The PTPN22 620W allele confers susceptibility to systemic sclerosis: findings of a large case-control study of European Caucasians and a meta-analysis.
OBJECTIVE
To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single-nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta-analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc.


METHODS
Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti-topo I) and for anticentromere antibodies (ACAs).


RESULTS
The co-occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 x 10(-7)) and a protective haplotype carrying the 1858C allele (P = 2.20 x 10(-16)) in our French Caucasian population. The meta-analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 x 10(-3), OR 1.08 [95% CI 1.02-1.15]) and mixed (P = 3.11 x 10(-3), OR 1.09 [95% CI 1.04-1.16]) populations, particularly in the anti-topo I-positive subset.


CONCLUSIONS
Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.
Dieudé
P
P
Université Paris 7, Paris, France. philippe.dieude@bch.aphp.fr
Guedj
M
M
Wipff
J
J
Avouac
J
J
Hachulla
E
E
Diot
E
E
Granel
B
B
Sibilia
J
J
Cabane
J
J
Meyer
O
O
Mouthon
L
L
Kahan
A
A
Boileau
C
C
Allanore
Y
Y
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics*; D044465:White People / Q000235:genetics
C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22