Genomic self-hacking: citizen science and the realization of personalized medicine

Genomic self-hacking: citizen science and the realization of

personalized medicine

Melanie SwanGenome Geek 650-681-9482

@DIYgenomics www.DIYgenomics.org

[email protected]

Quantified Self Meetup Group

NASA AMES - July 19, 2011

Slides: http://slideshare.net/LaBlogga

2July 19, 2011DIYgenomics.org

Future health: layers of preventive medicine

Individual

2. Preventive CareHealth Social NetworksCitizen Science Studies

Health Advisors

3. Traditional health care system and physicians

1. Automated digital health monitoring


New concept of health self-management

Source: Extended from Swan, M. Emerging patient-driven health care models: an examination of health social networks, consumer personalized medicine and quantified self-tracking. Int. J. Environ. Res. Public Health 2009, 2, 492-525, Figure 1.


Genome hacking philosophy

Goal: preventive medicine Realize preventive medicine by establishing baseline markers

of wellness and pre-clinical interventions

Generalized hypothesis One or more polymorphisms may result in out-of-bounds

baseline levels of phenotypic markers. These levels may be improved through personalized intervention.

Source: http://diygenomics.pbworks.com/MTHFR

Genotype Phenotype Intervention Outcome+ + =


DTC genomics – interpretation variance

Private data upload: Marat Nepomnyashy; https://addons.mozilla.org/en-US/firefox/addon/156946


Open-source mobile apps (5,000+ downloads)

Health condition, drug response, athletic performance

23andMe data upload

Android

iPhone

Android development: Michael Kolb, Lawrence S. Wong, Laura Klemme, Melanie SwaniPhone development: Ted Odet, Greg Smith, Laura Klemme, Melanie Swan

“genomics”

“genomics”

T T T

T T T

T C C


Vitamin B deficiency / MTHFR mutation

Do common mutations in the MTHFR gene prevent vitamin B from working correctly?

Test whether 2 variations in the MTHFR gene keep vitamin B9 (folic acid) from being metabolized into its active form (folate) rs1801133/C677T rs1801131/A1298C

Without this form of vitamin B, homocysteine may accumulate (risk of cardiovascular disease, etc.)

50% or more of the population may have some form of MTHFR polymorphism



Homocysteine metabolism pathway

Source: Swan, M., Hathaway, K., Hogg, C., McCauley, R., Vollrath, A. Citizen science genomics as a model for crowdsourced preventive medicine research. J Participat Med. 2010 Dec 23; 2:e20.


Vitamin B / MTHFR study protocol

1. Genotype

MTHFR gene SNPs:

rs1801133 (A/G)

rs1801131 (A/G)

2. Phenotype

Blood tests:

B-12 and

Homocysteine

3. Intervention

(2 week periods)

1. B-complex

2. L-methylfolate

3. B-complex + L-methylfolate

Investigate genotype-phenotype linkage and apply interventions to improve phenotypic outcomes

Protocol confirmed with two separate experts in the field



Vitamin B / MTHFR pilot study results

Drug store vitamin (Centrum) reduced homocysteine levels for 6/7 participants

Blood Test #

2. Homocysteine levels

DIYgenomics MTHFR Vitamin B deficiency study1

1. Genotype profiles

Baseline LMF

Source: Swan, M., Hathaway, K., Hogg, C., McCauley, R., Vollrath, A. Citizen science genomics as a model for crowdsourced preventive medicine research. J Participat Med. 2010 Dec 23; 2:e20.

1Results are not statistically significant and are intended as a pilot demonstration of citizen science genomic studies

Baseline+ LMF

Centrum

Homocysteine umol/l

Centrum

LMF = L-methylfolate


Athletic performanceCategory Genes V % S

Endurance, power, and energy

Endurance ACE, ACTN3, ADRB2/ ADRB3, BDKRB2, COL5A1, GNB3 7 50 22

Power ACE, ACTN3, AGT 3 50 8

Energy HIF1A, PPARGC1A 3 25 9

Musculature, and heart and lung capacity

Muscle fatigue and repair HNF4A, NAT2 and IL-1B 5 40 4

Strength HFE, HIF1A, IGF1, MSTN GDF8 5 17 15

Heart and lung capacity CREB1, KIF5B, NOS3, NPY and ADRB1, APOE, NRF1 9 36 11

Metabolism, recovery, and other

Metabolism AMPD1, APOA1, PPARA, PPARD 5 50 9

Recovery CKMM/CKM, IL6 2 50 5

Ligament and tendon strength

Ligament strength COL1A1, COL5A1, CILP 3 50 4

Tendon strength COL1A1, COL5A1, GDF5, MMP3 7 63 5

Image credit: http://www.istockphoto.com

V = number of variants; % = ratio of favorable polymorphisms to total alleles for a sample individual; S = number of studies

Source: Swan, M. Applied genomics: personalized interpretation of athletic performance GWAS. Jan 2011.


Preventive wellness

Personal uses of the personal genome Ancestry Carrier status Disease risk profiling Drug response Athletic performance capability Product response

Wellness profiling Cancer Immune system Aging


Predictive wellness profiling: cancer

Proto-oncogene/tumor suppressor gene polymorphisms

Source: DIYgenomics

Image credit: http://utmb.edu

Alleles 23andMe alleles

Gene RSID Poss Unf Fav Poss Fav Ex p-value OR Case Ctrl Citation

TP531 rs1042522 CG C G CG G CG 0.77 1.23 685 778 Joshi 2010

TP53 rs1860746 GT T G n/a n/a n/a 0.04 1.47 6,127 5,197 Liu 2009

MDM22 rs2279744 GT G T GT T GT 0.91 1.27 685 778 Joshi 2010

MDM41 rs1380576 CG G C n/a n/a n/a 0.95 1.03 4,073 n/a Sun 2010

HAUSP1 rs1529916 AG G A n/a n/a n/a 0.07 1.05 4,073 n/a Sun 2010

PTEN1 rs701848 CT C T CT T CT 0.00 0.12 53 107 Hosgood 2010

PTEN1 rs1903858 AG G A AG A AA 0.01 0.13 53 107 Hosgood 2010

BCL22 938C>A AC A C n/a n/a n/a 0.05 n/a 40 40 Fingas 2010

GNB32 rs5443 CT T C CT C CC 0.05 n/a 40 40 Fingas 2010

MYC2 rs6983267 GT G T GT T TT 0.00 1.21 930 960 Tomlinson 2007

MYC rs1050477 AC A C GT G GG 0.00 1.17 7,480 7,779 Zanke 2007 MYC rs7014346 AG A G AG G GG 0.00 1.19 14,500 13,294 Tenesa 2008

1Tumor Suppressor, 2Proto-oncogene

TP53: cell cycle arrest, PTEN: cell cycle progression modulator, MYC: cell cycle regulator


Lung cancer risk and drug response

Risk and drug response for specific cancers

Source: Swan, M. Review of cancer risk prediction in direct-to-consumer genomic services. (poster) Canary Foundation Early Detection Symposium, May 25-27, 2010, Stanford University, Stanford CA.

Image credit: http://www.xianet.net


Wellness profiling: immune system

Immune system genomic wellness profiling Immune response: T-cell activation

CTLA4, CD226, CD86, IL3

Source: DIYgenomics

Alleles 23andMe alleles

Gene RSID Poss Unf Fav Poss Fav Ex p-value OR Case Ctrl Citation CTLA4 rs231775 A/G A G AG G AA 0.007 0.642 172 145 Duan 2010 CTLA4 rs5742909 C/T C T CT T CC 0.098 0.67 172 145 Duan 2010 CTLA4 rs733618 C/T C T CT T TT 0.041 4.62 269 395 DallaCosta 2010 CD226 rs763361 C/T T C CT C CC 0.000 1.22 1,990 1,642 Dieudé 2010 CD86 rs1129055 A/G G A AG A GG 0.006 0.51 269 395 DallaCosta 2010 IL3 rs181781 A/G A G AG G GG 0.041 0.55 60 270 Lee 2010 IL3 rs2073506 A/G A G CT C CC 0.009 0.32 60 270 Lee 2010 IL3 rs40401 C/T T C CT C CC 0.014 2.18 60 270 Lee 2010

Image credit: http://www.iayork.com

CTLA4: T-cell inhibition; IL3: growth-promoting cytokine


Aging: TA-65, telomere length & TERC mutation

Herbal supplement TA-65 (astragalus root) taken by 1000 people worldwide. Telomere and immune system benefits in humans published Mar 2011.1

TERC (RNA gene that extends telomeres) SNPs: rs10511887, rs12696304, rs16847897, rs2293607,

rs610160

1Source: Harley CB, et al. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb;14(1):45-56.


Aging: applied healthspan engineering

Representative Rational Healthspan Interventions Target=process Intervention

1 Blood pressure Multiple; exercise, dietary, sodium restriction, see RAS (below)2 Heart rate Exercise, vagal nerve stimulation3 Dyslipidemia Fish oil; flaxseed oil, olive oil niacin, statins 4 Renin–angiotensin system (RAS) Exercise, dietary, sodium restriction, ACE inhibitors, ARBs, renin inhibitors5 Medial elastocalcinosis Vitamin K2 6 Glucose homeostasis Exercise, metformin, dietary-caloric restriction 7 mTOR pathway Resveratrol, rapamycin, dietary-caloric restriction 8 Inflammation Aspirin, NF-kB inhibitors (e.g., EGCG, quercetin, etc.) 9 Autophagy Verapamil, trephalose, others

10 Extracellular matrix cross-link Alagebrium, ALT-71111 Chemopreventive Aspirin, bioflavonoids

Source: Larrick JW, Mendelsohn A. Applied Healthspan engineering. Rejuvenation Res. 2010 Apr-Jun;13(2-3):265-80, Table 2.

Legend: ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers; EGCG, epigallocatechin 3-gallate; mTOR, mammalian target of rapamycin.


Personal health collaboration studies

More information: www.DIYgenomics.org www.DIYgenomics.org/DIYgenomics_poster.ppt


Study design template: MTHFR example

Source: http://diygenomics.pbworks.com/http://diygenomics.pbworks.com/w/file/36469280/DIYgenomics+study+design+template+blank.doc

CyanocobalaminImage credit: http://wikimedia.org


Health hackers need Blood Tests 2.0

Low-cost home-administered self-read finger-stick blood, urine, saliva tests:

Traditional blood tests (Homocysteine, Vitamin B-12, Folate, Vitamin D, Creatinine, eGFR, Cortisol, Calcium, Iron, Aldosterone)

Hormones (Estrogen, Progesterone, Testosterone, Estradiol)

Immune system: CD4, CD8/CD28 ratio, IL-1, IL-6 Chemical / heavy metal burden: mercury, cadmium,

lead, tin


Towards an epistemology of citizen science

Provide a structure and context for self-derived health knowledge

Q1: Are new kinds of knowledge are being formed through group collaborations such as wikipedia and health social networks?

Q2: Are there differences in the types of knowledge generated by traditional medicine, self-experimentation, and health collaboration communities?

Genomic self-hacking: citizen science and the realization of personalized medicine

Health & Medicine

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