Post on 31-Dec-2015
description
Gene-Environment Interactions in Complex Diseases
Jeppe Madura Larsen, MSc, PhDAssistant Professor
24/02/2012Gene-Environment Interactions in Complex Diseases 2 Introduction to Systems Biology
Life expectancy increase
24/02/2012Gene-Environment Interactions in Complex Diseases 3 Introduction to Systems Biology
Advances
• Nutrition, food availability
• Living conditions, urbanization
• Universal health care
• Vaccines: Polio, HepB/A, small pox
• Surgery: Transfusion, transplantation, technology
• Medicine: Penicillin, steriods, chemotherapy
24/02/2012Gene-Environment Interactions in Complex Diseases 4 Introduction to Systems Biology
On the flip side:what doesn’t kill us... (fast)
• Asthma
Eder et al, N Engl J Med, 2006
24/02/2012Gene-Environment Interactions in Complex Diseases 5 Introduction to Systems Biology
On the flip side:what doesn’t kill us... (fast)
• Asthma
• Hayfever, eczema
Latvala et al, BMJ, 2005
24/02/2012Gene-Environment Interactions in Complex Diseases 6 Introduction to Systems Biology
On the flip side:what doesn’t kill us... (fast)
• Asthma
• Hayfever, eczema
• Obesity, T2D
Kavey et al, Pediatrics, 2011
24/02/2012Gene-Environment Interactions in Complex Diseases 7 Introduction to Systems Biology
On the flip side:what doesn’t kill us... (fast)
• Asthma
• Hayfever, eczema
• Obesity, T2D
• Autoimmune diseases: IBD, RA, MS• Cancer
24/02/2012Gene-Environment Interactions in Complex Diseases 8 Introduction to Systems Biology
Societal challenges
• Patient morbidity
• Social-economic impact
• Health care expenditures
24/02/2012Gene-Environment Interactions in Complex Diseases 9 Introduction to Systems Biology
Disease characteristics
24/02/2012Gene-Environment Interactions in Complex Diseases 10 Introduction to Systems Biology
Genetics: GWAS• Define genotypes associated/predictive of disease
Manhattan plot
24/02/2012Gene-Environment Interactions in Complex Diseases 11 Introduction to Systems Biology
Genetics: GWAS findings• Several disease associated loci found
Colitis (McGovern el. al., Nat Gen, 2010)
24/02/2012Gene-Environment Interactions in Complex Diseases 12 Introduction to Systems Biology
Genetics: GWAS findings• Several disease associated loci found
BMI & T2D (O’Rahilly el. al., Nature, 2009)
24/02/2012Gene-Environment Interactions in Complex Diseases 13 Introduction to Systems Biology
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.
24/02/2012Gene-Environment Interactions in Complex Diseases 14 Introduction to Systems Biology
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
24/02/2012Gene-Environment Interactions in Complex Diseases 15 Introduction to Systems Biology
The environmental factors• Likely accountable for recent rise in disease
prevalence
• Act on genetic predisposition
24/02/2012Gene-Environment Interactions in Complex Diseases 16 Introduction to Systems Biology
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
24/02/2012Gene-Environment Interactions in Complex Diseases 17 Introduction to Systems Biology
Overview: Shaping disease risk
Renz et. al., Nat Imm, 2011
24/02/2012Gene-Environment Interactions in Complex Diseases 18 Introduction to Systems Biology
Translational research
Guo & Zakhari, NIAAA
24/02/2012Gene-Environment Interactions in Complex Diseases 19 Introduction to Systems Biology
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
24/02/2012Gene-Environment Interactions in Complex Diseases 20 Introduction to Systems Biology
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
24/02/2012Gene-Environment Interactions in Complex Diseases 21 Introduction to Systems Biology
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.
24/02/2012Gene-Environment Interactions in Complex Diseases 22 Introduction to Systems Biology
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.