“One Size Fits All”-Does It? Vidudala V.T.S. Prasad, Ph.D Head Research and Development...
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Transcript of “One Size Fits All”-Does It? Vidudala V.T.S. Prasad, Ph.D Head Research and Development...
“One Size Fits All”-Does It?
Vidudala V.T.S. Prasad, Ph.DHead
Research and DevelopmentBasavatarakam Indo-American Cancer Hospital
and Research InstituteRoad No.14, Banjara HillsHyderabad-500034, India
Cell: 9618207495, e-mail: [email protected]
[email protected] Helpline: 9989524365
Our Group
• Dr. Guru Prasad • Dr. Ram Prasad • Padma • Satish• Satish Kumar • Ravi• Shiva Satish• Ph.D Students: Sarika, Srivani and Padma
• Dr. Saritha (Volunteer Researcher)
Research Oral Cancer (OC)
Low incidence and low Priority accorded by the developed Countries, as judged
by the publications.
3.5% (M+F) of publications as compared to over 10% of female BC
Why Oral Cancer?
In India, it is one of the most prevalent Cancers, especially in males
Coupled with the low priority status of the OC in Developed Countries, the onus to address OC is on us, but not on US and others.
Paucity of gender and site specific data, on global perspective
Polymorphims
Drug Metabolism
Ultra Responders/Poor Responders/Non-Responders
Functional Consequences of Polymorphisms
Complications
Poor/No Clinical Outcome
Adverse Drug
Reactions
Disease Susceptibility
/Resistance
Receptor Sensitivity
Drug Transport Polymorphisms
A case for setting up specific data bases (DBs)
Polymorphisms
GlucosylcerebrosidaseLipoxygenasesFAS and FASLTP53 CASPs, SULT1A1 CYP3A5 etc.,
Epigenetic aspects of gene regulatory aspects and
Expression Profiles
Cell Culture
Selective Cellular Death
Epigenetic Mechanisms
CP
CERAMIDESphinganineCerS
UV therapy4-HPR
PaclitaxelEtoposide
SDZ PSC833AnthracyclinesVincs alkaloids
Ceramide kinase
SP
Sphingosine
Sphingolyase
Glu/Gal-CerGCB
Sphingosine kinase
TamoxifenToremifene
MifepristoneCyclosporin AKetoconazole
VerapamilPPMP
NB-DNJ
UV radiationCD95
AnthracyclinesAra-CTNF-α
DT GM-CSF
Sphingomyelin
SMas
e
Fatty acid + Sphinganine
Ser + Palm CoA
CerS
De novo pathway Salvage pathway
SM sy
ntha
se
Ceramidases
CERT/GTsCSLs
Growth factorsCytokines
Lipid phosphatases
ELP & HXD
SP lyase
S/G-transferases
Pro-apoptotic
CERAMIDE Glu-Cer SM CP SP
Glucosylceramide synthaseSphingomyelin synthase
Ceramide kinase Sphingosine kinase/ Ceramidase
Anti-apoptotic Mitogenic Anti-apoptotic, Pro-proliferative
Ratio of sphingolipids decides cellular fate
Pro-sur vival
Glucosyl cerebrosidase
Sphingomyelinase
Cer -Phosphatase
SP lyase
Pro-sur vival
Arachidonic acid Lipoxygenases
Inflammation and Cancer In 1863, German physician Rudolf Virchow hypothesized that certain
classes of irritants, together with the tissue injury and inflammation, promote enhanced cell proliferation.
In 1918, Yamagiwa and Ichikawa, who showed that repeated painting of coal tar onto rabbits' ears causes carcinomas.
the world’s first man-made cancer on the ears of a rabbitRudolf Virchow
FAS and FASL promoter SNPs Gene Loci: FAS 10q24.1; FASL 1q23
The SNPs of the FAS -1377 G>A, block the binding of Sp1 transcription factor and
FAS -670 A>G SNPs, STAT1 transcriptional factor binding site,
leading to down regulation of the FAS gene expression (Huang et al., 1997 and Sibley et al., 2003).
The FASL -844 T>C SNP at the binding site for CAAT/enhancer binding protein. The CC variant was shown to upregulate FASL gene compared to the TT variant (Wu et al., 2003).
Various ethnic groups have been shown to harbor variants of the FAS and FASL. All cancers have genetic basis and genetic pre-disposition to cancer is well established (Robson and Offit 2007 and Tan 2009).
FAS-FASL and Apoptosisnduction of Cell Death: Trimerization of the Fas receptor by Fas ligand results in activation of caspase 8 (FLICE/MACH1), mediated by the adapter protein Fas-associated death domain (FADD)/mediator of receptor-induced toxicity (MORT1). Active caspase 8 is then responsible for activation of downstream caspases and cell death. DNA-damaging agents, such as doxorubicin, can result in increased Fas expression via a p53-dependent pathway and hence induce killing by the Fas/Fas ligand pathway, if the newly synthesized Fas engages Fas ligand. Other modes of cellular stress, such as removal of simple media supplements like mercaptoethanol, can also result in enhanced Fas expression.
Our Data Caucasians Chinese Askhenzi Jews
Hetero %
Homo %
Hetero %
Homo %
Hetero %
Homo %
Hetero %
Homo %
GBA VAL394LEU
3 0 0.3 0-- -- -- --
GBA ASP409HIS 3 0 0 0 -- -- -- --GBA
ASN370SER 0 0 0.5 00.7 0 4.3 0
GBA LEU444PRO 0 0 0 0
1.1 0 2.4 05 LOX -292C >
T17 0 5 0 -- -- -- --
12 LOX 835 A>G 32.5 0.5 45 14 51 25 -- --FAS -1377 G>A 24 9 17 0.4 47 11 -- --
P 53 215 G>C 39 24 42 10 -- -- -- --P 53 216 bp
delition 8 22 17 2 -- -- -- --Variations in Genotypes Among Different Ethnic Populations
Genetic Variants Affecting Drug Response
1A219%
2D63%
2E110%
3A4/542%
2C92C19 26%
1A25%
2D624%
2E11%
3A4/551%
2C92C1919%
Primary CYP 450 Enzymes in Drug Metabolism
% of total enzyme
% of drugs metabolized
Biotransformation of Tamoxifen,pro-drug to active drug
CYP 3A4/5 converts TAM to N-desmethyl tamoxifen, whereas the generation of 4-hydroxy tamoxifen and ENDOXIFEN are predominantly catalyzed by CYP2D6. CYP2C19, CYP2C9, and
CYP2B6 play less important roles in tamoxifen metabolism in vitro at therapeutically relevant concentrations. Jin, Y. et al. J Natl Cancer Inst 2005;97:30-39
Gene and Variant Caucasians African-Americans Asians
CYP2D6*3 2% 0 0
CYP2D6*4 12-21% 2% 1%
CYP2D6*5 2-7% 4% 6%
CYP2D6*10 1-2% 6% 51%
CYP2D6*17 0 34% 0%
CYP2D6*2xN 1-5% 2% 0-2%
CYP2C9*2 8-14% 1% 0%
CYP2C9*3 4-16% 1-2% 2-3%
CYP2C9*5 - 1.7% -
CYP2C9*6 - 0.6% -
CYP2C19*2 15% 17% 30%
CYP2C19*3 0.04% 0.40% 5%
The table below lists common drug metabolism gene variants and their frequencies in major ethnic groups.
Adapted from Blue Cross Blue Shield Special report
Germline mutations of BRCA1 and BRCA2
A very high frequency: 31.6 %; non-Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado
(Mullineaux et al. 2003).
Moderate: 16.4% in India (Vaidhyanathan)
Low Frequency: 1.13–5.9%;white Americans, the Spanish from Spain, Polish, Iranian, Pakistani and Turkish women (Grzybowska et al.2002; Shih et al. 2002; Guran et al. 2005; Weitzel et al. 2005; Mehdipour et al. 2006; Rashid et al. 2006).
Absence of the 185delAG mutation: Chinese and Japanese families with breast cancer (Ikeda et al. 2001; Zhi et al. 2002).
Other Genetic Variations among different populations
• G6PD: Specific mutations are found in Indians and Africans.
• ALDH 1: Deficient activity in Orientals (Chinese& Japanese) results in high sensitivity to alcohol.
• Sickle cell anaemia: A mutation in sickle cell anaemia is not found across the globe but in specific geographical regions like Africa and Asia, mostly.
Asian Belly
Specific fat depots are influenced by ethnicity and gender
Kohli et al., 2009, Obesity Jr. DOI 10 1038/oby, 2010. 94; Liu et al., 2011, BMC Public Health, 11, 500
Cancer may occur in any part of the body
Dr. V. V. T. S Prasad, Ph.D, Chief, R&D, E mail :[email protected] , Cell: 09618207495
Increased risk of buccal mucosa cancer for females but not for males
FASL homozygous variant decreases risk of Female cancers while those of FAS variants alters the risk divergently
SULT1A heterozygous variant decreases Oral Cancer Risk but increase the Cancer Risk for females
The CYPA35*3 homozygous variant offers protection against breast cancer but not that of oral cancer
TP53 E-4 215G>C heterozygous variant increases Tongue Cancer risk in males but the homozygous variant increase risk of tongue and BM cancers in males. Intron 6 G>A het variant confers protection against tongue cancer in males
TP53 intron 3 homozygous variant lowers risk of both tongue and BM cancers in females
15-LOX promoter polymorphism (-292C>T) increases risk of the female cancers, though the degree of the risk varies for each of the cancers
12-LOX 835A>G heterozygous variant increases breast cancer but decreases risk of Cervical and Ovarian Cancers, whereas the homozygous variant increases risk for BC, Cx and OC cancers.
Rising Incidence of Breast cancer in India
www.breastcancerindia.net/statistics
Age shift: Breast cancer now is more common in 30’s and 40’s
www.breastcancerindia.net/statistics
Ceramide, Ceramide-1-Phosphate and LOXs* LOX mutation &
cancers
ROS Inflammation
Cell Death FAS/FASL, CASPases
*Cer and CP upregulate 12-LOX pathway and generate 12-HETE involved in cell proliferation, inflammation, VEGF) expression.
Ceramide elevates 12-hydroxyeicosatetraenoic acid levels and upregulates 12-lipoxygenase in rat primary hippocampal cell cultures containing predominantly astrocytes. Vidudala V.T.S. Prasad *, Kassem Nithipatikom, David R. Harder. Neurochemistry International 53 (2008) 220–229. CP manuscript is in review
Our Research, Mitochondria and Cancer
MembranePotential
Inhibits mt function
Personalized Medicine
“Here is my genomic sequence”
Sensitivity of cells even from same organ differs to anti-cancer agents
Annexin-V-FITC Propidium Iodide CAL-27 48hrs
Med
ium
con
trol
Tam
oxif
en
SCC9 48hrs
Annexin-V-FITC Propidium Iodide OverlayF
-1
A) B)Overlay
F
-1Ta
mox
ifen
P-1
Annexin-V-FITCM
ediu
m c
ontr
ol Overlay
MCF-7 48hrs
F-1
Tam
oxif
enMCF-10A 48hrs
Annexin-V-FITC Propidium Iodide P
-1C) D)
Propidium Iodide Overlay
Your Genes DictateYour Response
Genomics
“One Size Doesn’t Fit All”
CAL-27 Vs. SCC-9 apoptosis
0.00
1.00
2.00
3.00
4.00
5.00
6.00
F-1 25ul Curcumin100uM
Tam 50ul P-1 100ul
24H
48H
CAL-27 Vs. SCC-9 cell death
0.00
0.50
1.00
1.502.00
2.50
3.00
3.50
F-1 25ul Curcumin100uM
Tam 50ul P-1 100ul
24H
48H
MCF-7 Vs. MCF-10A apoptosis
0.00
0.50
1.00
1.50
2.00
2.50
F-1 25ul Curcumin100uM
Tam 50ul P-1 100ul
24H
48H
MCF-7 Vs. MCF-10A cell death
0.000.501.001.502.002.503.003.504.00
F-1 25ul Curcumin100uM
Tam 50ul P-1 100ul
24H
48H
Ratio of cell death
One-way Anova*p 0.05 **p0.005***p0.001
Fig. 3: Cytotoxic extract mediated cell death in breast cancer cell lines
0102030405060708090
100
Con
trol
FE
0.05
FE
0.1
FE
0.15
FE
0.2
Tam
0.2
PE
0.2
FE
0.1T
am0.
2
PE
0.2T
am0.
2
Treatment
% D
ead
cel
ls
MCF-7
MDAMB-435
ZR-75
**
*
*****
CYP2D6 Alleles in South Indians(% Allele frequency)
CYP2D6 Allele
TN Kerala Karnataka
AP South India
*3 0.0 0.0 0.0 0.0 0.0*4 6.1 7.5 4.8 10.8 7.3
*5 1.1 1.7 1.1 1.4 1.9
*10 12.9 7.0 11.2 9.0 10.2
Theophilus et al., Biol Pharm Bull, 29(8) 1655-1658, 2006
Note: Existence of CYP2D6 PM phenotype in south Indian population is also reported based on dextromethorphan and its metabolite levels in urine Abraham, B.K., et al., Acta Pharma Sin 21 (6) 494-4980
“Every individual is different from another and hence should be considered as a different entity. As many variations are there in the Universe, all are seen in Human being”
Charak Samhita
Most Drugs
Do Not Work Similarly in All Patients
The tiny difference in human genome translates into 3 million separate “spelling” differences in a genome of 3 billion bases, creates wide variety of phenotypesgh
Obvious enough!!!
Menacing !
Gotram
• Science of Genetics behind the Hindu Gotram System
• People within the gotra are regarded as kin Gotra is the lineage or clan assigned to a Hindu at birth
• The Gotra is a system which associates a person with his most ancient or root ancestor in an unbroken male lineage.
• to avoid cousin marriages which have been proved to increase the risk of genetic disorders in the off springs
The Jewish Rabbi as a DB
Concerns
• Privacy Issues• Ethical aspects• Integrity• Accuracy• Ownership• Genetic discrimination
The volume of information held in genetic research databases and quick access magnify these concerns.
India Needs G-P-L-M -Omics DBs more than any other countries
• Close Marriages– Caste– Distantly Related– Within family
– What we need is not only genetic DBs but also disease specific DBs----- Diabetes Mellitus, Cardiac Diseases and Cancer to start with
Late than Never
Let’s Develop Data Bases that Caters to the Needs of Diverse India
Let all Indians, “Have and Have Nots”, Reap the Benefits of
Biotechnological Advancements, alike.
Let us Light the Lamp of Knowledgeand Drive Away Ignorance
Sooner the BetterDhanyawad
Databases
• A ‘database’ is any methodical or systematic collection of data, structured that allows accessibility to individual or collective elements of that database .
• The human genetic research databases have been created primarily for the purposes of medical or other human research.
Variant India USA USA USA Brazil China Korea Spain
Gln/Gln (AA)
59.5 17 37 40.9 22.5 23.7 31.4 19
Gln/Arg (AG)
39.6 49.3 50.5 45.5 37.5 51 49.4 47
Arg/Arg (GG)
0.9 33.7 13.5 13.6 40 25.3 19.3 34
Gln/Arg (AG) +
Arg/Arg (GG)
40.5 83 64 59.1 77.5 76.3 68.7 81
Population / Gender
IndianFemal
e(100%)
PredominantlyCaucasians (88%),
Female (41% )
Caucasians
Female(52%)
Blacks(52%)
Brazilian
Female (69% )
ChineseFemale (37.2%)
KoreansFemale
(62.0% )
Spain Male
(100%)
Reference Our Study Gong et al., 2007 Goodman
et al., 2004
Goodman et al.,
2004
Fridman et al.,
2005
Tan et al.,
2007
Kim et al.,
2010
Quintana et al., 2006
Variations in the frequencies of the ALOX 12 polymorphism (A835G; Gln261Arg) in different populations (%)
Samples Parameter Frequency
AA
N
(%)
AG
N
(%)
GG
N
(%)
AG +GG
N
(%)
A allele
N
(%)
G Allele
N
(%)
Male, N =151 104
(68.9)
46
(30.4)
1
(0.7)
47
(40.1)
254
(84)
48
(16)
Female , N=166 94
(56.6)
69
(41.6)
3
(1.8)
72
(43.4)
257
(77)
76
(23)
p-value 0.03* 0.28 0.025* 0.50 0.02*
12-LOX polymorphism in control males and females
* Statistically significant (p<0.05); N = Number of samples
Three Billion Big
3 million ‘spelling’ variations, Just differ by 0.1%, 99.9 identical
ALOX1212-LOX ALOX12
Proliferation
12-LOX influences Cancer Related Processes
Adhesion
That tiny 0.1% difference in human genome translates into 3 million separate “spelling” differences in a genome of 3 billion bases, accounting for wide variety of phenotypes
Prevalence
Population Indian Ashkenazi Jews
Non-Jewish Americans of
SpanishAllele
Frequency 16.4% 18.0% 31.6%
Vaidyanathan et al., 2009 J. Biosci. 34(3)415–422
CYP450 genotypes: Patient classifications
1) Extensive metabolizers (EM) = 2 good copies
2) Intermediate metabolizers (IM) = 1 defective copy
3) Poor metabolizers (PM) = 2 defective copies
4) Ultra-rapid metabolizers (UM) = 3+ good copies
SULT1A1 Prevalence Populatio
n Turkish Caucasian African
American
Japanese
Chinese Korean
Allele Frequency
23.8% 36.5% 29.4% 16.0% 8.0% 12.4%
R&D Data (2010-Present )
Homozygous
Heterozygous Mutated
Normals 3.3% 21.7% 25.0%Breast cancer 6.7% 53.3% 60%Ovarian Cancer 13.3% 46.7% 60%
Arslan, 2010 Biochem genet 48:987-994
MTHFR Prevalence
Kumar et al., 2005 J Hum Genet 50:655-63
Population Indian Caucasian Chinese
Japanese
Frequency of
homozygous mutation
2.16 % 8.9% 16.9% 15.6%
R&D Data (2010-present )
Homozygous
Heterozygous Homo+Het
Normals 0.5% 6.0% 6.5%
Colorectal cancer 0% 13.8% 13.8%
Acute Lymphoblastic
Leukemia 1.5% 4.3% 5.8%
MTHFR Prevalence
Kumar et al., 2005 J Hum Genet 50:655-63
Population Indian Caucasian Chinese
Japanese
Frequency of
homozygous mutation
2.16 % 8.9% 16.9% 15.6%
R&D Data (2010-present )
Homozygous
Heterozygous Homo+Het
Normals 0.5% 6.0% 6.5%
Colorectal cancer 0% 13.8% 13.8%
Acute Lymphoblastic
Leukemia 1.5% 4.3% 5.8%
UGT1A1*28Mutation: Seven TA repeat sequence in the
promoter region
Locus: Chr 2q37
Impact of Mutation: Decrease enzyme production, leading to reduced glucuronidation (Iyer et al., 1998 and Iyer et al., 2002)
Drug Major Condition
Clinical Implication
Comment
Irinotecan Colorectal cancerDecreased UGT1A1 activity may increase the risk of toxicity
Genotyping is useful for dosage regimens >250 mg/m2.
Lee and McLeod, 2011 J Pathol; 223: 15–27
Drug Major Condition
Clinical Implication
Comment
Irinotecan Colorectal cancerDecreased UGT1A1 activity may increase the risk of toxicity
Genotyping is useful for dosage regimens >250 mg/m2.
Lee and McLeod, 2011 J Pathol; 223: 15–27
FDA advisory Committee’s Recommendation. Oct 18, 2006
Tamoxifen label should be updated to reflect the fact postmenopausal women with ER positive breast cancer who are CYP2D6 poor metabolizers with tamoxifen treatment (by genotype or drug interactions) are at increased risk for breast cancer recurrence.
The recommendation has not been withdrawn to the best of my knowledge
DPDMutation: *2A Exon-14-skipping
Gene location: Chromosome 1p22
Impact of Mutation: Nonfunctional enzyme
Drug Major Condition Clinical Implication
Comment
5-Fluorouracil
Colorectal, stomach,pancreaticcancer
DPD deficiency is associated withhigher risk of toxicity
Phenotypingmay be needed in some cases.
Lee and McLeod, 2011 J Pathol; 223: 15–27
Metabolic pathways of pyrimidines and dihydropyrimidine dehydrogenase (DPD)
Tanaka et al., 2005 Nagoya J. Med. Sci. 67. 117-124
DPD Prevalence
Population
Caucasian
African American
Finnish Dutch
Allele Frequency
3-5%(Jane et al.,
2007)
8%(Saif et al.,
2007)
2.2%(Eidens et al.,
2009)
1.2% (Eidens et al., 2009)
R&D data indicates the prevalence of the mutation in Indian population.
R&D Data (2010-Present )
Homozygous Heterozygous Mutated
0% 5.8% 5.8%
UGT1A1 PrevalencePopulatio
n African Europea
nAsian R&D Data
(2010-present )
Allele Frequency
43% 39% 16% Work in progress
Beutler et al., 1998 Proc Natl Acad Sci USA; 95:8170-74
Need for Data Bases pertinent to Diverse India
Age shift: Breast cancer now is more common in 30’s and 40’s
www.breastcancerindia.net/statistics
Age shift: Breast cancer now is more common in 30’s and 40’s
www.breastcancerindia.net/statistics
Rising Incidence of Breast cancer in India
www.breastcancerindia.net/statistics
“Every individual is different from another and hence should be considered as a different entity. As many variations are there in the Universe, all are seen in Human being”
Charak Samhita
Other Genetic Variations among different populations
• G6PD: Specific mutations are found in Indians and Africans.
• ALDH 1: Deficient activity in Orientals (Chinese& Japanese) results in high sensitivity to alcohol.
• Sickle cell anaemia: A mutation in sickle cell anaemia is not found across the globe but in specific geographical regions like Africa and Asia, mostly.
Many Races, Many Faces with Varied
features
Yet, human DNA sequence is 99.9% identical, differs by just 0.1% but
still -----
Variant India USA USA USA Brazil China Korea SpainGln/Gln
(AA)59.5 17 37 40.9 22.5 23.7 31.4 19
Gln/Arg (AG)
39.6 49.3 50.5 45.5 37.5 51 49.4 47
Arg/Arg (GG)
0.9 33.7 13.5 13.6 40 25.3 19.3 34
Gln/Arg (AG) +
Arg/Arg (GG)
40.5 83 64 59.1 77.5 76.3 68.7 81
Population / Gender
IndianFemale(100%)
Predominantly Caucasians
(88%),Female (41% )
CaucasianFemale(52%)
Blacks(52%)
BrazilFemale (69% )
ChineseFemale (37.2%)
KoreansFemale (62.0%
)
Spain Male
Reference Present Study
Gong et al., 2007
Goodman et al., 2004
Goodman et al., 2004
Fridman et al., 2003
Tan et al., 2007
Kim et al.,
2010
Quintana et al., 2006
Table 2: Variations in the frequencies of the ALOX 12 polymorphism (A835G; Gln261Arg) in different populations
Variant India USA USA USA Brazil China Korea SpainGln/Gln
(AA)59.5 17 37 40.9 22.5 23.7 31.4 19
Gln/Arg (AG)
39.6 49.3 50.5 45.5 37.5 51 49.4 47
Arg/Arg (GG)
0.9 33.7 13.5 13.6 40 25.3 19.3 34
Gln/Arg (AG) +
Arg/Arg (GG)
40.5 83 64 59.1 77.5 76.3 68.7 81
Population / Gender
IndianFemale(100%)
Predominantly Caucasians
(88%),Female (41% )
CaucasianFemale(52%)
Blacks(52%)
BrazilFemale (69% )
ChineseFemale (37.2%)
KoreansFemale (62.0%
)
Spain Male
Reference Present Study
Gong et al., 2007
Goodman et al., 2004
Goodman et al., 2004
Fridman et al., 2003
Tan et al., 2007
Kim et al.,
2010
Quintana et al., 2006
Table 2: Variations in the frequencies of the ALOX 12 polymorphism (A835G; Gln261Arg) in different populations
HGP: The most ambitious project in biological science was envisaged to spell out the human
genome in toto.
In other words, the project was meant to sequence the complete human genome of 3 billion bases
What does it mean!
Many Races, Many Faces with Varied
features
Yet, human DNA sequence is 99.9% identical, differs by just 0.1%
http://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asp
-- Sun Kim group at IU -- 86
Your Genes DictateYour Response
“One Size Doesn’t Fit All”
The Human Genome Program of the US DOE
• Human Genome Project started as US component 1990 US$3billion 15-year effort to find the estimated 80,000 human genes and determine the sequence of the 3-billion DNA building blocks that underlie all life's diversity.
• A new goal focuses on identifying regions of the human genome that differ from person to person. Our DNA sequences are estimated to be 99.9% identical genetically - these DNA sequence variations can have a major impact on how our bodies respond to disease; environmental insults, such as bacteria, viruses, and toxins; and drugs and other therapies.
• http://www.er.doe.gov/production/ober/HELSRD_top.html
!
What does it mean!
Many Races, Many Faces with Varied
features
Yet, human DNA sequence is 99.9% identical, differs by just 0.1%
That tiny 0.1% difference in human genome translates into 3 million separate “spelling” differences in a genome of 3 billion bases, accounting for wide variety of phenotypes
Does it matter in practicing medicine?
What does it mean!
Many Races, Many Faces with Varied
features
Yet, human DNA sequence is 99.9% identical, differs by just 0.1%
Pharmacogenomics
Personalized Medicine
Right Drug(s) @ Right Dose, and no ADRs
Meta
bolic
pathways
Identification of
polymorphisms
“Best Fit”
However, 0.1% difference in human genome translates into 3 million separate “spelling” differences in a genome of 3 billion bases,
accounting for wide variety of phenotypes
What these variations in DNA Sequence can do?
May results in a different phenotype
May impact expression of mRNA/protein
May serve as an unique molecular marker for a given
pathological condition
Genome: All the genetic material in the chromosomes of a particular organism; its size is generally given as its total number of base pairs.
Genomics: the study of genes and their function. Recent advances in genomics are bringing about a revolution in our understanding of the molecular mechanisms of disease, including the complex interplay of genetic and environmental factors. Genomics is also stimulating the discovery of breakthrough healthcare products by revealing thousands of new biological targets for the development of drugs, and by giving scientists innovative ways to design new drugs, vaccines and DNA diagnostics. Genomics-based therapeutics include "traditional" small chemical drugs, protein drugs, and potentially gene therapy.
Much before the advent of human genome Project ---- our Ancient Wisdom
proclaimed that;
“Every individual is different from another and hence should be
considered as a different entity. As many variations are there in the
Universe, all are seen in Human being”
Charak Samhita
How these variations are identified and put to use in practicing medicine!
Association of 12-LOX polymorphism with colorectal cancer.
Subjects (Gender and
Sample Size)
Frequency
AA
N (%)
AG
N (%)
GG
N (%)
AG + GG
N (%)
A allele
N (%)
G Allele
N (%)
Control (M+F, N=317)
Colorectal Cancer
(M+F, N=104) p-
value
OR
CI (at 95%)
198 (62.5) 115 (36.3) 4 (1.3) 119(37.5) 511(81) 123(19)
38 (36.5) 64 (61.5)* 2 (2.0) 66(64)* 140(65)* 68(35)*
0.0001 0.262 0.0001 0.0001 0.0001
2. 9 2.61 2.9 6.3 2.9
1.8-4.6 0.46-14.7 1.83-4.6 4.1-9.7 1.8-4.6
Control (F, N = 166)
Colorectal Cancer
(F, N= 45) p-value
OR
CI (at 95%)
94 (56.6) 69 (41.6) 3 (1.8) 72 (43) 257(77) 75(23)
21 (46.6) 23 (51.1) 1 (2.3) 24(53) 65(72) 25(28)
0.24 0.73 0.234 0.66 0.23
1.5 1.5 1.5 1.1 1.5
0.77-2.92 0.15-15.1 0.77-2.9 0.66-2.0 0.35-2.9
Control (M, N=151) 104 (68.9) 46 (30.4) 1 (0.7) 47 (31) 254(84) 48(16)
Colorectal Cancer,
(M, N=59) p-value
OR
CI (at 95%)
17(28.8) 41(69.5)* 1(1.6) 42(71)* 75(64)* 43(36)*
0.0001 0.154 0.0001 0.041 0.0001
5.5 6.2 5.5 1.8 5.5
2.9-10.6 0.37-102 2.8-10.6 1.0-3.2 2.8-10.6
* Statistically significant (p<0.05).