Replication of an Association Between the Lymphoid Tyrosine Phosphatase Locus (LYP/PTPN22) With Type 1 Diabetes, and Evidence for Its Role as a General Autoimmunity Locus

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 11; pp. 3020 - 3023
• Main Authors: SMYTH, Deborah, COOPER, Jason D, BARRATT, Bryan J, GUJA, Cristian, IONESCU-TIRGOVISTE, Constantin, SAVAGE, David A, DUNGER, David B, WIDMER, Barry, STRACHAN, David P, RING, Susan M, WALKER, Neil, CLAYTON, David G, COLLINS, Joanne E, TWELLS, Rebecca C. J, GOUGH, Stephen C. L, TODD, John A, HEWARD, Joanne M, FRANKLYN, Jayne A, HOWSON, Joanna M. M, VELLA, Adrian, NUTLAND, Sarah, RANCE, Helen E, MAIER, Lisa
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-11-2004
• Subjects: Adult; Autoimmune diseases; Autoimmunity - genetics; Biological and medical sciences; Child; Chromosome Mapping; Chromosomes; Diabetes; Diabetes Mellitus, Type 1 - enzymology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes. Impaired glucose tolerance; Diagnosis; DNA replication; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Genes; Genetic aspects; Genotype; Graves disease; Health aspects; Humans; Kinases; Male; Medical sciences; Nuclear Family; Phosphatase; Polymorphism; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases - genetics; Proteins; Reference Values; Regression Analysis; Rheumatoid arthritis; Risk factors; Type 1 diabetes; Tyrosine; White people; United Kingdom; United Kingdom > UK; United States > US; Autoimmunity; Endocrinopathy; Association; Enzyme; Type 1 diabetes; Phosphoric monoester hydrolases; Hydrolases; Replication; Esterases; Locus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.11.3020

Replication of an Association Between the Lymphoid Tyrosine Phosphatase Locus ( LYP/PTPN22 ) With Type 1 Diabetes, and Evidence for Its Role as a General Autoimmunity Locus
Deborah Smyth 1 ,
Jason D. Cooper 1 ,
Joanne E. Collins 2 ,
Joanne M. Heward 2 ,
Jayne A. Franklyn 2 ,
Joanna M.M. Howson 1 ,
Adrian Vella 1 ,
Sarah Nutland 1 ,
Helen E. Rance 1 ,
Lisa Maier 1 ,
Bryan J. Barratt 3 ,
Cristian Guja 4 ,
Constantin Ionescu-Tı̂rgovişte 4 ,
David A. Savage 5 ,
David B. Dunger 6 ,
Barry Widmer 6 ,
David P. Strachan 7 ,
Susan M. Ring 8 ,
Neil Walker 1 ,
David G. Clayton 1 ,
Rebecca C.J. Twells 1 ,
Stephen C.L. Gough 2 and
John A. Todd 1
1 Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust (WT) Diabetes and Inflammation Laboratory, Cambridge Institute
for Medical Research (CIMR), University of Cambridge, Cambridge, U.K
2 Division of Medical Sciences, University of Birmingham, Birmingham, U.K
3 AstraZeneca, Macclesfield, U.K
4 Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases “N. Paulescu,” Bucharest, Romania
5 Department of Medical Genetics, Queen’s University Belfast, Belfast City Hospital, Belfast, Northern Ireland
6 Department of Paediatrics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, U.K
7 Department of Public Health Sciences, St. George’s Hospital Medical School, London, U.K
8 Avon Longitudinal Study of Parents and Children (ALSPAC), University of Bristol, Bristol, U.K
Address correspondence and reprint requests to Professor John A. Todd, Juvenile Diabetes Research Foundation (JDRF)/Wellcome
Trust (WT) Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge,
Cambridge, U.K. E-mail: john.todd{at}cimr.cam.ac.uk
Abstract
In the genetic analysis of common, multifactorial diseases, such as type 1 diabetes, true positive irrefutable linkage and
association results have been rare to date. Recently, it has been reported that a single nucleotide polymorphism (SNP), 1858C>T,
in the gene PTPN22 , encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which has been shown to be a negative regulator of
T-cell activation, is associated with an increased risk of type 1 diabetes. Here, we have replicated these findings in 1,388
type 1 diabetic families and in a collection of 1,599 case and 1,718 control subjects, confirming the association of the PTPN22 locus with type 1 diabetes (family-based relative risk (RR) 1.67 [95% CI 1.46–1.91], and case-control odds ratio (OR) 1.78
[95% CI 1.54–2.06]; overall P = 6.02 × 10 −27 ). We also report evidence for an association of Trp 620 with another autoimmune disorder, Graves’ disease, in 1,734 case and control subjects ( P = 6.24 × 10 −4 ; OR 1.43 [95% CI 1.17–1.76]). Taken together, these results indicate a more general association of the PTPN22 locus with autoimmune disease.
GRID, Genetic Resource Investigating Diabetes
LYP, lymphoid protein tyrosine phosphatase
SNP, single nucleotide polymorphism
VNTR, variable number of tandem repeats
Footnotes
D.S. and J.D.C. contributed equally to this work.
Accepted August 17, 2004.
Received June 4, 2004.
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