Gene-Environment Interactions in Complex Diseases

Jeppe Madura Larsen, MSc, PhDAssistant Professor

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Life expectancy increase

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Advances

• Nutrition, food availability

• Living conditions, urbanization

• Universal health care

• Vaccines: Polio, HepB/A, small pox

• Surgery: Transfusion, transplantation, technology

• Medicine: Penicillin, steriods, chemotherapy

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On the flip side:what doesn’t kill us... (fast)

• Asthma

Eder et al, N Engl J Med, 2006

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On the flip side:what doesn’t kill us... (fast)

• Asthma

• Hayfever, eczema

Latvala et al, BMJ, 2005

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On the flip side:what doesn’t kill us... (fast)

• Asthma

• Hayfever, eczema

• Obesity, T2D

Kavey et al, Pediatrics, 2011

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On the flip side:what doesn’t kill us... (fast)

• Asthma

• Hayfever, eczema

• Obesity, T2D

• Autoimmune diseases: IBD, RA, MS• Cancer

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Societal challenges

• Patient morbidity

• Social-economic impact

• Health care expenditures

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Disease characteristics

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Genetics: GWAS• Define genotypes associated/predictive of disease

Manhattan plot

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Genetics: GWAS findings• Several disease associated loci found

Colitis (McGovern el. al., Nat Gen, 2010)

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Genetics: GWAS findings• Several disease associated loci found

BMI & T2D (O’Rahilly el. al., Nature, 2009)

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Genetics: GWAS findings• Several disease associated loci found

• However:– Frequently major alleles associates with disease– Low disease predictive value– In T1D: 30 % heritability explained– In T2D: 1 % heritability explained

• No single SNP is clearly associates with disease. However, several SNPs may collectively contribute to disease via a common pathway.

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GWAS challenge:Extracting disease “genotypes”

• Integrating GWAS data with:– Protein-protein interaction– Protein function– Metabolic pathway– Cell/tissue specificity– Cell interaction

• Future– Repetitive DNA– Copy-number variants– Epigenetics: DNA/histone methylation

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The environmental factors• Likely accountable for recent rise in disease

prevalence

• Act on genetic predisposition

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The environmental factorsin childhood asthma• Several diverse factors

– Living on a farm/rural area (increased bacterial diversity or microbial products)

– Airway microbiota composition– Nutrition (vitamin D, PUFA)– Parental smoking– C-section– Birth order– Siblings in home– Pets

• A role for both peri-natal and natal exposures

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Overview: Shaping disease risk

Renz et. al., Nat Imm, 2011

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Translational research

Guo & Zakhari, NIAAA

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Challenges for the clinic• Disease definitions are likely inadequate

• Define disease phenotypes/endotypes: “Endotype—a contraction of endophenotype—is a subtype of disease defined functionally and

pathologically by a molecular mechanism or by treatment response. Asthma, like many chronic disorders, is a heterogeneous and genetically complex disease, meaning that many genes (>100 have been identified) are likely to contribute, variably, to its different manifestations. Asthma is likely to have several specific endotypes associated with distinct clinical features, divergent underlying molecular causes, and distinct treatment responses.”

(Anderson, Lancet, 2008)

• A need for additional objective and quantitative parameters

• Standard treatment algorithms/guidelines• Run large cohorts for studies of disease

development and preventive intervention

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Challenges for basic science• Sampling and measuring environmental factors

• Develop/improve HTS methods in-depth genetic and biochemical characterization

• Translate human findings into focused disease relevant animal models for pharmacological development

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Challenges for systems biology• Develop methods for integration of new datasets

• Develop standardized data structures, data handling and pipelines

• Data sharing (both in academia and industry)

• Model development and validation. Unrestricted of previous disease definitions. To be tested in the clinic and/or animal models.

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Litterature• European Science Foundation, rapport 2011.

Forward Look: Gene-environment interaction in Chronic Disease.

• Renz et. al., JACI, 2011. Gene-environment interaction in Chronic Disease.

• Renz et. al., Nat. Imm., 2011. Gene-environment interaction in Chronic Inflammatory Disease.