5] MIT, Broad Inst, Cambridge, MA 02142 USA

[6] Harvard Univ, Cambridge, MA 02142 USA

[7] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA

[8] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[9] Vanderbilt Univ, Sch Med, Nashville, TN 37203 USA

[10] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA

[11] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst Canc Immunol & Metab Med, Brisbane, Qld 4102, Australia

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2010年 / 86卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; FAMILY; SAMPLE; GENES; CELLS;

D O I：

10.1016/j.ajhg.2009.12.008

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 1 cluster and influences CD8 levels, whereas the second is located in the class 11 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 It variants are associated with type-1 diabetes, suggesting that genetic variation at the MFIC may predispose one to immune-related diseases partly through disregulation of T cell homeostasis.

引用

页码：88 / 92

页数：5

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