PMID- 26912320
OWN - NLM
STAT- MEDLINE
DCOM- 20160803
LR  - 20170403
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 196
IP  - 7
DP  - 2016 Apr 1
TI  - Systematic Evaluation of Genes and Genetic Variants Associated with Type 1
      Diabetes Susceptibility.
PG  - 3043-53
LID - 10.4049/jimmunol.1502056 [doi]
AB  - Genome-wide association studies have found >60 loci that confer genetic
      susceptibility to type 1 diabetes (T1D). Many of these are defined only by
      anonymous single nucleotide polymorphisms: the underlying causative genes, as
      well as the molecular bases by which they mediate susceptibility, are not known. 
      Identification of how these variants affect the complex mechanisms contributing
      to the loss of tolerance is a challenge. In this study, we performed systematic
      analyses to characterize these variants. First, all known genes in strong linkage
      disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for
      each locus were tested for commonly occurring nonsynonymous variations. We found 
      only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous
      alleles. Next, we performed functional studies to examine the effect of non-HLA
      T1D risk alleles on regulating expression levels of genes in four different cell 
      types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified
      CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait
      loci and found 24 non-HLA loci that affected the expression of 31 transcripts
      significantly in at least one cell type. Additionally, we observed 25 loci that
      affected 38 transcripts in trans. In summary, our systems genetics analyses
      defined the effect of T1D risk alleles on levels of gene expression and provide
      novel insights into the complex genetics of T1D, suggesting that most of the T1D 
      risk alleles mediate their effect by influencing expression of multiple nearby
      genes.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Ram, Ramesh
AU  - Ram R
AUID- ORCID: http://orcid.org/0000-0002-4827-4778
AD  - Centre for Diabetes Research, Harry Perkins Institute of Medical Research,
      Nedlands, Western Australia 6009, Australia; Centre of Medical Research,
      University of Western Australia, Nedlands, Western Australia 6009, Australia;
FAU - Mehta, Munish
AU  - Mehta M
AUID- ORCID: http://orcid.org/0000-0003-1955-6976
AD  - Centre for Diabetes Research, Harry Perkins Institute of Medical Research,
      Nedlands, Western Australia 6009, Australia; Centre of Medical Research,
      University of Western Australia, Nedlands, Western Australia 6009, Australia;
FAU - Nguyen, Quang T
AU  - Nguyen QT
AD  - Centre for Diabetes Research, Harry Perkins Institute of Medical Research,
      Nedlands, Western Australia 6009, Australia; Centre of Medical Research,
      University of Western Australia, Nedlands, Western Australia 6009, Australia;
FAU - Larma, Irma
AU  - Larma I
AUID- ORCID: http://orcid.org/0000-0003-2177-0488
AD  - Centre for Diabetes Research, Harry Perkins Institute of Medical Research,
      Nedlands, Western Australia 6009, Australia; Centre of Medical Research,
      University of Western Australia, Nedlands, Western Australia 6009, Australia;
FAU - Boehm, Bernhard O
AU  - Boehm BO
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
      636921; Ulm University Medical Centre, Department of Internal Medicine I, Ulm
      University, 89081 Ulm, Germany;
FAU - Pociot, Flemming
AU  - Pociot F
AUID- ORCID: http://orcid.org/0000-0003-3274-5448
AD  - Department of Pediatrics, Herlev and Gentofte Hospital, 2730 Herlev, Denmark;
FAU - Concannon, Patrick
AU  - Concannon P
AD  - Department of Pathology, Immunology and Laboratory Medicine, University of
      Florida, Gainesville, FL 32610; and Genetics Institute, University of Florida,
      Gainesville, FL 32610.
FAU - Morahan, Grant
AU  - Morahan G
AUID- ORCID: http://orcid.org/0000-0002-8562-7325
AD  - Centre for Diabetes Research, Harry Perkins Institute of Medical Research,
      Nedlands, Western Australia 6009, Australia; Centre of Medical Research,
      University of Western Australia, Nedlands, Western Australia 6009, Australia;
      grant.morahan@uwa.edu.au.
LA  - eng
GR  - DP3 DK085678/DK/NIDDK NIH HHS/United States
GR  - 1DP3DK085678/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160224
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
SB  - AIM
SB  - IM
MH  - CD4-Positive T-Lymphocytes/metabolism
MH  - CD8-Positive T-Lymphocytes/metabolism
MH  - Cell Line, Transformed
MH  - Diabetes Mellitus, Type 1/*genetics
MH  - Epistasis, Genetic
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Gene Regulatory Networks
MH  - Genetic Association Studies
MH  - *Genetic Predisposition to Disease
MH  - *Genetic Variation
MH  - Genome-Wide Association Study
MH  - Genotype
MH  - Humans
MH  - Leukocytes, Mononuclear/metabolism
MH  - Linkage Disequilibrium
MH  - Polymorphism, Single Nucleotide
MH  - Quantitative Trait Loci
MH  - Reproducibility of Results
PMC - PMC4799766
MID - NIHMS756712
EDAT- 2016/02/26 06:00
MHDA- 2016/08/04 06:00
CRDT- 2016/02/26 06:00
PHST- 2015/09/24 00:00 [received]
PHST- 2016/01/25 00:00 [accepted]
PHST- 2016/02/26 06:00 [entrez]
PHST- 2016/02/26 06:00 [pubmed]
PHST- 2016/08/04 06:00 [medline]
AID - jimmunol.1502056 [pii]
AID - 10.4049/jimmunol.1502056 [doi]
PST - ppublish
SO  - J Immunol. 2016 Apr 1;196(7):3043-53. doi: 10.4049/jimmunol.1502056. Epub 2016
      Feb 24.