Psoriasis 4, Susceptibility To

For phenotypic information on psoriasis and general information on other psoriasis susceptibility loci, see PSORS1 (177900).

Mapping

Capon et al. (1999) studied 22 Italian families with psoriasis, including a total of 108 affected and 116 unaffected individuals. Linkage analysis with a set of microsatellite markers showed no linkage to chromosome regions 6p or 17q. A genomewide scan of a large 3-generation pedigree from this group of families disclosed putative linkage to chromosome 1cen-q21 markers. Analysis of these microsatellites in the remaining families of this sample showed significant linkage. The highest 2-point lod score was obtained with D1S305 (3.75 at a recombination fraction of 0.05).

Capon et al. (2001) carried out linkage disequilibrium analysis to achieve a finer localization of PSORS4. They recruited 79 triads from continental Italy and typed them at 5 loci spanning the 1.6-Mb region generating the highest multipoint lod scores in their previous linkage study (Capon et al., 1999). They observed significant evidence for association with marker D1S2346 (p = 0.004). Results consistent with these data were obtained by typing an independent sample that included 28 patients and 56 controls originating from Sardinia. They observed p values of 0.02 with markers D1S2346 and D1S2715. Typing both samples with 2 novel markers (140J1C and 140J1D) flanking D1S2346 generated a p value of 0.003 for marker 140J1D in the sample from continental Italy, where a D1S2346/140J1D haplotype was common. Their data indicated that the 1q21 susceptibility gene may be localized in the genomic interval spanned by D1S2346 and 140J1D.

Since psoriasis is considered a polygenic disorder, Capon et al. (1999) investigated the relationship between the HLA-C (142840) and 1q21 loci with respect to their contribution to psoriasis susceptibility. They first demonstrated an association with HLA-Cw6 in a sample of 1q-linked pedigrees by means of the transmission/disequilibrium test. In the second phase of the study, Capon et al. (1999) subjected fifteen 1q-linked families to an analysis of the correlation between the nonparametric linkage scores at HLA-C and D1S305. Data could be interpreted as preliminary evidence of an epistatic interaction between the 1q21 and 6p21 (PSORS1) psoriasis-susceptibility loci. In the third aspect of the study, they found a significant increment of the 'weighted' lod score with respect to the baseline lod. This provided the first significant evidence for linkage in the Italian population with the HLA region. Only the assumption of interaction allowed the authors to replicate the linkage to the HLA region. This suggested that some of the difficulties in replication of results obtained in genome scans for psoriasis susceptibility and, more generally, for complex disorders may be smoothed in the future by analyses allowing identification of potential interactions.

By linkage disequilibrium, Giardina et al. (2004) refined the critical region for the PSORS4 locus to an approximately 100-kb genomic interval containing the loricrin (LOR; 152445) gene. Although they found low expression of LOR in psoriatic skin of patients selected from families in which the disease was segregating with the PSORS4 locus, they found no evidence of association between novel polymorphisms in the LOR gene in these patients and psoriasis.

Zenz et al. (2005) reported that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB (165161), a gene localized in psoriasis susceptibility region PSORS6 (605364). Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun (165160) in adult mice led within 2 weeks to a phenotype resembling the histologic and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions required T and B cells and signaling through tumor necrosis factor receptor-1 (TNFR1; 191190). Prior to the disease onset, 2 chemotactic proteins (S100A8, 123885 and S100A9, 123886), which map to the psoriasis susceptibility region PSORS4, were strongly induced in mutant keratinocytes in vivo and in vitro. Zenz et al. (2005) proposed that the abrogation of JunB/activator protein-1 (AP1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis, thereby contributing to the phenotypic changes observed in psoriasis. Thus, their data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.

Sun et al. (2006) analyzed 13 SNPs in or near the PGLYRP3 (608197) and PGLYRP4 (608198) genes on chromosome 1q21 for association with psoriasis in 2 independent patient cohorts: a family-based patient set comprising 375 individuals from 101 families and a case-control collection of 282 patients and 192 controls. Results were conflicting: there was evidence for association with SNPs in both genes as well as transmission disequilibrium in the family analysis, but there was no association with any of the SNPs in the case-control analysis.

In genotype and haplotype analysis of 2 independent cohorts of 128 psoriasis triads and 120 atopic dermatitis (see 605803) triads, Giardina et al. (2006) detected a significant association between haplotypes defined by MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic dermatitis (p = 0.0276), colocalizing within a 42-kb interval of chromosome 1q21 containing a single gene, LOR. Analysis of LOR SNPS from regulatory and coding regions did not show evidence of association for either of the 2 diseases, but expression profiles of LOR in skin biopsies showed reduced levels in psoriasis and increased levels in atopic dermatitis, suggesting a specific misregulation of LOR mRNA production.

In a genomewide association study of 1,139 patients with psoriasis and 1,132 controls of Chinese Han ancestry, Zhang et al. (2009) found an association between psoriasis and rs4085613 within the LCE gene cluster on chromosome 1q21 (see, e.g., LCE1A; 612603). The findings were replicated in 2 independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry, respectively, yielding a combined p value of 6.69 x 10(-30).

In a genomewide search for copy number variants (CNV) using a sample pooling approach, de Cid et al. (2009) found that a deletion comprising the LCE3B (612614) and LCE3C (612615) genes on chromosome 1q21 was significantly associated with psoriasis among a total of 557 samples from Spain. The findings were replicated in 4 additional cohorts from the Netherlands, Italy, and the United States, yielding a total of 2,831 cases and a combined p value of 1.38 x 10(-8). The findings were also replicated in a family-based study of 2,473 individuals (p = 5.4 x 10(-4)). The deletion was tagged by rs4112788, which was also strongly associated with psoriasis (p less than 6.6 x 10(-9)). The LCE3C-LEC3B deletion showed epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. RT-PCR studies indicated that LCE expression could be induced in normal human epidermis by skin barrier disruption and was strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function may play a role in psoriasis susceptibility.

Using dense genotyping of SNPs within the PSORS4 locus on 1q21 in 474 Singaporean Chinese patients with psoriasis, Chen et al. (2009) found significant association in the proximity of the involucrin gene (IVL; 147360). The strongest association was seen in early-onset psoriasis patients (p = 0.0014 at rs6661932, 12.3 kb downstream of the IVL gene). The authors hypothesized a possible role for defects in epidermal barrier formation in the pathogenesis of psoriasis.

In a Chinese male psoriasis patient, whose paternal aunt and grandmother had been diagnosed with ichthyosis vulgaris (146700), Hu et al. (2012) analyzed the entire coding region of the FLG gene (135940) and identified homozygosity for a nonsense mutation (K4022X; 135940.0005). The variant was found in heterozygosity in his aunt and grandmother with ichthyosis vulgaris as well as in 4 unaffected family members, including his father and mother. Hu et al. (2012) noted that Nemoto-Hasebe et al. (2009) reported heterozygosity for the same variant, which they designated K4021X, in Japanese patients with atopic dermatitis (605803). Screening for K4022X in 441 unrelated Chinese psoriasis cases revealed another 2 patients who were homozygous; the variant was also found in heterozygosity in 29 (6.6%) of the patients and in 15 (3%) of 500 controls. The odds ratio for the dominant model was 2.552 (p = 0.002), suggesting an association of the K4022X variant with the psoriasis/ichthyosis vulgaris phenotype in the Chinese population. Analysis of the entire FLG coding sequence in the cohort of 441 sporadic psoriasis cases revealed 5 more variants, 1 novel and 4 that had previously been identified in ichthyosis vulgaris or atopic dermatitis patients. Although the 6 variants analyzed together did not show significant association with psoriasis, the K4022X variant alone was significantly associated (p = 0.01). Hu et al. (2012) concluded that FLG is associated with psoriasis in the Chinese population.