genetics science utility by andy goren

Vitiligo Genetics:scientific discovery to clinical utility

Presented by:Andy Goren, CEO

DermaGenoma, Inc.

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Venue

Vitiligo World SymposiumIV Russian Congress of Dermatovenerology

July 7, 2011Saint Petersburg, Russia

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Employee of DermaGenoma, Inc. - a company that develops and markets diagnostic and therapeutic products for cosmetic dermatology

Disclosure Statement

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• The information stored in each person’s cell nucleus holds the promise for early disease screening, preventive treatment and perhaps cure to some diseases

• To date the main effort focused on associating coding regions of DNA with disease state

• Discoveries of new associations between phenotype and genotype are made almost daily

• Are there any clinical implications to vitiligo?

Overview

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• SNP - single nucleotide polymorphism

• Sequencing - determine continuous sequence of DNA

• GWAS - Gene Wide Association Study

• Gene wide “scan” using of high density SNP Chip

Common Genetic Terms

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The Human DNA

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• Prior to starting a genetic study we review the hereditary evidence for the phenotypical trait

• Generalized Vitiligo (GV) suggest an inheritance model mediated by other factors

• Sibling risk in Caucasians approximately 6% or 16x increased risk (0.38% prevalence)

• Concordance in monozygotic twins is 23%

Genetic Association Studies

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• We then study disease etiology/pathogenesis to identify plausible genes or epigenetic mechanisms

• In GV immune related genes may be of interest

• We select patients with GV and normal controls

• Patient selection is often the limiting step in finding and replicating genetic association

Genetic Association Studies

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• We either sequence a very specific region or gene or perform a gene wide SNP “scan”

• Gene wide scans are good for broad discovery, but tend to result in weaker associations

• We statistically associate GV phenotype with the genetic variances

Genetic Association Studies

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Genetic Association Studies

• Select patients with GV and normal controls

• Use a SNP chip to discover association

Genetics of Vitiligo 245

have yet been identified with certainty. This limited progress has resulted, inlarge part, from the lack of a clear definition of the disorder and the lack of atractable experimental animal model of typical human generalized vitiligo thatcan be manipulated and studied in the laboratory.

In recent years, technological advances enabled by the Human GenomeProject, and methodological advances applied to analyses of polygenic multi-factorial diseases have led to efforts to map and identify specific genes involvedin vitiligo susceptibility and pathogenesis. As a result, there has been consider-able recent progress towards the identification of vitiligo susceptibility genes,some of which may provide novel therapeutic and prophylactic targets for newinterventional approaches to treat and even prevent vitiligo in the future.

Genetic Epidemiology of Generalized Vitiligo

Recent progress in defining the genetic underpinnings of vitiligo hashinged on clearly defining the disorder, thus permitting investigators to test spe-cific hypotheses via carefully controlled studies. Accordingly, most studies havefocused on generalized vitiligo. Generalized vitiligo is defined as an acquiredpigmentary disorder characterized by depigmentation due to melanocyte loss in

Fig. 1. A patient with generalizedvitiligo. Note obvious patches of white skinin typical distribution involving the perior-bital region and hands.

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• Results are often conflicting due to improper patient selection. GV presents a significant challenge due to diagnostics

• Good rule of thumb is a minimum of 3 replicated studies

• Additional markers are not always additive

• A high Relative Risk or increased risk with a low prevalence usually has little clinical value

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Genetic Association Studies

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Clinical Utility

• The DNA is a blueprint to one’s life hence has potential predictive power

• Can we use genetics to screen for a disease?

• Will the screening change the course of therapy?

• Can we use genetics to diagnose for a disease?

• Can we use genetics to predict treatment outcome? (PGx)

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Clinical Utility - Example

• Can we use genetics to screen for GV?

– To date traditional genetic association studies are not able to find a clinical useful screening model for GV

– GV prevalence is low (less then 1%)

– GV inheritance is not very strong (MZT 23%) i.e., environmental affects are strong

– Increased Risk not clinically useful

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Clinical Utility - Example

• Can we use genetics to screen for GV?

– New approach is needed

– Epigenetic could be influenced by environment

– Chicken model (feather depigmentation) induced demethylation exhibits auto-immune symptoms (Sreekumar et al)

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Clinical Utility - Example

• Can we use genetics to screen for GV?

– Abnormal DNA methylation in peripheral blood mononuclear cells in GV patients (Zhao et al)

– My group recently published AR epigenetics in female AGA. New evidence emerging in male AGA

– My group is embarking on a new cutaneous tissue methylation map study. Promising for GV

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Clinical Utility - Example

• Can we use genetics to predict treatment outcome?

– NB-UVB and PUVA are common treatments for GV

– Approximately 50% of patients respond to phototherapy. Expensive and time consuming.

– We recently completed a phototherapy response genetic study in psoriasis

– p53 homozygous alleles strongly predict response in psoriasis (90% PPV)

– We plan to next study the p53 pathway in GV

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Future Developments

• Better understanding of the basic science of DNA - epigenetics and marker interaction

• Full “nucleus” mapping and sequencing

• Discovery of new therapeutic targets (not always same as screening or diagnostic markers)

• ICD type classification not rich enough to describe molecular variants

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Q&A

Andy Goren, President & CEODermaGenoma, Inc.e-mail: andyg@dermagenoma.com

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