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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

* 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

• Agency for Toxic Substances and Disease Registry’s Tox Profiles
  http://www.atsdr.cdc.gov/toxpro2.html
  
• National Library of Medicine’s ToxNet
  http://toxnet.nlm.nih.gov/
  
• PubMed
  http://www.ncbi.nlm.nih.gov/sites/entrez
  
• National Institute of Environmental Health Sciences Environmental Genome Project
  http://www.niehs.nih.gov/research/supported/programs/egp/
  
• National Toxicology Program Report on Carcinogens
  http://ntpserver.niehs.nih.gov/NewHomeRoc/AboutRoC.html
  
• National Institute for Occupational Safety and Health's (NIOSH's) Registry of Toxic Effects of Chemical Substances (RTECS)
  http://www.cdc.gov/niosh/rtecs/default.html

Gene Families

• Cytochrome P450s
  http://www.cypalleles.ki.se/
  
• N-Acetyl Transferases
  http://www.louisville.edu/medschool/pharmacology/NAT.html

Genetic Information Web sites

• On-line Mendelian Inheritance in Man (OMIM)
  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
  
• Human Genome Epidemiology (HuGE) Net
  http://www.cdc.gov/genetics/hugenet/
  
• Cancer Genome Anatomy Project (CGAP)
  http://cgap.nci.nih.gov/
  
• PubMed
  http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed
  
• SNPs Consortium
  http://snp.cshl.org/
  
• National Center for Biotechnology Information (NCBI) dbSNPs
  http://www.ncbi.nlm.nih.gov/SNP/

Informed Consent

• http://www.ncbi.nlm.nih.gov/pubmed/11710898?dopt=Abstract
  
• Department of Health and Human Services
  

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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
TNF	Cytokine	G-308A	Altered transcriptional regulation	151

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