Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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20045101
TITLE
Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control.
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.
DATE PUBLISHED
2010 Jan
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2009/11/04
revised 2009/12/09
accepted 2009/12/10
entrez 2010/01/05 06:00
pubmed 2010/01/05 06:00
medline 2010/02/26 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Ferreira MA Ferreira Manuel A R MA Queensland Institute of Medical Research, Brisbane, QLD, Australia. manuel.ferreira@qimr.edu.au
Mangino M Mangino Massimo M
Brumme CJ Brumme Chanson J CJ
Zhao ZZ Zhao Zhen Zhen ZZ
Medland SE Medland Sarah E SE
Wright MJ Wright Margaret J MJ
Nyholt DR Nyholt Dale R DR
Gordon S Gordon Scott S
Campbell M Campbell Megan M
McEvoy BP McEvoy Brian P BP
Henders A Henders Anjali A
Evans DM Evans David M DM
Lanchbury JS Lanchbury Jerry S JS
Pereyra F Pereyra Florencia F
International HIV Controllers Study
Walker BD Walker Bruce D BD
Haas DW Haas David W DW
Soranzo N Soranzo Nicole N
Spector TD Spector Tim D TD
de Bakker PI de Bakker Paul I W PI
Frazer IH Frazer Ian H IH
Montgomery GW Montgomery Grant W GW
Martin NG Martin Nicholas G NG
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Agan Brian B
Agarwal Shanu S
Allen Brady B
Altidor Sherly S
Altschuler Eric E
Ambardar Sujata S
Anastos Kathryn K
Anderson Ben B
Andrady Ushan U
Angell Teresa T
Appelbaum Jonathan J
Arnold Kathy K
Arroyo Julio J
Arthur Ernie E
Barbaro Daniel D
Barrett Tom T
Barrie William W
Barthel Vincent V
Bartlett Mary E ME
Barton Simon S
Basden Pat P
Basgoz Nesli N
Bellos Nicholas N
Berger Judith J
Bernard Annette A
Bernard Nicole N
Blair Donald D
Bodner Stanley S
Bolan Robert R
Boudreaux Emilie E
Braun James J
Brndjar Jon J
Brooks Edward E
Brown Kathy K
Brown Stephen S
Bryant Susan S
Bryson Rena R
Buchbinder Susan S
Bullock Diane D
Burack Jedidah J
Busalacchi Mary M
Bush Larry L
Cafaro Virginia V
Campbell John J
Cardosi Beth B
Carlson Rob R
Carmichael Kevin K
Carr Pat P
Carrington Mary M
Cavacuiti Chris C
Celestin Greg G
Chaborek Michele M
Chau John J
Chez Nancy N
Cimoch Paul P
Cohen Daniel E DE
Cohn Bruce B
Cohn Lillian L
Conway Brian B
Cooper David D
Cooper Julie J
Cornellson Brian B
Cowles Anastacia A
Cox David D
Cox-Iyamu Roxanne R
Cuchural George G
Daily Michael M
Daly Jennifer J
Dang Son S
Davis Benjamin B
Davis Kristine K
De Koning P P
DeCardi Hladek Melissa M
Dechter Mark M
Deeks Steven S
DeFoto Joseph J
DeJesus Edwin E
Dennis Deborah T DT
Dolan Matthew M
Duggan Joan J
Dunn Michael M
Egenes Karen K
Ellerin Todd T
Elliott Kathy K
Eron Joe J
Fangman John J
Ferlazzo Helen H
Figueroa Yvette Y
Fiola Terri T
Fisk Stuart S
Flaherty Maureen M
Fleenor-Ford Anita A
Forster Alice A
Fralich Todd T
Francke Elliott E
Frankel Renee R
Freedburg Kenneth K
French Neel N
Fuchs Jonathan D JD
Fuller John J
Gaberman Jonna I JI
Gallant Joel J
Gandhi Rajesh R
Ganesan Anurdha A
Garcia Efrain E
Gardner Adrian A
Garver Patricia P
Gastaldo Joseph J
Gathe Joseph J
Gaultier Cyril C
Gebre Wondwoosen W
Gelman Marcy M
Gilman Frank F
Gilmore John J
Gimbarevsky Boris B
Glaser Jordan J
Goepfert Paul P
Good Gary G
Gottlieb Michael M
Goulston Claudia C
Grimm William W
Groger Richard R
Guiteau Jacques J
Gurley T Douglas TD
Haber Stuart S
Hale Braden B
Halpenny Roberta R
Hardin Theresa T
Hardy W David WD
Hargan Todd T
Harrigan Richard R
Haston Janna J
Hawkins Trevor T
Hellinger Walter W
Henderson Robert R
Henderson Tom T
Henry Keith K
Hermann Susan S
Hernandez Salvador S
Hicks Claire C
Hoffman Robert R
Holland Chris C
Horton James J
Hoskinson Scott S
Hsu Ricky K RK
Huber Janice J
Huhn Gregory G
Humphrey Rene R
Hupert Mark M
Hurtado Rocio R
Illeman Mark M
Israelski Dennis D
Jellinger Robert R
Jessen Heiko H
John Mina M
Johnson Kay K
Jones Mary M
Jordan Wilbert W
Kauffman Carol C
Keba Anna A
Khanlou Homayoon H
Killian Rob R
Kim Arthur A
Kim David D
Kinder Ford F
Kirchner Jeff J
Kish Mary Ann MA
Kocurek Kathryn K
Kogelman Laura L
Kojic E Milu EM
Kortuis Todd T
Kovacs Julia J
Kreiswirth Stacey S
Kuldanek Greg G
Kurisu Wayne W
Lackey Phillip P
Ladan Ahmadi A
Lanzafame Massimiliano M
Lederman Michael M
Lee David D
Lee Ed E
Lee Jenny J
Lee Marah M
LeGrand James J
Lemoine Janice J
Levin Steve S
Levy Jay J
Liguori Michael M
Lin Nina N
Little Susan S
Livine Richard R
Llibre Josep M JM
Lopez Al A
Loutfy Mona M
Loy Dawn D
Lubarda Barbara B
Magee Thomas T
Maksvytis Harvey H
Man Alan A
Mancuso Stacey S
Marconi Vincent V
Markowitz Martin M
Marques Rui R
Martin William W
Mayer Gal G
Mayer Kenneth K
McCrone Cindy C
McDonald Cheryl C
McGhee Theresa T
McIntyre Dawn D
McLean P Scott PS
McNett Michael M
Mead Hazel H
Mechling Katherine K
Melia Michael M
Metroka Craig C
Meyer-Olson Dirk D
Michael Brent B
Miller Andy A
Montana John J
Montgomery Kate K
Morice Anthony A
Mounzer Karam K
Munoz Michael M
Nagin Iris I
Nahass Ron R
Ndung'u Thumbi T
Nelson Sandra S
Nielsen Craig C
Norene David D
Novales Susan S
O'Connor David D
O'Donnell Laura L
Oldfield Edward E
Olender Susan S
Ojikutu Bisola B
Owens William W
Panzer Todd T
Parks Brad B
Pattison Julie J
Pavlatos Andy A
Perlmutter Aaron A
Pierce Michael Norman MN
Pollak Deborah D
Rowe Emile E
Pressnell Richard R
Price Lawrence L
Proia Laurie L
Prokesch Richard R
Prutch Peter P
Pujet Heather H
Rausch Michael M
Ravinshankar Jayashree J
Restrepo Dalilah D
Rhame Frank F
Richards Constance C
Richman Douglas D DD
Robbins Gregory G
Rose Richard R
Rosenthal Daniel D
Ross Polly P
Rubin David D
Rumbaugh Elease E
Sanchez Will W
Sanjana Veeraf V
Santiago Stephen S
Santos Rene R
Sax Paul P
Scherman Debra D
Schmidt Wolfgang W
Shrader Shannon S
Schuitemaker Hanneke H
Scribner Anita A
Sestak Phillip P
Shalit Peter P
Shay William W
Sherman Jeffrey J
Shirvani Vivian V
Sims James J
Sizemore Jay J
Slotten Ross R
Smiddy Joseph J
Sokol-Anderson Marcia M
Somogi Rachel R
Sordjan Renee R
Sosman James J
Stabile Paul P
Stapleton Jack J
Starrett Sharee S
Staszkow Kaleo K
Stearn Ben B
Stellbrink Hans-Jurgen HJ
Sterman Lisa L
Steyn Tinus T
Stone David D
Stone Valerie V
Ta Ha H
Tambussi Giuseppe G
Taplitz Randy R
Tashmia Karen K
Tavari Daniel D
Tedaldi Ellen E
Telenti Amalio A
Tierney Marianne M
Tillquist Carolyn C
Tosiello Lorraine L
Tremblay Cécile C
Triant Virginia Jeanne VJ
Tribble Marc M
Trinh P P
Tuscher Susan S
Vaccaro Anthony J AJ
Valadas Emilia E
Vecino Isabel I
Wagner Theresa T
Walworth Charles C
Wanidworanun Chingchai C
Ward Douglas D
Warner Daniel D
Watson Terry T
Weber Karl K
Weber Terry T
Webster Duncan D
Weinberg Winkler W
Weintrob Amy A
Weis Steve S
Wenger Scott S
Werntz Gary G
Wheeler David D
White David D
Wilkins Ed E
Winston Alan A
Wlodaver Clifford C
Wolf Eva E
Wright David D
Yang Otto O
Yawetz Sigal S
Yurdin David L DL
Zabukovic Brandon B
Zachary Kimon K
Zeeman Beth B
Baker Brett B
Block Brian B
Braaten Conrad C
Darrah Aisha Tiala AT
LaTour Brooke B
Lian Jeffrey J
McClurg Cheryl C
Piechocka-Trocha Alicja A
Proudfoot Jacqueline J
Rothchild Alissa A
Toth Ildiko I
Barefoot Laurie L
Bazner Suzane S
Cutrell Emily E
Johnston Mary M
Lemay Paul P
Moss Kristin K
Oladehin Olakunle O
Rosenberg Rachel R
Tinsley Jake J
Tsao Alice A
Pereyra Florencia F
Addo Marylyn M
Allen Todd T
Alter Galit G
Altfeld Marcus M
Legall Sylvie S
Pereyra Florencia F
Walker Bruce B
Yu Xu X
Burtt Noël N
Carmago Amy A
Crawford Gabriel G
Crenshaw Andrew A
Davies Leela L
Gabriel Stacey S
Gianniny Lauren L
Guiducci Candace C
Brumme Chanson C
de Bakker Paul P
Jia Xiaoming X
McLaren Paul P
Haas David D
Kuritzkes Daniel D
Gulick Roy R
Ribaudo Heather H
Pereyra Florencia F
Deeks Steve S
de Bakker Paul P
Carrington Mary M
Allen Todd T
Henn Matthew M
Altfeld Marcus M
Le Gall Sylvie S
Heckerman David D
Brumme Chanson C
Walker Bruce B
JOURNAL
VOLUME: 86
ISSUE: 1
TITLE: American journal of human genetics
ISOABBREVIATION: Am J Hum Genet
YEAR: 2010
MONTH: Jan
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Child immunology
Diabetes Mellitus, Type 1 immunology
Genetic Predisposition to Disease immunology
Genetic Variation immunology
Genotype immunology
HIV Infections immunology
HIV-1 metabolism
Humans metabolism
Killer Cells, Natural immunology
Lymphocyte Count immunology
Quantitative Trait Loci immunology
Risk immunology
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's