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Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5. Hum Mol Genet 2009 Aug 15;18(16):3125-35

Date

05/16/2009

Pubmed ID

19443489

Pubmed Central ID

PMC2714722

DOI

10.1093/hmg/ddp231

Scopus ID

2-s2.0-68049090045   135 Citations

Abstract

Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.

Author List

Wang JC, Cruchaga C, Saccone NL, Bertelsen S, Liu P, Budde JP, Duan W, Fox L, Grucza RA, Kern J, Mayo K, Reyes O, Rice J, Saccone SF, Spiegel N, Steinbach JH, Stitzel JA, Anderson MW, You M, Stevens VL, Bierut LJ, Goate AM, COGEND collaborators and GELCC collaborators

Authors

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Yian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Amino Acid Substitution
Brain
Cohort Studies
Female
Gene Expression
Humans
Lung Neoplasms
Male
RNA, Messenger
Receptors, Nicotinic
Risk Factors
Tobacco Use Disorder
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d