Genomics : Coming to a clinical theater near you! Philip E. TARR, Infectious Diseases Service Kantonsspital Bruderholz, University of Basel, Switzerland.

Genomics: Coming to a clinical theater near you!

Philip E. TARR, Infectious Diseases ServiceKantonsspital Bruderholz, University of Basel, Switzerland

Agenda

1)Genomics everywhere

2)Applications in HIV Medicine

3)|What will be showing at the theater ?

Agenda



3)What will be showing at the theater ?

29 May 2010

« More that 130.000 members of Kaiser Permanente have

volunteered to have their DNA scanned »

« The goal of the study is to (…) help uncover the genetic roots

of chronic disease and, perhaps, to find out why some people

live longer than others »

Candidate gene(limited

genotyping)

1$ per SNP*

1 to 100 SNPs

Genomics: Extraordinary Technical Progress and Decreasing Cost

* SNP, single nucleotide polymorphism

2007


genotyping)

1$ per SNP*

1 to 100 SNPs

Genome-wide genotyping (GWAS)

250$

1 millionSNPs



2007


genotyping)

1$ per SNP*

1 to 100 SNPs

2011

Genome-wide genotyping (GWAS)

250$

1 millionSNPs

2014 ?

Exome sequencing

1000$

60 million nucleotides

Whole genome sequencing

< 1000$

3000 million

nucleotides



Agenda




Agenda




Until 2007: Candidate Gene Studies aiming at Prediction of Toxicity of Antiretroviral Therapy

Marsh Hum Mol Genet 2006

Haas HIV Clin Trials 2011

The toxicogenetic paradigm: HLA-B*5701 Screening

Mallal NEJM 2008

HLA-B*5701 negative OK to give abacavir essentially 100% negative predictive value for abacavir hypersensitivity reaction

HLA-B*5701 carrier Do not give abacavir, risk of hypersensitivity reaction

Slide: Bruno Ledergerber, SHCS

Toxicity-related changes in antiretroviral therapy remain common

Lubomirov JID 2011

UGT1A1 SNPs and Atazanavir-associated Hyperbilirubinemia

15% have unfavorable genotype hazard rate 9.13 for ATV discontinuation

Lubomirov JID 2011

CYP 2B6 SNPs and Efavirenz-associated CNS toxicity

5% have unfavorable CYP 2B6 genetic score hazard rate 3.17 for EFV discontinuation

Lubomirov JID 2011

No solid genetic markers for discontinuation of tenofovir (renal toxicity)

APOL1 gene variants and HIV associated nephropathyKopp JASN 2011Atta Kidney Intl 2012

Before ART

Genetic markers of HIV-related Lipoatrophy

After d4T/AZT exposure

Hemochromatosis Gene VariantsHulgan JID 2008

APOC3Tarr JID 2005, Zanone Poma (ICONA) AIDS 2008

FASZanone Poma AIDS 2008

TNF -238G>AMaher AIDS 2002, Nolan AIDS 2003, Tarr JID 2005, Capeau 2007

Mitochondrial DNA Haplogroups

Hulgan JID 2008 + CID 2010 Nasi CID 2008, Hendrickson JAIDS 2009

Mitochondrial DNA insertions, deletions, point mutations:

Shikuma AIDS 2001 (Yes)White AIDS 2001 (Yes)Vittecocq JAIDS 2002 (Yes)Walker JAIDS 2002 (Yes)McComsey AIDS 2002, JAIDS 2005 (No)Martin AJHG 2003 (Yes)Ortiz JID 2011 (No)Morse JID 2012 (No)

ARβ2Zanone Poma

(ICONA) AIDS 2008

HLA B*4001(Thailand, d4T)

Wangsomboonsiri CID 2010

Before ART

Genetic markers of HIV-related Lipoatrophy

Hemochromatosis Gene VariantsHulgan JID 2008

APOC3Tarr JID 2005, Zanone Poma (ICONA) AIDS 2008

FASZanone Poma AIDS 2008

TNF -238G>AMaher AIDS 2002, Nolan AIDS 2003, Tarr JID 2005, Capeau 2007

Mitochondrial DNA Haplogroups

Hulgan JID 2008 + CID 2010 Nasi CID 2008, Hendrickson JAIDS 2009

Mitochondrial DNA insertions, deletions, point mutations:

Shikuma AIDS 2001 (Yes)White AIDS 2001 (Yes)Vittecocq JAIDS 2002 (Yes)Walker JAIDS 2002 (Yes)McComsey AIDS 2002, JAIDS 2005 (No)Martin AJHG 2003 (Yes)Ortiz JID 2011 (No)Morse JID 2012 (No)

ARβ2Zanone Poma

(ICONA) AIDS 2008

HLA B*4001(Thailand, d4T)

Wangsomboonsiri CID 2010

NOT CONFIRMED

After d4T/AZT exposure

HIV Host Genetics: An integrated view (beyond antiretroviral toxicity)

Resistant to infection2-3 %

HIV Infection possible97-98 %

Multiple HIV Exposures




CCR5 variants(Δ 32)

Genetic Factors

Genes involved in risk taking, addictive, impulsive behavior


Long term non progressor

10%

Progressive Immunosuppression

90%



without ART CCR5 variants(Δ 32)

Genetic Factors




10%


90%




Genetic Factors


HLA TypeB*5701/03, (HCP), B*27, B*5101, HLA-C, ZNRD1, CXCR6 B*0801, B*4501



10%

Favorable course under ART

70-80%

«Virological Failure» or ART toxicity

20-30%


90%



ART



Genetic Factors




10%


70-80%


20-30%


90%



ART


HLA Type (CD4 Increase)

Genetic Factors

e.g. HLA B*5701 (ABC HSR)CYP 2B6 (EFV + CNS)UGT1A1 (ATV + Hyperbili)



without ART



10%


70-80%


20-30%


90%



ART


HLA Type (CD4 Increase)

Genetic Factors

e.g. HLA B*5701 (ABC HSR)CYP 2B6 (EFV + CNS)UGT1A1 (ATV + Hyperbili)



without ART

ART regimens begun in2004-2006:

95 % 5 %

Prolonged survival New concerns

New concerns: “Metabolic complications”, “non-AIDS conditions”, liver failure, aging-related conditions

Tarr + Telenti 2010

IL-28B SNPs contribute to response to Hepatitis C treatment with peg-interferon/ribavirin

Ge Nature 2009, Thomas Nature 2009, Tanaka Nat Genet 2009, Suppiah Nat Genet 2009, Rauch Gastroenterology 2010

Probability of sustained virological

response (SVR):

TT: 15-35%CT: 20-40%CC: 75-80%

Genetic Prediction of aging-related conditions in HIV-infected persons

In the general population: these are all complex metabolic disorders influenced by multiple genetic

variants (and environmental factors)

Diabetes risk in HIV+ increases according to number of risk alleles

Rotger CID 2010

≈20% of patients have unfavorable genetic background relative risk of diabetes = 2.74

At level of study population:

Genetic background explains far more of

the diabetes risk than does ART

…. but less than does obesity

✔ GWAS in general population: 22 common SNPs associated with diabetes

Genetics of Coronary Artery Disease in HIV+ persons✔ GWAS meta-analysis in general population: 23 common SNPs assoc. with CAD

Schunkert Nature Genetics 2011Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature 2007. Samani N Engl J Med 2007. McPherson Science 2007. Helgadottir Science 2007. Willer Nat Genet 2008. Broadbent Hum Mol Genet 2008. Saxena Science 2007. Kathiresan Nat Genet 2008 and NEJM 2008

The MAGNIFICENT Consortium

TOTAL: 681 HIV+ CAD cases and 1,691 HIV+ controls without CAD events

designed by representatives of 7 GWAS meta analysis consortia.‐

a custom array of 196,725 SNPs from gene regions associated with multiple metabolic/cardiovascular traits.

Preuss et al (CARDIoGRAM) Circulation Cardiovasc Genet 2010Buyske et al PLoS One 2012

Genotyping: HumanCardio-Metabo BeadChip® (Illumina)

Risk factors contributing to CAD events in HIV+ individuals

Rotger M, MAGNIFICENT Consortium, manuscript in preparation

Genetic Score

HIV-related factors

Traditional CAD risk factors

Risk factors contributing to CAD events in HIV+ individuals

Rotger M, MAGNIFICENT Consortium, manuscript in preparation

Genetic Score

HIV-related factors

Traditional CAD risk factors

Effect of unfavorable genetic score:

Similar effect size (odds ratio for CAD) as diabetes, hypertension, dyslipidemia

Independent of family history for CAD, and similar effect size

Agenda1) Genomics everywhere

2) Applications in HIV Medicine

3) What will be showing at the theater ?

Agenda1)Genomics everywhere



Limitations of GWAS:much of the heritability of common disorders remains unexplained

Maher Nature 2008 Manolio Nature 2009

Heritability = the proportion of the risk that is explained by genetic background

Lusis Nature Rev Genet 2008, Cirulli + Goldstein Nat Rev Genet 2010, www.1000genomes.org

This proportion is likely to increase substantially as many rare genetic variants (with small effect sizes)

are identified

Smoking explains approx. 10-12% of lung cancer risk in different populations

At the level of study population, SNPs typically explain a small proportion of e.g. diabetes or CAD risk

Genome-wide genotyping

(GWAS)

250$

1 millionSNPs

Whole Exome

sequencing1000$


Whole genome sequencing

< 1000$


Common genetic variants

(minor allele frequency >3-5%)

Metabochip (39$)

Rare genetic variants (minor allele frequency

>0.1%)Exome chip (50$)

Coming soon to a theater near you:Whole exome/genome sequencing

Whole exome/genome sequencing: Enormous potential and some challenges

1) Cost will not be main issue (within 1-2 years will be done for few $$$)

2) Cost-effectiveness, clinical utility ? (need to show improved outcomes, ideally in randomized clinical trials)

3) Researchers: database of rare mutations, automated interpretation, integration of gene-gene/gene-environment interactions

4) Patient: Access to data, protection of personal genome privacy, avoidance of discrimination, stigma, psychological distress

Khoury Genet Med 2009, Ashley Lancet 2010 + 2 editorials, Ayday unpublished

5) For physicians: Training (interpret results, how avoid “cascade effect” of additional testing), communication with patient

• X % increase/decrease in disease risk• chance of error• chance of finding high risk for serious disease for which no

cure exists• reproductive implications • how find the time and how bill for a “whole genome

discussion” that might take several hours, assuming that each individual will carry thousands of risk-modifying variants for multiple conditions

Khoury Genet Med 2009, Ashley Lancet 2010 + 2 editorials

Summary

1. Increasingly complete assessment of cumulative genetic background: GWAS whole exome/genome sequencing

2. In HIV medicine: ≈ 100% genetic prediction of abacavir hypersensitivity (HLA B*5701)

3. For a number of drugs (ATV, EFV, etc.), we have a pretty good understanding of the genetic determinants of plasma drug levels and toxicity

4. More complex situations: Susceptibility to infection, HIV progression (HLA), Success of hepatitis C treatment (IL-28B)

5. Increasing opportunities to apply «general population» genomics data to complex metabolic conditions in HIV+ individuals:

• aging-related conditions (diabetes, osteoporosis, coronary artery disease etc.)

Institute for Microbiology, University of Lausanne Amalio Telenti, Marga Rotger

Ecole Polytechnique Fédérale, LausanneJacques Fellay, Thomas Junier

Institute for Social and Preventive Medicine, Univ BernThomas Gsponer

[email protected]

Acknowledgments:

Disclosures: Grants/research support, Consultant/advisory board member, Travel support to attend medical conferences: Abbott, MSD, Gilead, Janssen, BMS, ViiV

Genomics : Coming to a clinical theater near you! Philip E. TARR, Infectious Diseases Service Kantonsspital Bruderholz, University of Basel, Switzerland.

Documents

common slide

switzerland slide

atv discontinuation

efv discontinuation

snps genomics

hiv medicine

lubomirov jid

nucleotides genomics