PMID- 33483996
OWN - NLM
STAT- MEDLINE
DCOM- 20210928
LR  - 20231111
IS  - 1440-1711 (Electronic)
IS  - 0818-9641 (Print)
IS  - 0818-9641 (Linking)
VI  - 99
IP  - 5
DP  - 2021 May
TI  - De-coding genetic risk variants in type 1 diabetes.
PG  - 496-508
LID - 10.1111/imcb.12438 [doi]
AB  - The conceptual basis for a genetic predisposition underlying the risk for 
      developing type 1 diabetes (T1D) predates modern human molecular genetics. Over 
      half of the genetic risk has been attributed to the human leukocyte antigen (HLA) 
      class II gene region and to the insulin (INS) gene locus - both thought to confer 
      direction of autoreactivity and tissue specificity. Notwithstanding, questions 
      still remain regarding the functional contributions of a vast array of minor 
      polygenic risk variants scattered throughout the genome that likely influence 
      disease heterogeneity and clinical outcomes. Herein, we summarize the available 
      literature related to the T1D-associated coding variants defined at the time of 
      this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, 
      CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and 
      studies from the non-obese diabetic (NOD) mouse are presented to describe the 
      functional impact of these variants in relation to innate and adaptive immunity 
      as well as to beta-cell fragility, with expression profiles in tissues and 
      peripheral blood highlighted. The contribution of each variant to progression 
      through T1D staging, including environmental interactions, are discussed with 
      consideration of how their respective protein products may serve as attractive 
      targets for precision medicine-based therapeutics to prevent or suspend the 
      development of T1D.
CI  - (c) 2021 Australian and New Zealand Society for Immunology, Inc.
FAU - Shapiro, Melanie R
AU  - Shapiro MR
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Thirawatananond, Puchong
AU  - Thirawatananond P
AUID- ORCID: 0000-0003-4973-7380
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Peters, Leeana
AU  - Peters L
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Sharp, Robert C
AU  - Sharp RC
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Ogundare, Similoluwa
AU  - Ogundare S
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Posgai, Amanda L
AU  - Posgai AL
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Perry, Daniel J
AU  - Perry DJ
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
FAU - Brusko, Todd M
AU  - Brusko TM
AUID- ORCID: 0000-0003-2878-9296
AD  - Department of Pathology, Immunology, and Laboratory Medicine, College of 
      Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
AD  - Department of Pediatrics, College of Medicine, Diabetes Institute, University of 
      Florida, Gainesville, FL, 32610, USA.
LA  - eng
GR  - P01 AI042288/AI/NIAID NIH HHS/United States
GR  - T32 DK108736/DK/NIDDK NIH HHS/United States
GR  - UG3 DK122638/DK/NIDDK NIH HHS/United States
GR  - R01 DK106191/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20210224
PL  - United States
TA  - Immunol Cell Biol
JT  - Immunology and cell biology
JID - 8706300
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 1/genetics
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Polymorphism, Single Nucleotide
PMC - PMC8119379
MID - NIHMS1693426
OTO - NOTNLM
OT  - coding variant
OT  - human
OT  - precision medicine
OT  - risk gene
OT  - single nucleotide polymorphism
OT  - type 1 diabetes
COIS- CONFLICT OF INTEREST The authors declare that no relevant conflicts of interest 
      exist.
EDAT- 2021/01/24 06:00
MHDA- 2021/09/29 06:00
PMCR- 2021/05/14
CRDT- 2021/01/23 05:42
PHST- 2021/01/08 00:00 [revised]
PHST- 2020/10/30 00:00 [received]
PHST- 2021/01/20 00:00 [accepted]
PHST- 2021/01/24 06:00 [pubmed]
PHST- 2021/09/29 06:00 [medline]
PHST- 2021/01/23 05:42 [entrez]
PHST- 2021/05/14 00:00 [pmc-release]
AID - 10.1111/imcb.12438 [doi]
PST - ppublish
SO  - Immunol Cell Biol. 2021 May;99(5):496-508. doi: 10.1111/imcb.12438. Epub 2021 Feb 
      24.