Celera (ROCKVILLE, Maryland), an Applera Corporation business, announced findings that variants in the genes encoding interleukin-12 (IL12B) and interleukin-23 (IL23R), involved in regulating the behavior of cells of the immune system, independently contribute to psoriasis risk. Individuals who carry two copies of the risk alleles for both these genes, which occur in approximately 25% of Caucasians, were found to have a three-fold increased risk for psoriasis relative to individuals with certain other genotypes of these genes. These research findings provide genetic evidence to support the ongoing development of therapeutics that target the interleukin-12 and interleukin-23 (IL-12 and IL-23) pathways.

The researchers performed a multitiered, case-controlled genetic association study of psoriasis in three independent, white North American sample sets (1446 cases and 1432 controls) with over 25,000 gene-centric single nucleotide polymorphisms (SNPs) and identified a single SNP in the IL12B gene, extending the findings from an earlier smaller Japanese study. A second risk allele, located approximately 60kb upstream of the IL12B-coding region, was identified after Celera researchers resequenced the coding regions of IL12B in 96 individuals with psoriasis and then tested 30 additional IL12B-region SNPs.

Because IL12B encodes IL-12p40, a subunit of both the IL-12 and IL-23 heterodimeric cytokines, the scientists targeted other genes in these two pathways for follow-up studies and identified two SNPs in IL23R, one of the two IL-23 receptor subunits, which are associated with psoriasis independently of the IL12B SNPs. One of these same IL23R SNPs was recently associated with risk for inflammatory bowel disease and at least one of the psoriasis-associated IL12B SNPs was not, therefore providing evidence for both shared and distinct underlying mechanisms of these autoimmune diseases. These genetic findings may provide an explanation for the increased incidence of inflammatory bowel disease in subjects with psoriasis.

IL-12 and IL-23 are both produced by activated dendritic cells and macrophages, but their expression differs both spatially and temporally, and they are functionally-distinct cytokines: IL-12 induces Th1 cells while IL-23 is key to the expansion and maintenance of ThIL-17 T cells.

Monoclonal antibodies directed against the IL12B-encoded IL-12p40 subunit are now in clinical trials for autoimmune indications by other parties. For example, Centocor is conducting a phase II, multi-center, randomized, double-blind, placebo-controlled trial of CNTO 1275 (a fully human monoclonal antibody targeting IL-12p40) administered subcutaneously in subjects with active psoriatic arthritis. Celera intends to work with pharmaceutical partners to determine whether the IL12B and IL23R psoriasis risk alleles identified in the current study are also associated with response to anti-IL-12p40 therapy and/or the most effective dosage of this antibody. It remains to be determined if antibodies targeting IL-12p40 (and thus both the IL-12 and IL-23 cytokine pathways) will be as safe as treatment approaches based on more selective modulation of the immune system.

The genetics of psoriasis are complex and the disease is highly heritable as evidenced by an increased rate of concordance in monozygotic twins over dizygotic twins (35%–72% vs 12%–23%) and a substantially increased incidence in family members of affected individuals (first-degree relatives 6%). Ten genome-wide linkage scans have resulted in strong evidence for a susceptibility locus in the major histocompatibility complex (MHC) on 6p21 (PSORS1). Approximately 10 other genes have also been associated with psoriasis.  However, it is clear that environmental effects are also responsible for disease susceptibility.

—A. Techman

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