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Am J Hum Genet. 2010 Jan;86(1):88-92. doi: 10.1016/j.ajhg.2009.12.008. Epub 2009 Dec 31.

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

Collaborators (398)

Agan B, Agarwal S, Allen B, Altidor S, Altschuler E, Ambardar S, Anastos K, Anderson B, Andrady U, Angell T, Appelbaum J, Arnold K, Arroyo J, Arthur E, Barbaro D, Barrett T, Barrie W, Barthel V, Bartlett ME, Barton S, Basden P, Basgoz N, Bellos N, Berger J, Bernard A, Bernard N, Blair D, Bodner S, Bolan R, Boudreaux E, Braun J, Brndjar J, Brooks E, Brown K, Brown S, Bryant S, Bryson R, Buchbinder S, Bullock D, Burack J, Busalacchi M, Bush L, Cafaro V, Campbell J, Cardosi B, Carlson R, Carmichael K, Carr P, Carrington M, Cavacuiti C, Celestin G, Chaborek M, Chau J, Chez N, Cimoch P, Cohen DE, Cohn B, Cohn L, Conway B, Cooper D, Cooper J, Cornellson B, Cowles A, Cox D, Cox-Iyamu R, Cuchural G, Daily M, Daly J, Dang S, Davis B, Davis K, De Koning P, DeCardi Hladek M, Dechter M, Deeks S, DeFoto J, DeJesus E, Dennis DT, Dolan M, Duggan J, Dunn M, Egenes K, Ellerin T, Elliott K, Eron J, Fangman J, Ferlazzo H, Figueroa Y, Fiola T, Fisk S, Flaherty M, Fleenor-Ford A, Forster A, Fralich T, Francke E, Frankel R, Freedburg K, French N, Fuchs JD, Fuller J, Gaberman JI, Gallant J, Gandhi R, Ganesan A, Garcia E, Gardner A, Garver P, Gastaldo J, Gathe J, Gaultier C, Gebre W, Gelman M, Gilman F, Gilmore J, Gimbarevsky B, Glaser J, Goepfert P, Good G, Gottlieb M, Goulston C, Grimm W, Groger R, Guiteau J, Gurley TD, Haber S, Hale B, Halpenny R, Hardin T, Hardy WD, Hargan T, Harrigan R, Haston J, Hawkins T, Hellinger W, Henderson R, Henderson T, Henry K, Hermann S, Hernandez S, Hicks C, Hoffman R, Holland C, Horton J, Hoskinson S, Hsu RK, Huber J, Huhn G, Humphrey R, Hupert M, Hurtado R, Illeman M, Israelski D, Jellinger R, Jessen H, John M, Johnson K, Jones M, Jordan W, Kauffman C, Keba A, Khanlou H, Killian R, Kim A, Kim D, Kinder F, Kirchner J, Kish MA, Kocurek K, Kogelman L, Kojic EM, Kortuis T, Kovacs J, Kreiswirth S, Kuldanek G, Kurisu W, Lackey P, Ladan A, Lanzafame M, Lederman M, Lee D, Lee E, Lee J, Lee M, LeGrand J, Lemoine J, Levin S, Levy J, Liguori M, Lin N, Little S, Livine R, Llibre JM, Lopez A, Loutfy M, Loy D, Lubarda B, Magee T, Maksvytis H, Man A, Mancuso S, Marconi V, Markowitz M, Marques R Jr, Martin W, Mayer G, Mayer K, McCrone C, McDonald C, McGhee T, McIntyre D, McLean PS, McNett M, Mead H, Mechling K, Melia M, Metroka C, Meyer-Olson D, Michael B, Miller A, Montana J, Montgomery K, Morice A, Mounzer K, Munoz M, Nagin I, Nahass R, Ndung'u T, Nelson S, Nielsen C, Norene D, Novales S, O'Connor D, O'Donnell L, Oldfield E, Olender S, Ojikutu B, Owens W, Panzer T, Parks B, Pattison J, Pavlatos A, Perlmutter A, Pierce MN, Pollak D, Rowe E, Pressnell R, Price L, Proia L, Prokesch R, Prutch P, Pujet H, Rausch M, Ravinshankar J, Restrepo D, Rhame F, Richards C, Richman DD, Robbins G, Rose R 3rd, Rosenthal D, Ross P, Rubin D, Rumbaugh E, Sanchez W, Sanjana V, Santiago S, Santos R, Sax P, Scherman D, Schmidt W, Shrader S, Schuitemaker H, Scribner A, Sestak P, Shalit P, Shay W, Sherman J, Shirvani V, Sims J, Sizemore J, Slotten R, Smiddy J, Sokol-Anderson M, Somogi R, Sordjan R, Sosman J, Stabile P, Stapleton J, Starrett S, Staszkow K, Stearn B, Stellbrink HJ, Sterman L, Steyn T, Stone D, Stone V, Ta H, Tambussi G, Taplitz R, Tashmia K, Tavari D, Tedaldi E, Telenti A, Tierney M, Tillquist C, Tosiello L, Tremblay C, Triant VJ, Tribble M, Trinh P, Tuscher S, Vaccaro AJ, Valadas E, Vecino I, Wagner T, Walworth C, Wanidworanun C, Ward D, Warner D, Watson T, Weber K, Weber T, Webster D, Weinberg W, Weintrob A, Weis S, Wenger S, Werntz G, Wheeler D, White D, Wilkins E, Winston A, Wlodaver C, Wolf E, Wright D, Yang O, Yawetz S, Yurdin DL, Zabukovic B, Zachary K, Zeeman B, Baker B, Block B, Braaten C, Darrah AT, LaTour B, Lian J, McClurg C, Piechocka-Trocha A, Proudfoot J, Rothchild A, Toth I, Barefoot L, Bazner S, Cutrell E, Johnston M, Lemay P, Moss K, Oladehin O, Rosenberg R, Tinsley J, Tsao A, Pereyra F, Addo M, Allen T, Alter G, Altfeld M, Legall S, Pereyra F, Walker B, Yu X, Burtt N, Carmago A, Crawford G, Crenshaw A, Davies L, Gabriel S, Gianniny L, Guiducci C, Brumme C, de Bakker P, Jia X, McLaren P, Haas D, Kuritzkes D, Gulick R, Ribaudo H, Pereyra F, Deeks S, de Bakker P, Carrington M, Allen T, Henn M, Altfeld M, Le Gall S, Heckerman D, Brumme C, Walker B.

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.

2010 The American Society of Human Genetics. Published by Elsevier Inc.

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