Presentation: A Genetic Screen of the Type 1 Interferon Pathway in Human Systemic Lupus Erythematosus (2007)

811 A Genetic Screen of the Type 1 Interferon Pathway in Human Systemic Lupus Erythematosus

The type-I interferon (T1-IFN) pathway plays a central role in the pathogenesis of systemic lupus erythematosus (SLE), as evidenced by the overexpression of interferon inducible genes in immune effector cells in the majority of patients with SLE. Recently, inherited variation in a transcription factor central to the T1-IFN pathway, Interferon Regulatory Factor 5 (IRF5), was found to influence susceptibility to SLE. To comprehensively assess for additional genetic effects in the T1-IFN pathway we tested common variation from 25 candidate genes upstream of IRF5 in the T1-IFN signaling pathway and the IRF5 family of proteins for an association to SLE in a large collection of affected offspring pedigrees.
In 25 candidate genes, tagSNPs were selected to capture common variation (minor allele frequency >5% at an R2 > 0.8) based on the HapMap Phase II data, plus all known putative functional SNPs (variants altering protein coding, splice sites, and conserved elements in the 3'UTR). In 550 trio pedigrees of European ancestry from the United States and the United Kingdom, 170 SNPs were examined for association using the transmission disequilibrium test. In the 6 regions that had nominal evidence for association (P<0.05), 65 additional markers were selected to densely map the region and were tested for association in the 550 SLE pedigrees.
In the SLE pedigrees, variants from 6 candidate genes had evidence of nominal association to disease (P < 0.05), including IRF7, IRF8, MYD88, IRAK4, TLR7 and TLR8. An additional 65 SNPs were selected to more fully capture known variation in these regions and were tested for an association to SLE. After fine-mapping of the putatively associated regions, several variants within IRF8 were modestly associated to SLE (rs524432; P = 0.007). The nominally associated variants from all 6 loci showed no statistically significant interaction with the known IRF5 risk alleles.
Beyond the known variants of IRF5, no highly significant association to SLE risk was observed within the type-I interferon pathway candidate genes. However, modest association of variants within IRF8 may warrant testing in additional cohorts.

 R.R. Graham, None; L.R. Davies, None; C. Lessard, None; N. Burtt, None; T.W. Behrens, Genentech, salary, 3; D.S. Cunninghame Graham, None; T.J. Vyse, None; K. Moser, None; D. Altshuler, None; P.M. Gaffney, None.

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