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Göteborgs universitets publikationer

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Författare och institution:
T. E. Thorgeirsson (-); S. Steinberg (-); G. W. Reginsson (-); G. Bjornsdottir (-); T. Rafnar (-); I. Jonsdottir (-); A. Helgadottir (-); S. Gretarsdottir (-); H. Helgadottir (-); S. Jonsson (-); S. E. Matthiasson (-); T. Gislason (-); T. Tyrfingsson (-); T. Gudbjartsson (-); H. J. Isaksson (-); H. Hardardottir (-); A. Sigvaldason (-); L. A. Kiemeney (-); A. Haugen (-); S. Zienolddiny (-); H. J. Wolf (-); W. A. Franklin (-); A. Panadero (-); J. I. Mayordomo (-); I. P. Hall (-); E. Ronmark (-); Bo Lundbäck (Krefting Research Centre); A. Dirksen (-); H. Ashraf (-); J. H. Pedersen (-); G. Masson (-); P. Sulem (-); U. Thorsteinsdottir (-); D. F. Gudbjartsson (-); K. Stefansson (-)
Publicerad i:
Molecular Psychiatry, 21 ( 5 ) s. 594-600
ISSN:
1359-4184
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
NATURVETENSKAP ->
Biologiska vetenskaper ->
Biokemi och molekylärbiologi
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Neurovetenskaper
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin ->
Neurologi
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin ->
Psykiatri
Nyckelord:
nicotinic acetylcholine-receptors, genome-wide association, lung-cancer, pharmacological chaperone, susceptibility locus, sequence variants, fagerstrom test, heavy smoking, dependence, smokers, Biochemistry & Molecular Biology, Neurosciences & Neurology, Psychiatry
Postens nummer:
236906
Posten skapad:
2016-05-25 14:18
Posten ändrad:
2016-05-25 14:18

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