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PMID: 22446964 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.

Nature genetics ·Vol. 44 ·No. 5 ·2012-03-25 ·Pages 502-10

Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC

Abstract

Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

MeSH Terms
Alleles Autoimmune Diseases/etiology B-Lymphocytes/immunology,metabolism Gene Expression Profiling Gene Expression Regulation Genetic Markers/genetics Genetic Predisposition to Disease Genome-Wide Association Study HLA Antigens/genetics Humans Kruppel-Like Factor 4 Kruppel-Like Transcription Factors/genetics Monocytes/immunology,metabolism PPAR gamma/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics
Chemicals
Genetic Markers HLA Antigens KLF4 protein, human Kruppel-Like Factor 4 Kruppel-Like Transcription Factors PPAR gamma
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Fairfax Benjamin P
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. bfairfax@well.ox.ac.uk
Makino Seiko
Radhakrishnan Jayachandran
Plant Katharine
Leslie Stephen
Dilthey Alexander
Ellis Peter
Langford Cordelia
Vannberg Fredrik O
Knight Julian C
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2205
Email
bfairfax@well.ox.ac.uk
Published
2012-03-25
Epub
2012-00-25
Pages
502-10
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3437404
Subset
IM
Grants
Department of Health · 439 · United Kingdom
Wellcome Trust · 075491/Z/04 · United Kingdom
Wellcome Trust · 074318 · United Kingdom
Wellcome Trust · 090532 · United Kingdom
European Research Council · 281824 · International
Wellcome Trust · 088891 · United Kingdom
Corrections
CommentIn
PMID: 22538719
External Links
PubMed source DOI: 10.1038/ng.2205 PMC Full Text View journal details
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