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Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease

 

 


Part II:
Methods and Approaches 1: Assessing Disease Associations and Interactions


 

Chapter 9 Tables


Applications of Human Genome Epidemiology to Environmental Health

Samir N. Kelada, David L. Eaton, Sophia S. Wang, Nathaniel R. Rothman, Muin J. Khoury



Table 9-1
Proposed Genetic Effect Modifiers of Common Exposures

Exposure
Outcome
Gene(s)
Classification*
References
Arsenic
Arsenic metabolites in urine GSTM1
GSTT1 methyl-transferase
2
2
2
56,57
Beryllium
Chronic beryllium disease HLA-DP ß1
1
58-60
Lead
Blood Lead Level

Bone Lead Level
ALAD

ALAD
VDR
1

1
1
61-63

64,65
66,67
Mercury
Atypical porphyrin profiles CPOX
UROD
2
2
68,69
70, 71
Alcohol
Esophageal cancer ALDH2
1
72-76
Aflatoxin B1
Aflatoxin-albumin adducts CYP1A2
CYP3A4
2
2
77
78
Hepatocellular carcinoma GSTM1
EPHX1
1
1
22
23
Heterocyclic amines
Colon cancer NAT2
1
79-82
Breast cancer NAT2
SULT1A1
1
1
83
84
Aromatic amines
(dye industry)
Bladder cancer NAT2
1
11,12
Halomethanes
Metabolite levels in blood GSTT1
1
85,86
Benzene
Hematoxicity CYP2E1
NQO1
1
1
87,88
Sister chromatid exchange in lymphocytes GSTT1
1
89
Halogenated solvents (e.g. TCE)
Renal cell carcinoma GSTT1
1
90,91
Organochlorine compounds
(e.g. PCBs, TCDD)
Immunotoxicity CYP1A1
CYP1A2
AHR
2
2
2
Organophosphate Pesticides (OPs)
Chromosomal aberrations PON1
GSTM1
GSTT1
CYP3A4
1
1
1
2
95


96,97
Butadiene
Sister chromatid exchange in lymphocytes GSTT1
1
98-100
Lipopolysaccharide (endotoxin)
Decreased forced expiratory volume (FEV1) TLR4
1
31
Hay dust
TNFα production in hypersensitivity pneumonitis TNFα
1
101
Ozone
Influx of inflammatory cells in the lung TLR4
2
102
Airborne Polycyclic aromatic hydrocarbons (PAHs)
PAH metabolites in urine, DNA adducts, or measures of genotoxicity CYP1A1
GSTM1
NAT2
GSTP1
EPHX1
1
1
1
1
1
103-110
Lung cancer GSTM1
1
111
Nitro-PAHs
Genotoxic effects in respiratory tract NAT2
2
112,113
Ultraviolet light (UV)
Basal cell carcinoma XP-D
1
114
Ionizing radiation (IR)
DNA damage in lymphocytes XP-D
XP-F
XRCC1
2
2
2
115-117
Prolonged cell cycle delay APE1
1
118

Tobacco Smoke

 

 

 

 

 

 

 

Environmental Tobacco Smoke (ETS)

Lung cancer

 




Bladder cancer



Bronchogenic carcinoma

Emphysema, Chronic Obstructive Pulmonary Disease

Lung cancer

CYP1A1
GSTM1
NAT1
NAT2
EPHX1
XRCC1

CYP1A2
NAT2
GSTM1

AHR

EPHX1
GSTM1

GSTM1

1
1
1
1
1
1

1
1
1

2

1
1

1
119-121
121-123
80,124
125
126

92
13,127
128


92

129


130

* Classification 1 = Associations with laboratory evidence and suggestive epidemiologic data
2 = Associations proposed from basic scientific laboratory evidence

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Appendix 9-1
List of Web sites

Environmental Health Web sites

Gene Families

Genetic Information Web sites

Informed Consent

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Appendix 9-2
Genes and Polymorphisms with Relevance to Environmental Health

Gene
Gene Product
Polymorphism
Effect of Polymorphism
References
CYP1A1
Aryl hydrocarbon hydroxylase
T3801C (m1)A2455G (m2)
Unknown
None
131
132
CYP1A2
Arylamine hydroxylase
C-164A
Decreased inducibility
133,134
CYP2E1
Ethanol-indudible P450
5’ flanking repeat region
Increased activity after ethanol exposure
135,136
CYP3A4
Steroid-inducible P450
5’ promoter
A->G mutation
Unknown, perhaps
expression levels
137,138
AHR
Aryl hydrocarbon receptor
G1721A
CYP1A1 inducibility?
139
EPHX1
Epoxide hydrolase
Tyr113His
His139Arg
Altered protein stability
140
NQ01
NAD(P)H:quinone oxido-reductase 1
C609T
Inactive enzyme
88,141
NAT1
N-Acetyl transferase 1
Many alleles
Rapid vs. slow acetylation
80
NAT2
N-Acetyl transferase 2
Many alleles
Rapid vs. slow acetylation
80
SULT1A1
Sulfotransferase
Arg213His
Low activity and low
thermal stability
142
GSTM1
Glutathione S-Transferase-µ
Deleted (null) allele(s)
No enzyme produced
143
GSTP1
Glutathione S-Transferase-π
Ile104Val
Ala113Val
Altered activity and substrate affinity
144
GSTT1
Glutathione S-Transferase-θ
Deleted (null) allele(s)
No enzyme produced
145,146
PON1
Paraoxonase
Arg192Gln
Met55Leu
Promoter point mutations
Change in Activity and substrate specificityChange inenzyme expression levels
147-149
VDR
Vitamin D Receptor
RFLP in 3’ UTR; multiple point mutations
3’ UTR = unknownknown effects for some point mutations
148
HLA-DP ß1
Antigen recognition protein
Lys69Glu
Change in CD4+ recognition
58

XPD (ERCC2)

XPF

Nucleotide Excision Repair (NER) enzyme system
Lys751Gln
Improved function



Amino acid sequence change
114



116
XRCC1
Base Excision Repair (BER)
Arg399Gln
Unknown
149
APE1
Apurinic/apyrimidinic endonuclease 1
Asp148Glu
Reduced endonuclease activity
150
ALAD
d-Amino-levulinic Acid Dehydratase
G177C
Alleles 1and 2, 2 allele yields a more electronegative protein
61
TLR4
Type I trans-membrane protein
A896G
D299G
Altered cell signal transduction by D299G after LPS exposure
31
TNFalpha
Cytokine
G-308A
Altered transcriptional regulation
151

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