PMID- 34254975
OWN - NLM
STAT- MEDLINE
DCOM- 20211004
LR  - 20211004
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 62
IP  - 9
DP  - 2021 Jul 1
TI  - Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between 
      Clinically Distinct Forms of Childhood Uveitis.
PG  - 19
LID - 10.1167/iovs.62.9.19 [doi]
LID - 19
AB  - PURPOSE: Classical alleles of the human leukocyte antigen (HLA) complex have been 
      linked to specific entities of pediatric noninfectious uveitis, yet genetic 
      predisposition encoded by the HLA super-locus across the patient population 
      remains understudied. METHODS: We performed next-generation full-length 
      sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. 
      Dense genotype data from 499 Dutch controls from Genome of the Netherlands were 
      imputed using an HLA-specific reference panel (n = 5225 samples from European 
      ancestry). Cases and controls were compared using logistic regression models 
      adjusting for sex. RESULTS: In total, 179 common and rare alleles were detected. 
      Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were 
      identified as the principal HLA association, which was mainly driven by 92 cases 
      with juvenile idiopathic arthritis-associated uveitis (JIA-U). The 
      HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the 
      phenotypically similar idiopathic chronic anterior uveitis without arthritis 
      (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in 
      JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide 
      associations (P < 2.79 x 10-4) for HLA-DRB1*01:02, HLA-DRB1*04:03, and 
      HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. 
      Finally, amino acid substitution modeling revealed that aspartic acid at position 
      57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) 
      from nonrisk alleles, significantly increased the binding capacity of naturally 
      presented ligands to HLA-DQ. CONCLUSIONS: These results uncovered novel shared 
      HLA associations among clinically distinct phenotypes of pediatric uveitis and 
      highlight genetic predisposition affecting the antigen presentation pathway.
FAU - Wennink, Roos A W
AU  - Wennink RAW
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
AD  - Center of Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - de Boer, Joke H
AU  - de Boer JH
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - Hiddingh, Sanne
AU  - Hiddingh S
AD  - Center of Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - Haasnoot, Anne-Mieke J W
AU  - Haasnoot AJW
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - Kalinina Ayuso, Viera
AU  - Kalinina Ayuso V
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - de Hoop, Talitha
AU  - de Hoop T
AD  - Center of Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - van Setten, Jessica
AU  - van Setten J
AD  - Department of Cardiology, Division Heart and Lungs, University Medical Center 
      Utrecht, Utrecht University, The Netherlands.
FAU - Spierings, Eric
AU  - Spierings E
AD  - Center of Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
FAU - Kuiper, Jonas J W
AU  - Kuiper JJW
AD  - Department of Ophthalmology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
AD  - Center of Translational Immunology, University Medical Center Utrecht, Utrecht 
      University, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (HLA Antigens)
SB  - IM
MH  - Adolescent
MH  - Alleles
MH  - Child
MH  - Female
MH  - Gene Frequency
MH  - *Genetic Predisposition to Disease
MH  - Genotype
MH  - HLA Antigens/*genetics/metabolism
MH  - Haplotypes
MH  - Humans
MH  - Male
MH  - Phenotype
MH  - Sequence Analysis
MH  - Uveitis/*genetics/metabolism
PMC - PMC8287043
COIS- Disclosure: R.A.W. Wennink, None; J.H. de Boer, None; S. Hiddingh, None; A.M.J.W. 
      Haasnoot, None; V. Kalinina Ayuso, None; T. de Hoop, None; J. van Setten, None; 
      E. Spierings, None; J.J.W. Kuiper, None
EDAT- 2021/07/14 06:00
MHDA- 2021/10/05 06:00
PMCR- 2021/07/13
CRDT- 2021/07/13 12:19
PHST- 2021/07/13 12:19 [entrez]
PHST- 2021/07/14 06:00 [pubmed]
PHST- 2021/10/05 06:00 [medline]
PHST- 2021/07/13 00:00 [pmc-release]
AID - 2776464 [pii]
AID - IOVS-21-32509 [pii]
AID - 10.1167/iovs.62.9.19 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2021 Jul 1;62(9):19. doi: 10.1167/iovs.62.9.19.