A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.
Graham
Robert R
RR
Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Kozyrev
Sergey V
SV
Baechler
Emily C
EC
Reddy
M V Prasad Linga
MV
Plenge
Robert M
RM
Bauer
Jason W
JW
Ortmann
Ward A
WA
Koeuth
Thearith
T
González Escribano
Ma Francisca
MF
Pons-Estel
Bernardo
B
Petri
Michelle
M
Daly
Mark
M
Gregersen
Peter K
PK
Martín
Javier
J
Altshuler
David
D
Behrens
Timothy W
TW
Alarcón-Riquelme
Marta E
ME
D016022:Case-Control Studies; D015331:Cohort Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012326:RNA Splicing / Q000502:physiology*
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors