Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study.
BACKGROUND
A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry.


METHODS
4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci.


RESULTS
Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 p(MH)=1.94×10(-4), OR 1.19; rs4958881 p(MH)=3.26×10(-5), OR 1.19; rs3792783 p(MH)=2.16×10(-4), OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets.


CONCLUSIONS
These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
Department of Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain. larabc@ipb.csic.es
Lara
L
Bossini-Castillo
Jose Ezequiel
JE
Martin
Jasper
J
Broen
Carmen P
CP
Simeon
Lorenzo
L
Beretta
Olga Y
OY
Gorlova
Madelon C
MC
Vonk
Norberto
N
Ortego-Centeno
Gerard
G
Espinosa
Patricia
P
Carreira
Paloma
P
García de la Peña
Natividad
N
Oreiro
José Andrés
JA
Román-Ivorra
María Jesús
MJ
Castillo
Miguel A
MA
González-Gay
Luis
L
Sáez-Comet
Ivan
I
Castellví
Annemie J
AJ
Schuerwegh
Alexandre E
AE
Voskuyl
Anna-Maria
AM
Hoffmann-Vold
Roger
R
Hesselstrand
Annika
A
Nordin
Claudio
C
Lunardi
Raffaella
R
Scorza
Jacob M
JM
van Laar
Paul G
PG
Shiels
Ariane
A
Herrick
Jane
J
Worthington
Carmen
C
Fonseca
Christopher
C
Denton
Filemon K
FK
Tan
Frank C
FC
Arnett
Shervin
S
Assassi
Bobby P
BP
Koeleman
Maureen D
MD
Mayes
Timothy R D J
TR
Radstake
Javier
J
Martin
D004268:DNA-Binding Proteins / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000453:epidemiology* / Q000235:genetics*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D020743:rhoB GTP-Binding Protein / Q000235:genetics*
D004268:DNA-Binding Proteins; C484393:PSORS1C1 protein, human; D011506:Proteins; C117046:TNIP1 protein, human; D020743:rhoB GTP-Binding Protein