Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms

A. Joseph Bloom; Timothy B. Baker; Li Shiun Chen; Naomi Breslau; Dorothy Hatsukami; Laura J. Bierut; Alison Goate

doi:10.1093/hmg/ddt432

Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms

A. Joseph Bloom
, Timothy B. Baker
, Li Shiun Chen
, Naomi Breslau
, Dorothy Hatsukami
, Laura J. Bierut
, Alison Goate

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novelmechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.

Original language	English (US)
Pages (from-to)	555-561
Number of pages	7
Journal	Human molecular genetics
Volume	23
Issue number	2
DOIs	https://doi.org/10.1093/hmg/ddt432
State	Published - Jan 2014

Bibliographical note

Funding Information:
The National Institute of Mental Health (5T32MH014677-33 to A.J.B.); the National Cancer Institute (P01 CA-089392 to L.J.B., and P50 CA-84724 and K05 CA-139871 to T.B.B.); the National Institute on Drug Abuse (K02 DA-021237 to L.J.B.) and the National Human Genome Research Institute (U01 HG-004422 to L.J.B.). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200 782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of datasets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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title = "Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms",

abstract = "Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novelmechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.",

author = "Bloom, \{A. Joseph\} and Baker, \{Timothy B.\} and Chen, \{Li Shiun\} and Naomi Breslau and Dorothy Hatsukami and Bierut, \{Laura J.\} and Alison Goate",

note = "Funding Information: The National Institute of Mental Health (5T32MH014677-33 to A.J.B.); the National Cancer Institute (P01 CA-089392 to L.J.B., and P50 CA-84724 and K05 CA-139871 to T.B.B.); the National Institute on Drug Abuse (K02 DA-021237 to L.J.B.) and the National Human Genome Research Institute (U01 HG-004422 to L.J.B.). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200 782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of datasets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",

year = "2014",

month = jan,

doi = "10.1093/hmg/ddt432",

language = "English (US)",

volume = "23",

pages = "555--561",

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T1 - Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms

AU - Bloom, A. Joseph

AU - Baker, Timothy B.

AU - Chen, Li Shiun

AU - Breslau, Naomi

AU - Hatsukami, Dorothy

AU - Bierut, Laura J.

AU - Goate, Alison

N1 - Funding Information: The National Institute of Mental Health (5T32MH014677-33 to A.J.B.); the National Cancer Institute (P01 CA-089392 to L.J.B., and P50 CA-84724 and K05 CA-139871 to T.B.B.); the National Institute on Drug Abuse (K02 DA-021237 to L.J.B.) and the National Human Genome Research Institute (U01 HG-004422 to L.J.B.). Funding support for genotyping, which was performed at the Center for Inherited Disease Research (CIDR), was provided by X01 HG005274-01. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200 782096C. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies (GENEVA) Coordinating Center (U01 HG004446). Funding support for collection of datasets and samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50 CA084724). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2014/1

Y1 - 2014/1

N2 - Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novelmechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.

AB - Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novelmechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.

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AN - SCOPUS:84895832391

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VL - 23

SP - 555

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JO - Human molecular genetics

JF - Human molecular genetics

IS - 2

ER -

Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms

Abstract

Bibliographical note

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