1. Institute of Social and Preventive Medicine, University of Lausanne
Revolution in genetics: what should NCD programme managers know about it? (focus on LMIC)
Murielle Bochud, MD, PhD
Institute of Social and Preventive Medicine, University of Lausanne

2. Angelina Jolie's preventive double mastectomy
Angelina Jolie has a positive family history of breast cancer.
A genetic screening test determined that Jolie was at increased risk of developing breast cancer (BRCA1).
Angelina Jolie underwent a preventive double mastectomy.
 Mutations in BRCA1 and BRCA2 account for small proportion of all breast cancer cases (1-2%).

3. Katsanis Nat Rev Genet 2013

4. Technological advances have boosted our ability to make genetic testings

6. Human genome in numbers46
Chromo
somes
Human genome in numbers
6 billions
DNA letters A C
22’000
GENES G T
Cost to sequence
$10’000

7. Organization of DNA in human cells

8. Each cell with a nucleus contains our genome composed of DNA
Human being
Organ
Cell
Nucleus
Chromosome
DNA

9. SNPs are the most common genetic markers
ATTCCGAGTTTACCGCGTA
Maternal chromosome
ATTCCGAGTTTATCGCGTA
Paternal chromosome
> 20 millions SNPs identifed
in the human genome
SNP (single nucleotide polymorphism)

10. Type, frequency and novelty of genetic variants
The 1000 genomes project; Nature 2010; 467: 1061

11. A locus is a specific location on the genome that can carry multiple alleles
ACCGTTACGTTA
ACCGTCACGTTA
Locus 1
Locus 1
An allele is the form that the DNA can take at a particular locus. A subject can carry carry either a T or a C allele at locus 1.

12. The allele is the unit of transmission from parents to their offspring
Parents transmit ALLELES (AND NOT GENOTYPES) to their offspring AC CC
father
mother
Family
tree
Possible genotypes:
AA, AC, CC
Allele A is paternally
transmitted
Allele C is maternally
transmitted

13. A gene is composed of coding (exons) and non-coding (introns) parts
DNA sequence:
AATGCTGACAGTCCGATATGCTCGATGGATCTCCAGAATGTGCGA
exon 1
exon 2
exon 3
intron 1
intron 2
A gene is the unit of heredity
Human genetics is the study of human gene variation

14. Genes code for proteins
exon 1
exon 2
exon 3
exon 4
intron 1
intron 2
intron 3
contiguous genomic sequence
segmented genomic sequence
mRNA
PROTEINS

15.  a few rare mutations Several common mutations strong effect sizes
POPULATION
INDIVIDUALS / FAMILIES
Polygenic diseases
(Common complex diseases)
Monogenic diseases
(Mendelian diseases) 
a few rare mutations
strong effect sizes
Several common mutations
weak to moderate effect sizes
SNPs genetic markers
promoter
coding region
gDNA
Aminoacid change in highly conserved regions that are functionally important
functional SNPs
Courtesy of PY Bochud

16. Published GWA Reports, 2005 – 6/2012
1350
Total Number of Publications
Calendar Quarter
Through 6/30/12 postings

17. Published Genome-Wide Associations through 12/2012
Published GWA at p≤5X10-8 for 17 trait categories
NHGRI GWA Catalog

18. Common alleles usually have small effects…
Manolio et al, Nature 2009; 461(7265): 747–753

19. We are probably only seeing the tip of the iceberg
1-5% via one-marker-at-a-time
analysis: common variants with
small effects
Other common variants with
Small effect
Rare variants with
large effects
Gene-gene and
gene-environment
interactions

20. Manhattan plot for renal function
CKDGen Consortium
Manhattan plot for renal function
29 known or novel GFR loci
Pattaro et al, PLoS Genet, 2012

21. Genetic risk score does not predict incident chronic kidney disease
Framingham Heart Study
Outcome: incident stage 3 CKD (eGFR <60 mL/min/1.73 m(2)) at follow-up.
O'Seaghdha et al, Am J Kidney Dis. 2012

22. For type 2 diabetes, genetic information does not improve risk prediction when compared with classical risk factors such as age, sex, family history, BMI, etc.
Talmud et al, BMJ 2010

23. Cumulative effect of obesity variants: association of obesity genetic risk score with BMI
Vimaleswaran & Loos Exp Rev Mol Med 2010, 12:e7

24. Narrowing the valley of death…
Research
findings
Clinically useful
applications

25. The PharmGKB Knowledge Pyramid
                                                            
The PharmGKB Knowledge Pyramid
The PharmGKB (pharmacogenomics knowledge) resource collects, curates and disseminates knowledge about the impact of human genetic variation on drug responses:
dosing guidelines and drug label
potentially clinically actionable gene-drug associations
genotype-phenotype relationships.
Clinical
implementation
Clinical interpretation
Knowledge annotation,
Aggregation & interpretation
Knowledge extraction
Primary pharmacogenomics literature
Variant
Gene
Type
Level of evidence
Drugs
Phenotype/ disease rs
TPMT
Toxicity/ADR 1A
mercaptopurine
Some cancers rs
CYP2C19
Efficacy,Toxicity/ADR
clopidogrel
Acute coronary syndrome, CAD
rs776746
CYP3A5
toxicity/ADR 2A
tacrolimus
Kidney Transplantation

26. Genetic variants for hyperuricaemia or gout. 2008–2011
Reginato et al, Nat Rev Rheumatol 2012

27. Major contribution of GWAS findings to urate (patho)physiology
Reginato et al, Nat Rev Rheumatol 2012

28. Major contribution of GWAS findings to gout pathophysiology
Reginato et al, Nat Rev Rheumatol 2012

29. Ethical considerations for genetic testing
Secondary findings in whole exome and whole genome sequencing data will identify several mutations that are disease-causing variants.
No consensus on whether or how to share this information with patients.
Need to confirm results by a clinical laboratory before returning to a patient.
Exploration of informed consent models allowing patients to elect what information to disclose.
The duty to inform patients of predictable risks could be influenced by the legal pressure and threat of malpractice.
Ethical challenge for genetic testing in children to decide whether to test or to disclose results for adult-onset genetic conditions.
Privacy and discrimination
Country-specific legislations in Europe aiming at protecting for health and life insurance discrimination on the basis of genetics. In the US: GINA (Genetic Information Non-discrimination Act).
It is not clear whether discrimination based on genetic testing will become an issue worldwide. Until this has been clarified, the question is how to protect currently generated WES and WGS data.
Katsanis Nat Rev Genet 2013

30. Conclusions
Rapid technological advances have boosted our ability to screen the human genome, raising important and new ethical challenges.
Rapidly evolving understanding of the structure and function of the human genome.
Massive number of new genetic variants-disease associations (useful mainly to advance knowledge on disease biology).
These findings will likely to lead to reclassification of many diseases.
Clinical utility of genetic testing limited for common complex diseases.
Aim: more personalized treatment and prevention

31. Thank you.

32. Ethnic differences in breast cancer incidence
Hines – Cancer

33. Breast cancer
One in nine women will develop breast cancer in their lifetime.
Mutations in BRCA1 and BRCA2 account for small proportion of all breast cancer cases (1-2%).
Much higher proportion of cases with a strong family history of breast or ovarian cancer.
Prophylactic mastectomy is the most effective strategy to reduce the risk of breast cancer in women at high-risk, but there is no clear evidence for mortality reduction after prophylactic mastectomy.