Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus.
OBJECTIVE
Several candidate genes have been implicated in susceptibility for systemic lupus erythematosus (SLE), a complex autoimmune disease. The proposed genes include members of the type I interferon (IFN) pathway and genes involved in immunological defense functions. Our aim was to systematically replicate 6 such genes, TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2.


METHODS
Single-nucleotide polymorphisms in TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2 were genotyped in 277 SLE patients and 356 healthy controls from Finland, giving a power of 42%-70% for different genes at published allele frequencies.


RESULTS
Significant association was seen for rs2304256 (p = 0.0001) and rs12720270 (p = 0.0031) in TYK2 and rs10954213 (p = 0.0043) in IRF5 in our samples, but not for the other genes. We found evidence for genetic interaction (p = 0.014) between rs2304256 in TYK2 and rs10954213 in IRF5, both members of the type I IFN pathway, strengthening the role of the type I IFN pathway in the pathogenesis of SLE.


CONCLUSIONS
The IFN pathway genes IRF5 and TYK2 may act epistatically in increasing risk for SLE, but our lack of replication does not exclude effects of the other genes studied.
Hellquist
Anna
A
Department of Biosciences and Nutrition, Karolinska Institutet, Sweden.
Järvinen
Tiina M
TM
Koskenmies
Sari
S
Zucchelli
Marco
M
Orsmark-Pietras
Christina
C
Berglind
Linda
L
Panelius
Jaana
J
Hasan
Taina
T
Julkunen
Heikki
H
D'Amato
Mauro
M
Saarialho-Kere
Ulpu
U
Kere
Juha
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D060908:CTLA-4 Antigen; D002648:Child; D004843:Epistasis, Genetic / Q000276:immunology*; D005260:Female; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007370:Interferon Type I / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D061026:Programmed Cell Death 1 Receptor; D017452:Receptors, IgG / Q000235:genetics; D012307:Risk Factors; D053634:TYK2 Kinase / Q000235:genetics*; D055815:Young Adult
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C445323:FCGR2A protein, human; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D017452:Receptors, IgG; D053634:TYK2 Kinase; C070139:TYK2 protein, human