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. 2008 Mar 28;4(3):e1000041.
doi: 10.1371/journal.pgen.1000041.

A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci

Ying Liu  1 , Cynthia Helms, Wilson Liao, Lisa C Zaba, Shenghui Duan, Jennifer Gardner, Carol Wise, Andrew Miner, M J Malloy, Clive R Pullinger, John P Kane, Scott Saccone, Jane Worthington, Ian Bruce, Pui-Yan Kwok, Alan Menter, James Krueger, Anne Barton, Nancy L Saccone, Anne M Bowcock
Affiliations

A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci

Ying Liu et al. PLoS Genet. .

Abstract

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).

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Conflict of interest statement

Patent application on findings in process.

Figures

Figure 1
Figure 1. Summary of genome-wide association scan results for all cases and the PSA subgroup.
Negative LOG10 P values for the Cochran-Armitage test of trend for genome-wide association across the genome and by chromosome are shown. Trend P values were adjusted with the genomic control (GC) method. The spacing between SNPs on the plot is uniform and does not reflect actual physical distances. Adjacent chromosomes are shown in red and then in blue. The horizontal dashed lines display a cutoff of P = 5×10−5. A: Results obtained with all cases. B: Results obtained with the subgroup of 91 psoriatic arthritis cases (PSA).
Figure 2
Figure 2. Association localization plots for the MHC following discovery and replication phases.
Results for SNPs used in the discovery phase (adjusted for GC) are presented as diamonds. Negative LOG P values are provided on the Y axis. The X axis corresponds to the locations of SNPs. The P value for all samples (original GWA scan plus replication samples) are shown as circles. The P value obtained with the most highly associated SNP (from the original GWA scan plus the replication samples) is shown as a red circle. The SNPs shown as orange diamonds are in r2>0.8 (European HapMap CEPH (CEU) samples) with the most significant SNP identified in our study. The recombination rate based on the CEU HapMap is shown in light blue along the x axis (scale on the right). The LD relationship of Illumina discovery SNPs derived from CEU HapMap genotypes are shown below the graph. The most highly associated SNPs are indicated with an asterisk. The green arrows indicate the locations of select genes.
Figure 3
Figure 3. Association localization plots for the ILI23R region on chromosome 1.
Symbols are the same as those used in Figure 2. SNPs indicated with an asterisk are rs11465804, rs11209026 (R381Q) and rs12131065.
Figure 4
Figure 4. Association localization plots for novel replicated region on chromosome 13.
Symbols are the same as those used in Figure 2. SNPs indicated with an asterisk are rs3812888 and rs7993214.
Figure 5
Figure 5. Immunostaining of normal, non-lesional and lesional skin for IL2, IL21, COG6 and SPPL2A proteins.
The size bar is 100 micrometers.
Figure 6
Figure 6. Association localization plots for novel replicated region on chromosome 15.
Symbols are the same as those used in Figure 2. SNPs indicated with an asterisk are rs4775912 and rs3803369.
See this image and copyright information in PMC

Comment in

References

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