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

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 tes... Full description

Journal Title: American journal of human genetics 2010, Vol.86 (1), p.88-92
Main Author: Ferreira, Manuel A.R
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
HIV
Quelle: Alma/SFX Local Collection
Publisher: Cambridge, MA: Elsevier Inc
ID: ISSN: 0002-9297
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title: Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
format: Article
creator:
  • 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
subjects:
  • Acquired immune deficiency syndrome
  • Adolescent
  • AIDS
  • Autoimmune diseases
  • Biological and medical sciences
  • CD4 antigen
  • CD4-Positive T-Lymphocytes - cytology
  • CD4-Positive T-Lymphocytes - immunology
  • CD56 antigen
  • CD8 antigen
  • CD8-Positive T-Lymphocytes - cytology
  • CD8-Positive T-Lymphocytes - immunology
  • Child
  • Diabetes
  • Diabetes mellitus
  • Diabetes Mellitus, Type 1 - blood
  • Diabetes Mellitus, Type 1 - immunology
  • Diabetes. Impaired glucose tolerance
  • Endocrine pancreas. Apud cells (diseases)
  • Endocrinopathies
  • Etiopathogenesis. Screening. Investigations. Target tissue resistance
  • Fundamental and applied biological sciences. Psychology
  • Gene loci
  • General aspects. Genetic counseling
  • Genes
  • Genetic aspects
  • Genetic diversity
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genetics
  • Genetics of eukaryotes. Biological and molecular evolution
  • Genetics(clinical)
  • Genotype
  • Health aspects
  • HIV
  • HIV infection
  • HIV Infections - blood
  • HIV Infections - immunology
  • HIV-1 - metabolism
  • Homeostasis
  • Human immunodeficiency virus
  • Human immunodeficiency virus 1
  • Humans
  • Immunologic diseases
  • Killer Cells, Natural - immunology
  • Lymphocyte Count
  • Lymphocyte receptors
  • Lymphocytes
  • Lymphocytes T
  • Major histocompatibility complex
  • Medical genetics
  • Medical sciences
  • Molecular and cellular biology
  • Natural killer cells
  • Quantitative Trait Loci
  • Report
  • Risk
  • Risk factors
  • Single-nucleotide polymorphism
  • Type 1 diabetes
ispartof: American journal of human genetics, 2010, Vol.86 (1), p.88-92
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleQuantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
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creatorFerreira, 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
creatorcontribFerreira, 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 ; International HIV Controllers Study
descriptionAbnormal 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.
identifier
0ISSN: 0002-9297
1EISSN: 1537-6605
2DOI: 10.1016/j.ajhg.2009.12.008
3PMID: 20045101
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languageeng
publisherCambridge, MA: Elsevier Inc
subjectAcquired immune deficiency syndrome ; Adolescent ; AIDS ; Autoimmune diseases ; Biological and medical sciences ; CD4 antigen ; CD4-Positive T-Lymphocytes - cytology ; CD4-Positive T-Lymphocytes - immunology ; CD56 antigen ; CD8 antigen ; CD8-Positive T-Lymphocytes - cytology ; CD8-Positive T-Lymphocytes - immunology ; Child ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 1 - blood ; Diabetes Mellitus, Type 1 - immunology ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fundamental and applied biological sciences. Psychology ; Gene loci ; General aspects. Genetic counseling ; Genes ; Genetic aspects ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic Variation ; Genetics ; Genetics of eukaryotes. Biological and molecular evolution ; Genetics(clinical) ; Genotype ; Health aspects ; HIV ; HIV infection ; HIV Infections - blood ; HIV Infections - immunology ; HIV-1 - metabolism ; Homeostasis ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Immunologic diseases ; Killer Cells, Natural - immunology ; Lymphocyte Count ; Lymphocyte receptors ; Lymphocytes ; Lymphocytes T ; Major histocompatibility complex ; Medical genetics ; Medical sciences ; Molecular and cellular biology ; Natural killer cells ; Quantitative Trait Loci ; Report ; Risk ; Risk factors ; Single-nucleotide polymorphism ; Type 1 diabetes
ispartofAmerican journal of human genetics, 2010, Vol.86 (1), p.88-92
rights
02010 The American Society of Human Genetics
1info:eu-repo/semantics/restrictedAccess
22015 INIST-CNRS
32010 The American Society of Human Genetics. Published by Elsevier Inc.
4Copyright University of Chicago, acting through its Press Jan 8, 2010
52010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2010 The American Society of Human Genetics
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0Ferreira, Manuel A.R
1Mangino, Massimo
2Brumme, Chanson J
3Zhao, Zhen Zhen
4Medland, Sarah E
5Wright, Margaret J
6Nyholt, Dale R
7Gordon, Scott
8Campbell, Megan
9McEvoy, Brian P
10Henders, Anjali
11Evans, David M
12Lanchbury, Jerry S
13Pereyra, Florencia
14Walker, Bruce D
15Haas, David W
16Soranzo, Nicole
17Spector, Tim D
18de Bakker, Paul I.W
19Frazer, Ian H
20Montgomery, Grant W
21Martin, Nicholas G
22International HIV Controllers Study
title
0Quantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
1American journal of human genetics
addtitleAm J Hum Genet
descriptionAbnormal 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.
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0Acquired immune deficiency syndrome
1Adolescent
2AIDS
3Autoimmune diseases
4Biological and medical sciences
5CD4 antigen
6CD4-Positive T-Lymphocytes - cytology
7CD4-Positive T-Lymphocytes - immunology
8CD56 antigen
9CD8 antigen
10CD8-Positive T-Lymphocytes - cytology
11CD8-Positive T-Lymphocytes - immunology
12Child
13Diabetes
14Diabetes mellitus
15Diabetes Mellitus, Type 1 - blood
16Diabetes Mellitus, Type 1 - immunology
17Diabetes. Impaired glucose tolerance
18Endocrine pancreas. Apud cells (diseases)
19Endocrinopathies
20Etiopathogenesis. Screening. Investigations. Target tissue resistance
21Fundamental and applied biological sciences. Psychology
22Gene loci
23General aspects. Genetic counseling
24Genes
25Genetic aspects
26Genetic diversity
27Genetic Predisposition to Disease
28Genetic Variation
29Genetics
30Genetics of eukaryotes. Biological and molecular evolution
31Genetics(clinical)
32Genotype
33Health aspects
34HIV
35HIV infection
36HIV Infections - blood
37HIV Infections - immunology
38HIV-1 - metabolism
39Homeostasis
40Human immunodeficiency virus
41Human immunodeficiency virus 1
42Humans
43Immunologic diseases
44Killer Cells, Natural - immunology
45Lymphocyte Count
46Lymphocyte receptors
47Lymphocytes
48Lymphocytes T
49Major histocompatibility complex
50Medical genetics
51Medical sciences
52Molecular and cellular biology
53Natural killer cells
54Quantitative Trait Loci
55Report
56Risk
57Risk factors
58Single-nucleotide polymorphism
59Type 1 diabetes
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1Mangino, Massimo
2Brumme, Chanson J
3Zhao, Zhen Zhen
4Medland, Sarah E
5Wright, Margaret J
6Nyholt, Dale R
7Gordon, Scott
8Campbell, Megan
9McEvoy, Brian P
10Henders, Anjali
11Evans, David M
12Lanchbury, Jerry S
13Pereyra, Florencia
14Walker, Bruce D
15Haas, David W
16Soranzo, Nicole
17Spector, Tim D
18de Bakker, Paul I.W
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titleQuantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
authorFerreira, 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
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1Adolescent
2AIDS
3Autoimmune diseases
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5CD4 antigen
6CD4-Positive T-Lymphocytes - cytology
7CD4-Positive T-Lymphocytes - immunology
8CD56 antigen
9CD8 antigen
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11CD8-Positive T-Lymphocytes - immunology
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20Etiopathogenesis. Screening. Investigations. Target tissue resistance
21Fundamental and applied biological sciences. Psychology
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23General aspects. Genetic counseling
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25Genetic aspects
26Genetic diversity
27Genetic Predisposition to Disease
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30Genetics of eukaryotes. Biological and molecular evolution
31Genetics(clinical)
32Genotype
33Health aspects
34HIV
35HIV infection
36HIV Infections - blood
37HIV Infections - immunology
38HIV-1 - metabolism
39Homeostasis
40Human immunodeficiency virus
41Human immunodeficiency virus 1
42Humans
43Immunologic diseases
44Killer Cells, Natural - immunology
45Lymphocyte Count
46Lymphocyte receptors
47Lymphocytes
48Lymphocytes T
49Major histocompatibility complex
50Medical genetics
51Medical sciences
52Molecular and cellular biology
53Natural killer cells
54Quantitative Trait Loci
55Report
56Risk
57Risk factors
58Single-nucleotide polymorphism
59Type 1 diabetes
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15Haas, David W
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22International HIV Controllers Study
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0Ferreira, Manuel A.R
1Mangino, Massimo
2Brumme, Chanson J
3Zhao, Zhen Zhen
4Medland, Sarah E
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6Nyholt, Dale R
7Gordon, Scott
8Campbell, Megan
9McEvoy, Brian P
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11Evans, David M
12Lanchbury, Jerry S
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14Walker, Bruce D
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atitleQuantitative Trait Loci for CD4:CD8 Lymphocyte Ratio Are Associated with Risk of Type 1 Diabetes and HIV-1 Immune Control
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0A full list of members is provided in the Supplemental Data, available online.
1Current address: MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol BS8 2BN, UK.
abstractAbnormal 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.
copCambridge, MA
pubElsevier Inc
pmid20045101
doi10.1016/j.ajhg.2009.12.008
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