Genetics, Environment and Insurance

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Genetics, Environment and Insurance
Christoph Nabholz, Ph.D. ICLAM 2004 Life Health
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Agenda

• The Genetic Revolution
• Genotype Environment - Phenotype
• Environmental Risk Factors
• Underwriting Measurable Lifestyle Risk

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Genetic Revolution
Draft
2000
Human Genome Project F.S. Collins
1990
PCR
DNA Double Helix Watson Crick
Laws of Heredity Gregor Mendel
1985

1953
1865
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Genotype Phenotype
Environment
Major Gene(s) Modifier Genes
Genotype
Non - Genetic
Phenotypes
Genotype
Non - Genetic
Spectrum of Disease
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Genotype Phenotype
Environment
Major Gene(s) Modifier Genes
Genotype
Non - Genetic
Phenotypes
Genotype
Non - Genetic
Quantification Monozygotic (MZ) twins same
genotype Dizygotic (DZ) twins half of genes
are common
Lichtenstein et al. 2000, NEJM 343 78
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Quantification
Cancer by site
Shared environmental
Non shared environmental
Heritable
Phenotypes
Genotype
Non - Genetic
Stomach 0.28 0.10 0.62 Colorectum 0.35 0.05
0.60 Pancreas 0.36 0.00 0.64 Lung 0.26 0.12
0.62 Breast 0.27 0.06 0.67 Cervix
uteri 0.00 0.20 0.80 Corpus uteri 0.00 0.17
0.82 Ovary 0.22 0.00 0.78 Prostate 0.42 0.00
0.58 Bladder 0.31 0.00 0.69 Leukemia 0.21 0
.12 0.66
Lichtenstein et al. 2000 NEJM 343 78
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Genotype Phenotype
Environment
Major Gene(s) Modifier Genes
Genotype
Non - Genetic
Phenotypes
Genotype
Non - Genetic
Spectrum of Cancer
Lichtenstein et al. 2000, NEJM 343 78
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Breast cancer susceptibility genes
Familial breast cancer
All breast cancer
Genotype 27
FH 10
Environment 73
10 hereditary
90 sporadic
Wooster and Weber 2003 NEJM 348 2339
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HNPCC susceptibility genes
HNPCC
All colorectal cancer
Different Genes One Disease
Genotype 35
FH
Environment 65
Genes and of disease -causing mutations
Lynch and Chapelle 2003 NEJM 348 919
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MLH1 and MSH2 increase the risk for cancer

• Cancer type Mutation General
• carrier risk population risk
• Colorectal 70-82 2
• Endometrial 42-60 1.5
• Stomach 13 lt1
• Ovarian 12 1
• Kidney/ 4 lt1
• Urinary tract
• Brain 3.7 lt1
• Biliary tract 2 lt1
• Central nervous 2 lt1
• system
• Small bowel 1-4 lt1

One Gene Different Syndromes
http//www.myriadtests.com
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HNPCC cancer risk reduction

• Increased Surveillance
• Colonoscopy every one to three years beginning at
  age 20-25 years
• Prophylactic Surgery
• Prophylactic subtotal colectomy with ileo-rectal
  anastomosis
• Chemoprevention
• Aspirin, COX inhibitors

Schoen 2002 Nat Rev Cancer 2 65
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Chemoprevention for colorectal cancer
at Risk Placebo 258 243 197 179 154 130 48 Aspi
rin 259 241 212 191 162 131 50
Sandler et al. 2003 NEJM 348 883
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Agenda

• The Genetic Revolution
• Genotype Environment - Phenotype
• Environmental Risk Factors
• Underwriting Measurable Lifestyle Risk

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Environment, genetics, and sporadic cancer

• Genetic effect 30
• Environmental effect 70
• Socio-economic forces
• Ethnicity / Behavior
• Lifestyle / Alcohol / Smoking
• Diet (35)
• Psychosocial stress
• Infectious diseases
• Impacts of natural environment (air, water, soil)

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Genotype Phenotype
Environment
Major Gene(s) Modifier Gene(s)
Genotype
Non - Genetic
Phenotypes
Genotype
Non - Genetic
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Cystic FibrosisGenotype Phenotype
Environment
Modifier Gene(s)
Major Gene(s)
Infection Antibiotics Tobacco smoke
TGF-?1 HLA II TNF-? MBL NOS1 Alpha-1
CFTR - Allelic Variation
I II III IV V VI
CFTR Synthesis CFTR Processing CFTR
Regulation CFTR Conductance Reduced Amount Unknown
CFM1 Muc1 HFE
Nutrition Insurance status Socioeconomic
Genotype
Non - Genetic
CF Phenotypes
Respiratory Pulmonary disease
Nabholz et al. 2004 JIM 36 48-55
Gastrointestinal Pancreatic insufficiency
Fertility Azoospermia
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Breast cancer susceptibility genes
Familial breast cancer
All breast cancer
Genotype 27
FH 10
Environment 73
10 hereditary
90 sporadic
Wooster and Weber 2003 NEJM 348 2339
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Family history of breast cancer
Family with BRCA1 mutation
Ponder 1997 Science 278 1050
40 chance for breast cancer before 70 25 chance
of ovarian cancer
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Management of familial breast cancer
High Risk e.g. Family History
Genetic Testing
Genetic Counselling
Mutation Carrier
Genetic Testing of Relatives
Cancer prevention Screening (Mammography
CA-125, Pelvic Ultrasound) Surgery (Oophorectomy,
Mastectomy) Chemoprevention (Tamoxifen)
Kennedy 2002 Lancet 360 1008
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Breast cancer risk
Ponder 1997 Science 278 1050
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Percentage cumulative risks(penetrance) by age
of breast and ovarian cancer
Ford et al. 1998 AJHG 62676
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BRCA1 and BRCA2 testing in breast cancer
BRCA mutation increases the risk of cancer
56-87
33-50
27-44
7
2
lt2
Breast cancer by age 50
Breast cancer by age 70
Ovarian cancer by age 70
http//www.myriadtests.com
BRCA mutation carriers
General population
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New York Breast Cancer Study

• Cohort of female Ashkenazi Jewish patients
• Incident, invasive breast cancer
• Regardless of family history or age
• Three ancient mutant alleles genotyped
• 185delAG in BRCA1
• 5382insC in BRCA1
• 6174delT in BRCA2

King et al. 2003 Science 302 643-646
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Male carriers of BRCA mutations
50 of BRCA mutation carriers from
low-incidence families with no breast or ovarian
cancer among mothers, sisters, grandmothers, or
aunts.
Nearly all low-incidence families inherited BRCA
mutation from father.
King et al. 2003 Science 302 643-646
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Environmental change - Increased BRCA penetrance
King et al. 2003 Science 302 643-646
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Pregnancy history - Protection
1.0
E
.8
WT
WT
.6
V
V
Cummulative proportion diagnosed
.4
V BRCA WT wild-type
.2
never pregnant
1 pregnancies
0
King et al. 2003 Science 302 643-646
20
30
40
50
70
80
60
Age
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Exercise as teenager - Protection
King et al. 2003 Science 302 643-646
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Breast cancerGenotype Phenotype
Environment
Modifier Genes
Major Gene(s)
RAD51 NCOA3 Androgen Receptor
Smoking Age at menarche Exercise Weight /
Diet Hormones Pregnancy history
BRCA1 PTEN BRCA2 ATM TP53 CHEK2
HRAS1 Androgen Receptor
Genotype
Non - Genetic
Phenotypes
Major
Minor
Breast cancer
Prostate cancer
Colon cancer
Pancreatic cancer
Ovarian cancer
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Agenda

• The Genetic Revolution
• Genotype Environment - Phenotype
• Environmental Risk Factors
• Underwriting Measurable Lifestyle Risk

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Mortality experience in 2000
National Vital Statistics for 2000 USA
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Underwriting for cancer
Traditional New Family history Genetic
test Smoker status Physical activity BMI Alcoh
ol consumption Few ways in which to assess
potential for cancer Tumor markers Expression
profile Past history of cancer
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BMI and cancer mortality
Calle et al. 2003 NEJM 348 1625
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BMI and cancer mortality
Calle et al. 2003 NEJM 348 1625
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Exercise capacity and mortality
Myers et al. 2002 NEJM 346 793
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Physical activity
Bioelectrical Impedance Analysis (BIA)
Body composition Body fat / Fat-free
mass Nutritional status Obesity
Kyle et al. 2003 Nutrition 19 597
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New reliable alcohol tests

• Phosphatidyl ethanol (PEth) in whole blood
• Lasts for up to three weeks in the blood
• 100 accurate compared to 47 of CDT
• Fatty Acid Ethyl Ester (FAEE) in hair
• Even longer-term as stored in hair
• Distinguishes social, moderate drinkers from
  alcoholics

Wurst et al. 2004 Alcohol Alcohol. 39 33
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Underwriting Lifestyle Risk

• Should life underwriters increase their efforts
  to profile applicants for lifestyle and current
  health status especially those who are young
  and currently non-symptomatic ?

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Genetics, Environment and Insurance
Christoph Nabholz, Ph.D. ICLAM 2004 Life Health