what´s next after the genes?

What’s Next After the Genes for Autoimmunity?

Juan-Manuel AnayaCenter for Autoimmune Diseases Research

Universidad del RosarioBogota, Colombia


• 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/

Pathophysiology of Autoimmune Diseases

Anaya JM. Autoimmun Rev 2012, 11:781-784.

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.

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

Autoimmune Diseases with Significant Genetic Variants

http://www.genome.gov/gwastudieshttp://www.ncbi.nlm.nih.gov/gap

http://www.genome.gov/gwastudies

http://www.genome.gov/gwastudies

http://www.ncbi.nlm.nih.gov/gap

http://www.ncbi.nlm.nih.gov/gap

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

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


• 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/

Limitations of Complex Trait Analysis

• Epistasis and gene interactions• Genetic heterogeneity• Pleiotropy• History of mutations/polymorphisms• Population stratification• Sample size• Refined phenotype (and genotype)

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

IRF5 Interaction Network


• 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

Wandstrat & Wakeland. Nat Immunol 2001;2:802-9.

?

How many genes are needed for autoimmunity to occur?

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

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

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.

Courtesy of Leah C. Kottyan

IRF5 is a Pleiotropic Autoimmune GeneReported IRF5-TNPO3 associations

PTPN22 1858C>T Distribution in Europe and Association with Rheumatoid Arthritis

Totaro et al. PLoS One. 2011;6:e24292.

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

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.

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.

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

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)

Post-Genomics and P4 Medicine


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).

Hood L. Annu Rev Anal Chem (Palo Alto Calif). 2008;1:1-43.

Overt RA Genotype

Prediction of Autoimmune Diseases The case of Rheumatoid Arthritis

Pre-clinical RA

Severity? HLA-DRB1*0404

TNF2PTPN22

TobaccoAnti-CCPFamilial

Autoimmunity T’

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

• 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.


Castiblanco J, Arcos-Burgos M, Anaya JMBMC Medicine 2013

http://www.biomedcentral.com/1741-7015/11/197

“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.

what´s next after the genes?

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