Genetics of Psoriasis and Psoriatic Arthritis: A Report from the GRAPPA 2010 Annual Meeting

Summary

Psoriasis vulgaris (PsV) and psoriatic arthritis (PsA) are inter-related disorders, with PsA representing a disease within a disease. From an epidemiological perspective, the genetic contributions of PsV and PsA are now well documented. HLA-C is firmly established as a PsV/PsA gene, with HLA-Cw*0602 as a major risk allele. Fine mapping studies within the MHC region in PsV and PsA have identified novel loci that are independent of the HLA-Cw6 allele. Recent genome-wide association scans have led to a substantial increase in the number of candidate genes reaching genome-wide significance in PsV and PsA cohorts. Most of these genes can be grouped into an integrated pathogenic model of PsV/PsA comprised of distinct signaling networks affecting skin barrier function (LCE3, DEFB4, GJB2), innate immune responses involving NFkB and interferon signaling (TNFAIP3, TNIP1, NFKBIA, REL, FBXL19, TYK2, NOS2), and adaptive immune responses involving CD8 T-lymphocytes and IL-23/IL-17-mediated lymphocyte signaling (HLA-C, IL12B, IL23R, IL23A, TRAF3IP2, ERAP1). Further development of a global genetic risk score and inclusion of potential gene/gene and gene/environment interactions will likely enhance the predictive value of recently identified genetic variants.

Genetics of PsV and PsA

The most dominant genetic effect of PsV/PsA exists within the major histocompatibility complex (MHC) region located on chromosome 6p21.3. This region was initially localized to ~300 kb segment known as PSORS1. Based on a re-sequencing study by Nair et al, human leukocyte antigen (HLA)-Cw*0602 was revealed to be the PSORS1 risk variant that confers susceptibility to PsV.(1) The association of PsV with several HLA-B alleles and non-HLA genes (such as CDSN, HCR, and PSORS1C3) within the MHC has also been reported, but their independence from HLA-C has not been established.(2) Recently, two other loci associated with PsV susceptibility that are independent of HLA-Cw*0602 were identified: single-nucleotide polymorphism (SNP) rs2073048, a polymorphism within c6orf10 gene; and SNP rs13437088, a variant 30 kb centromeric of HLA-B and 16 kb telomeric of MICA.(3)

HLA-Cw*0602 is also associated with PsA; however, the magnitude of association is lower than in PsV.(2) HLA antigens associated with PsA include HLA-B13, HLA-B27, HLA-B38/39, HLA-B57, and HLA-DRB1*04.(2) Non-HLA candidates include TNF-α promoter polymorphisms (TNF -238G/A and -857T) and MIC alleles, of which the trinucleotide repeat polymorphism MICA-A9 that corresponds to MICA*002 appears to be associated with PsA independent of HLA Cw6, MICB, or TNF.(2) Recent fine mapping of the MHC region in PsA noted a significant association with SNP rs1150735, located 1.5 kb upstream from ring finger protein 39 gene (RNF39).(4)

Multiple genome-wide linkage studies and candidate-gene studies have been performed in an attempt to identify non-MHC candidate genes in PsV, but very few genes have been consistently replicated.(5, 6)

Genome-wide association scans (GWAS) represent an important advancement for gene identification in PsV/PsA. Presently six GWAS have been published involving either PsV or PsA cohorts, five of which are cohorts of European ancestry totaling 5,335 PsV patients, among whom 21% had PsA.(7–11) Nineteen loci have reached genome-wide significance among Caucasians (Figure 1).

Figure 1.

Candidate genes reaching genome-wide significance in Caucasian psoriasis patients. The magnitude of the risk for each gene is shown above each gene, and the year identified is shown below.

GWAS has identified many candidate genes that strongly suggest that the pathophysiology underpinning PsV and PsA reflect an integrated complex interplay encompassing distinct signaling networks in skin barrier function and innate immune responses.(7) Genes implicated in skin barrier function include LCE3, DEFB4 and GJB2. A genome-wide investigation targeting CNVs identified a 32.2 kb deletion within the PSORS4 locus that encompasses both LCE3B and LCE3C genes with increased susceptibility to PsV.(12) Increased DEFB4 copy number is associated with PsV, with each additional copy above two copies increasing the relative risk and a variant residing in GJB2 is a PsV susceptibility locus.(13, 14) Variations within numerous genes that encode proteins critical for NFkB signaling and subsequent transcription have reached genome-wide significance (TNFAIP3, TNIP1, NFκBIA, REL, TYK2, IFIH1, and FBXL19). Finally, genes in the adaptive immune response involving CD8 T-lymphocytes and Th-17 lymphocyte signaling (HLA-C, ERAP1, IL12B, IL23R, IL23A, and TRAF3IP2) have also reached genome-wide significance.

TRAF3IP2 is of particular interest due to its biological relevance and the suggestion that its genetic contribution may be more prominent in PsA rather than PsV. TRAF3IP2 encodes Act1, an adapter protein essential for Th17-mediated inflammatory responses, including IL-17-dependent NFκB activation.(15) In epithelial cells, IL-17-dependent receptor ligation recruits Act1 to bind to the cytoplasmic tail of the IL-17 receptor.(16) This results in incorporation of TRAF6 (and possibly TRAF3) into the signaling complex and the subsequent downstream activation of the NFκB, p38, and MAPK pathways.(15, 16) It is reasonable to assume that genetic variation within TRAF3IP2 and the resultant dysregulation of Act1 may significantly alter IL-17 signaling and subsequent activation of NFκB pathways.(11) Studies in TRAF3IP2 knockout mice also suggest that Act1 is a negative regulator of humoral immunity through its inhibitory effect on CD40 and BAFFR-mediated signaling.(11)

PsA-weighted genes from GWAS

Multiple genes achieving genome-wide significance are shared between PsV and PsA cohorts, which strongly reiterates the inter-relatedness of these inflammatory diseases. Regarding PsA weighted genes there is a slightly higher effect size for TRAF3IP2 in PsA (p=4.5×10⁻¹²) compared with psoriasis (p=2.0×10⁻⁶).(10) Also, a variant residing in FBXL19 is more frequent in PsA than PsV as evidenced by a minor allele frequency (MAF) of 0.412 in SNP rs10782001 in PsA compared with 0.385 in PsV (p=0.02).(10)

Predicting disease risk from genetic variants

With the exception of HLA-Cw6 (and marker HLA-Cw0602), the effect size for each individual gene identified in PsV and PsA is small and has minimal predictive ability. One way to improve the predictive capacity is to combine multiple loci of mild to modest effects into a global genetic risk score (GRS), as done recently by Chen et al.(17) They found that a GRS combining 10 psoriasis risk loci captured significantly more risk than individual SNP markers. Furthermore, a weighted GRS that accounts for the odds ratio of each allele is a better discriminator that just a simple count of the disease alleles among cases and controls. Finally, further stratifying the highest quartile of the weighted GRS increased the risk of psoriasis 10-fold compared with persons in the lowest quartile.

Once genes are identified, further genetic complexities may need to be evaluated. Recently, the first compelling statistical interaction was noted between two GWAS loci, SNPs tagging HLA-Cw*0602 and ERAP1.(13) This finding is of particular interest given the role of HLA-C and ERAP-1 in class I antigen presentation.

Predicting disease prognosis from genetic variants

Phenotypic association with disease expression for PsV has been most strongly noted for HLA-Cw*0602. As summarized by Duffin et al, HLA-Cw*0602 has been associated with early age of onset of psoriasis, higher prevalence of family history, presence of guttate psoriasis, and Koebner phenomenon.(2) For PsA, HLA-B39 alone, HLA-B27 (only in the presence of HLA-DR7), and HLA-DQ3 (only in the absence of HLA-DR7), conferred an increased risk for disease progression along with HLA-DRB1*04 allele, which is associated with radiographic progression.(18) PsA patients carrying both HLA-Cw6 and HLA-DRB1*07 alleles have a less severe course of arthritis (19). Finally, the AA genotype of the IL4R SNP (rs1805010, encoding the amino acid change I50V) is associated with joint erosions in PsA.(12) In patients with no radiographic joint damage, the carrier frequency for the AA genotype was 16%, compared with 27% among those with 1–5 damaged joints and 40% among those with ≥5 damaged joints.(20) The estimated increase in the rate of damaged joints among patients with the AA genotype was 53%. Of note, the effect sizes for most of these associations are modest, and their clinical utility and discriminating ability have yet to be determined.

Despite the recent advances in GWAS studies, a substantial portion of the genetic risk for PsV and in particular PsA (given the high sibling heritability) has yet to be identified. However, the fact that approximately 90% of PsA patients develop skin lesions prior to the onset of joint disease,(21) and because only 1–2% of European-origin populations develop psoriasis, the predictive value of genetic testing among newly-diagnosed patients with cuteaneous psoriasis is greater than can be expected in the general population. Further GWAS studies are warranted, particularly in PsA cohorts, and next generation sequencing technologies and systematic evaluation of structural variants must be conducted to identify novel causal variants that likely account for a significant proportion of the missing heritability in PsV and PsA.