A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus - PubMed (original) (raw)

. 2009 Nov;41(11):1228-33.

doi: 10.1038/ng.468. Epub 2009 Oct 18.

Johanna K Sandling, Geoff Hom, Kimberly E Taylor, Sharon A Chung, Xin Sun, Ward Ortmann, Roman Kosoy, Ricardo C Ferreira, Gunnel Nordmark, Iva Gunnarsson, Elisabet Svenungsson, Leonid Padyukov, Gunnar Sturfelt, Andreas Jönsen, Anders A Bengtsson, Solbritt Rantapää-Dahlqvist, Emily C Baechler, Elizabeth E Brown, Graciela S Alarcón, Jeffrey C Edberg, Rosalind Ramsey-Goldman, Gerald McGwin Jr, John D Reveille, Luis M Vilá, Robert P Kimberly, Susan Manzi, Michelle A Petri, Annette Lee, Peter K Gregersen, Michael F Seldin, Lars Rönnblom, Lindsey A Criswell, Ann-Christine Syvänen, Timothy W Behrens, Robert R Graham

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Vesela Gateva et al. Nat Genet. 2009 Nov.

Abstract

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

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Conflict of interest statement

COMPETING INTERESTS STATEMENT

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/.

Figures

Figure 1

Figure 1

Overview of experimental design. Variants were selected from loci with P < 0.05 in a genome-wide scan of 1,310 cases and 7,859 controls, previously reported SLE risk loci, confirmed loci from other autoimmune diseases and over 7,000 ancestry-informative markers, and these variants were incorporated into an Illumina custom SNP array. The array was genotyped in independent cases and controls from the United States and Sweden. 823 of the Swedish controls were genotyped using the Illumina 310K SNP array. Variants were analyzed as described in Online Methods.

Figure 2

Figure 2

Newly discovered genome-wide significant associations in SLE. (a–e) Association results from the GWA scan are plotted on the y axis versus genomic position on the indicated chromosome on the x axis within a 500-kb region surrounding the loci defined by (a) TNIP1, (b) PRDM1, (c) JAZF1, (d) UHRF1BP1 and (e) IL10. The meta-analysis P value for the most strongly associated marker is indicated by a red square. P values from the genome scan are shaded to indicate LD to the genome-wide associated variant: red, _r_2 > 0.8; yellow, _r_2 > 0.5; green, _r_2 > 0.2; gray, _r_2 < 0.2. Along the bottom are the recombination rates from the CEU HapMap (light blue line) and the known human genes (blue). A previously reported and independent SLE risk locus at the nearby ATG5 gene is indicated (b; rs2245214). (f) Histogram of P values of 1,256 independent SNPs (_r_2 < 0.1 to any other SNP in the array) in the 1,963 case and 4,329 control replication samples. Under a null distribution, the expected density of results is indicated by the dashed line. A significant enrichment of results with P < 0.05 was observed.

Figure 3

Figure 3

Percentage of newly discovered variants reaching candidate (P < 1 × 10−5) and confirmed (P < 5 × 10−8) status in the meta-analysis stratified by the P value in the original GWAS.

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