Celera Identifies Two Genetic Variations Predisposing Individuals to Increased Risk for Psoriasis
Discoveries Present Opportunities for Therapeutic and Pharmacogenomic
ROCKVILLE, MD - December 14, 2006
Celera Genomics (NYSE:CRA), an Applera Corporation business, today announced the publication of its findings that variants in two genes (IL12B and 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 percent 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. This publication is currently available on the American Journal of Human Genetics’ website at http://www.journals.uchicago.edu/AJHG/, and will appear in the February 2007 print edition.
“The identification of these two psoriasis susceptibility genes provides additional justification for targeting these pathways with new therapeutics for psoriasis and suggests that IL-23 may be the relevant cytokine,” said Gerald G. Krueger, M.D., Professor of Dermatology and Benning Presidential Endowed Chair at the University of Utah, Salt Lake City, UT, and co-author on this publication. “Further studies should help determine whether any of the identified risk alleles are also associated with response to therapy and could help determine the most effective dosage of new monoclonal antibody therapies currently in clinical trials.”
A single nucleotide polymorphism in the IL12B gene was identified in a multi-tiered case-control association study of psoriasis in three independent Caucasian North American sample sets (1,446 cases/1,432 controls), using 25,215 gene-centric SNPs, extending the findings from an earlier smaller Japanese study1. A second risk allele 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 cytokines, the authors 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 disease2 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.
Monoclonal antibodies directed against the IL12B-encoded IL-12p40 subunit are now in clinical trials by other parties for Crohn’s disease, multiple sclerosis and psoriasis3. Preliminary data suggest that one of these biologics is highly effective in the treatment of psoriasis . 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.
“These data suggest that these genes play a fundamental role in the development of psoriasis, and add further support to the premise that common genetic variants contribute to general immune dysregulation and susceptibility to autoimmunity,” said Thomas J. White, Ph.D., Chief Scientific Officer of Celera, and co-author on the paper. “In addition to the potential molecular diagnostic and pharmacogenomic opportunities that these findings may present for Celera, we’re starting to explore how partners can use these experimental SNP biomarkers in their development of new biological and small molecule therapies for psoriasis and other autoimmune indications.”
The senior author on this paper was Ann B. Begovich, Ph.D., Director of Inflammation at Celera, and the study was done in collaboration with the Departments of Dermatology and Human Genetics at the University of Utah, Salt Lake City, Genomics Collaborative Division of SeraCare Life Sciences, Cambridge, MA, and LineaGen Research Corporation, Salt Lake City, UT.
Psoriasis is a chronic inflammatory skin disease characterized by thickened, scaly skin patches that affects between 5.8 and 7.5 million people in the United States. The disease frequently develops in early adulthood and appears about equally in males and females. It is caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the skin. Once psoriasis appears, it is usually a life-long disease; spontaneous improvement is rare and severe disease is usually associated with a progressive increase in the amount of skin surface covered. In the past, doctors have generally treated psoriasis based on the severity of the disease, size of the areas involved, type of psoriasis, and the patient's response to initial treatments using therapies with limiting toxicities4 . Newer treatments have been more selective and less toxic. 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%). However, it is clear that environmental effects are also responsible for disease susceptibility.
1Tsunemi Y et al, (2002) Interlukin-12 p40 gene (IL12B) 3’-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161-166.
2Duerr, RH et al., (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461-1463.
3Kauffman CL et al., (2004) A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol. 123:1037 –1044
4National Institute of Arthritis and Musculoskeletal and Skin Diseases: http://www.niams.nih.gov/hi/topics/psoriasis/psoriasis.htm
About Applera Corporation and Celera
Applera Corporation consists of two operating groups. Celera is primarily a molecular diagnostics business that is using proprietary genomics and proteomics discovery platforms to identify and validate novel diagnostic markers, and is developing diagnostic products based on these markers as well as other known markers. Celera maintains a strategic alliance with Abbott for the development and commercialization of molecular, or nucleic acid-based, diagnostic products, and is also developing new diagnostic products outside of this alliance. Through its genomics and proteomics research efforts, Celera is also discovering and validating therapeutic targets, and has established and is seeking strategic partnerships to develop therapeutic products based on these discovered targets. The Applied Biosystems Group serves the life science industry and research community by developing and marketing instrument-based systems, consumables, software, and services. Customers use these tools to analyze nucleic acids (DNA and RNA), small molecules, and proteins to make scientific discoveries and develop new pharmaceuticals. Applied Biosystems’ products also serve the needs of some markets outside of life science research, which we refer to as “applied markets,” such as the fields of: human identity testing (forensic and paternity testing); biosecurity, which refers to products needed in response to the threat of biological terrorism and other malicious, accidental, and natural biological dangers; and quality and safety testing, for example in food and the environment. Applied Biosystems is headquartered in Foster City, CA, and reported sales of over $1.9 billion during fiscal 2006. Information about Applera Corporation, including reports and other information filed by the company with the Securities and Exchange Commission, is available at http://www.applera.com, or by telephoning 800.762.6923. Information about Celera is available at http://www.celera.com.
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