Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.
Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
Graham
Robert R
RR
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Kyogoku
Chieko
C
Sigurdsson
Snaevar
S
Vlasova
Irina A
IA
Davies
Leela R L
LR
Baechler
Emily C
EC
Plenge
Robert M
RM
Koeuth
Thearith
T
Ortmann
Ward A
WA
Hom
Geoffrey
G
Bauer
Jason W
JW
Gillett
Clarence
C
Burtt
Noel
N
Cunninghame Graham
Deborah S
DS
Onofrio
Robert
R
Petri
Michelle
M
Gunnarsson
Iva
I
Svenungsson
Elisabet
E
Rönnblom
Lars
L
Nordmark
Gunnel
G
Gregersen
Peter K
PK
Moser
Kathy
K
Gaffney
Patrick M
PM
Criswell
Lindsey A
LA
Vyse
Timothy J
TJ
Syvänen
Ann-Christine
AC
Bohjanen
Paul R
PR
Daly
Mark J
MJ
Behrens
Timothy W
TW
Altshuler
David
D
D016022:Case-Control Studies; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012307:Risk Factors
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D020033:Protein Isoforms