A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.
Begovich
Ann B
AB
Celera Diagnostics, Alameda, CA 94502, USA. Ann.Begovich@celeradiagnostics.com
Carlton
Victoria E H
VE
Honigberg
Lee A
LA
Schrodi
Steven J
SJ
Chokkalingam
Anand P
AP
Alexander
Heather C
HC
Ardlie
Kristin G
KG
Huang
Qiqing
Q
Smith
Ashley M
AM
Spoerke
Jill M
JM
Conn
Marion T
MT
Chang
Monica
M
Chang
Sheng-Yung P
SY
Saiki
Randall K
RK
Catanese
Joseph J
JJ
Leong
Diane U
DU
Garcia
Veronica E
VE
McAllister
Linda B
LB
Jeffery
Douglas A
DA
Lee
Annette T
AT
Batliwalla
Franak
F
Remmers
Elaine
E
Criswell
Lindsey A
LA
Seldin
Michael F
MF
Kastner
Daniel L
DL
Amos
Christopher I
CI
Sninsky
John J
JJ
Gregersen
Peter K
PK
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009928:Organ Specificity / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000502:physiology
D012333:RNA, Messenger; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases