What´s next after the genes?
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What’s Next After the Genes for Autoimmunity?
Juan-Manuel AnayaCenter for Autoimmune Diseases Research
Universidad del RosarioBogota, Colombia
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What’s Next After the Genes for Autoimmunity?
• How important is genetics in autoimmune diseases?
• What have we learned about genetics of autoimmune diseases?
• Pitfalls and challenges of complex trait analysis
• http://www.authorstream.com/Presentation/pramod.rathor1-1207664-nanobiology-post-genomics-bioinformatics/
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Pathophysiology of Autoimmune Diseases
Anaya JM. Autoimmun Rev 2012, 11:781-784.
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5-100.5-12-412-15Rheumatoid Arthritis
20-400.22-524-57SLE
200.13-525Multiple Sclerosis
150.4630-50Type 1 DM
Non-twins Siblings
Monozygotic Twins
s**
Population Prevalence
(%)
Concordance (%)*Disease
Wandstrat & Wakeland. Nat Immunol 2001;2:802-9.
How Important is the Genetic Predisposition on Susceptibility to Autoimmune Diseases?
Concordance and Familial Aggregation ()
* Concordance: the presence of the same trait in both members of a pair of twins, or in sets of individuals. **Aggregation (s): relative risk to siblings. Disease prevalence in siblings of affected / Disease prevalence in general population.
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Function
Gene
FUNCTIONAL
Phenotype
Mapping
POSITIONAL
Gene
Phenotype
Mapping Function
Genome-wide screen or candidate gene?
Genome-wide screen• Hypothesis-free• High-cost: large genotyping
requirements• Multiple-testing issues
Possible many false positives, fewer misses
Candidate gene• Hypothesis-driven• Low-cost: small genotyping
requirements• Multiple-testing less important
Possible many misses, fewer false positives
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Autoimmune Diseases with Significant Genetic Variants
http://www.genome.gov/gwastudieshttp://www.ncbi.nlm.nih.gov/gap
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Why limited success after all?
• ~ 9000 papers on SLE AND Genetics• ~ 50 genes involved and replicated• Only around 20-30% of the inherited risk for SLE can be explained
at present. • Most of the common variants individually or in combination
confer relatively small increments in risk (1.1- to 1.5-fold) and explain only a small proportion of heritability.
2012:522
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HLA discloses the strongest association with autoimmune diseases
Lessard CJ et al. Nat Genetics 2013 (in press)MS: International Multiple Sclerosis Genetics Consortium. NEJM 2007 30;357:851-62.
Hom G et al. NEJM 2008;358:900Wellcome Trust Case Control Consortium Nature 2007; 447: 661.
Nature 2010; 464: 713.
Sjögren's Syndrome Multiple Sclerosis
Systemic Lupus Erythematosus Rheumatoid Arthritis
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What’s Next After the Genes for Autoimmunity?
• How important is genetics in autoimmune diseases?
• What have we learned about genetics of autoimmune diseases?
• Pitfalls and challenges of complex trait analysis
• http://www.authorstream.com/Presentation/pramod.rathor1-1207664-nanobiology-post-genomics-bioinformatics/
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Epistasis is a form of gene interaction in which one gene masks the phenotypic expression of another.
Interactions between genes at different loci that affect the same phenotype.
Mani et al. Proc Natl Acad Sci U S A. 2008;105:3461-6.
Gene Interactions
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IRF5 Interaction Network
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity
• Allelic heterogeneityDifferent mutations within the same locus result in the same phenotype
• Locus heterogeneity Different genes cause the same
clinical syndrome
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Wandstrat & Wakeland. Nat Immunol 2001;2:802-9.
?
How many genes are needed for autoimmunity to occur?
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Genetic Pleiotropy
single causal variant
Solovieff et al. Nat Rev Genet. 2013;14:483-95.
Different causal variants colocalizing in same gene and tagged by the same
genetic variant
Different causal variants colocalizing the same gene
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DR4 OR: 3.9 (2.89-5.27)DRB1*0405 OR:7.2 (3.36-15.27)
DQ2 OR:1.93 (1.09-3.41) DQB1*0201 OR:2.32
(1.12-4.8)
DRB1*0301 OR:3.63 (1.25-10.47)
Common Autoimmune HLA Alleles in Latin America
Cruz-Tapias et al. Autoimmune Dis. 2012
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Rheumatoid ArthritisColombiansRamírez et al. Clin Exp Rheumatol 2012
Systemic Lupus Erithematosus ColombiansAnaya et al. Genes Immun. 2005;6:628.Ramírez et al. Clin Exp Rheumatol 2012ArgentiniansOrrú et al. Hum Mol Genet 2009;18:569.
PTPN22 (1858 T) is a Pleiotropic Autoimmune Allelein Latin Americans
Sjögren´s SyndromeColombiansAnaya et al. Genes Immun. 2005;6:628.
Type 1 DiabetesColombiansAnaya et al. Genes Immun. 2005;6:628-31.BraziliansChagastelles et al .Tissue Antigens 2010;76:144.Rassi et al. Ann N Y Acad Sci. 2008;1150:282.
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Courtesy of Leah C. Kottyan
IRF5 is a Pleiotropic Autoimmune GeneReported IRF5-TNPO3 associations
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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PTPN22 1858C>T Distribution in Europe and Association with Rheumatoid Arthritis
Totaro et al. PLoS One. 2011;6:e24292.
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Ancestry in Latin America
Sans M. Hum Biol 2000;72:155. 503711Cuba
80<10<10Peru
80<10<10Ecuador
>80<10>10Bolivia
<4010>50Venezuela
25.96.567.5Argentina
43~057Chile
201565Brazil
1-207-15>80Uruguay
56341Mexico
>15>15<60Colombia
Amerindian (%)
African (%)
European (%)
Country
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Stratification
The presence of a systematic difference in allele frequencies between subpopulations in a population due to different ancestry, especially in the context of association studies.
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Statistical Power and Sample Size
MAF PrevalenceAssociation
(NA)0.05 0.01 2,2780.05 0.20 2,4480.20 0.01 6590.20 0.20 700
MAF = Minor allele frequencyNA = Number of case-control pairsOdds Ratio = 1.5
Roeder et al. Am J Hum Genet. 2006;78:243-52.
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Limitations of Complex Trait Analysis
• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)
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Refining the Phenotype-Genes
• Make the effect of certain genes in the sample more easily detectable
• Genetic effects may be stronger for extremes of the risk factor distribution– restrict sample to people with onset at a very young or very
old age• Genetic effects may be stronger for particular
presentations– restricting sample to patients with rheumatoid arthritis and
anti-CCP– restricting sample to SLE with nephropathy
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Refining the Phenotype-Environment
• Minimize effect of known environmental confounders– restrict sample to RA and nonsmokers– restrict sample to EBV negative patients
• Collect data in a genetically homogenous population such as a particular ethnic group or genetically isolated population– Reduce the number of genes contributing to the
phenotype (i.e. the Paisa community, Colombia)
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Post-Genomics and P4 Medicine
What’s Next After the Genes for Autoimmunity?
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Post-Gen“omics”
Post-genomics evaluate patterns in how genes are transcribed into RNA (transcriptomics), in the way genes are expressed as proteins (proteomics), in how they influence the chemicals that control the cellular biochemistry and metabolism (metabolomics).
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Hood L. Annu Rev Anal Chem (Palo Alto Calif). 2008;1:1-43.
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Overt RA Genotype
Prediction of Autoimmune Diseases The case of Rheumatoid Arthritis
Pre-clinical RA
Severity? HLA-DRB1*0404
TNF2PTPN22
TobaccoAnti-CCPFamilial
Autoimmunity T’
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Tebbutt et al. Chest 2007;131:1216©2007 by American College of Chest Physicians
Personalized Medicine
1. Informed consent2. Blood (or even hair) sample3. DNA extraction4. Genotyping 5. Analysis of SNPs 6. Bioinformatic tools. 7. Structural and functional correlation
of the genotype 8. Plan of action. Predict the biological
and treatment implications
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• Deciphering the genetics of complex diseases remains challenging.
• Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to understand the nature of human biological systems.
• Making accurate predictions for autoimmune diseases is an ambitious goal.
• Personalized medicine is committed to survey, monitor and diagnose risks to provide patients with a specific treatment, taking into account their particular genetic profile.
What’s Next After the Genes for Autoimmunity?
Castiblanco J, Arcos-Burgos M, Anaya JMBMC Medicine 2013
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“It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has.”
Caleb Parry. Bath, 1755-1822.