TY - JOUR
T1 - Association between genetic variants on chromosome 15q25 locus and objective measures of Tobacco exposure
AU - Munafò, Marcus R.
AU - Timofeeva, Maria N.
AU - Morris, Richard W.
AU - Prieto-Merino, David
AU - Sattar, Naveed
AU - Brennan, Paul
AU - Johnstone, Elaine C.
AU - Relton, Caroline
AU - Johnson, Paul C.D.
AU - Walther, Donna
AU - Whincup, Peter H.
AU - Casas, Juan P.
AU - Uhl, George R.
AU - Vineis, Paolo
AU - Padmanabhan, Sandosh
AU - Jefferis, Barbara J.
AU - Amuzu, Antoinette
AU - Riboli, Elio
AU - Upton, Mark N.
AU - Aveyard, Paul
AU - Ebrahim, Shah
AU - Hingorani, Aroon D.
AU - Watt, Graham
AU - Palmer, Tom M.
AU - Timpson, Nicholas J.
AU - Bierut, L. J.
AU - Davey Smith, George
N1 - Funding Information:
The British Regional Heart Study (BRHS) is supported by the British Heart Foundation. The British Women’s Heart and Health Study (BWHHS) is commissioned by the Department of Health Policy Research Programme and the British Heart Foundation. The European Prospective Investigation into Cancer and Nutrition (EPIC) study has been supported by the Europe Against Cancer Program of the European Commission (SANCO); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra; the ISCIII Network RCESP, Spain; Cancer Research UK; Medical Research Council, UK; Hellenic Health Foundation; Stavros Niarchos Foundation; Greek Ministry of Health; Italian Association for Research on Cancer (AIRC); Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy; Compagnia di San Paolo; Ministero della Salute-Regione Toscana— Programma Integrato Oncologia; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Västerbotten, Sweden; Norwegian Cancer Society; Research Council of Norway; French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Générale de l’Education Nationale (MGEN), France; 3M Co, France; Gustave Roussy Institute (IGR), France; and General Councils of France. The Midspan study is supported by the Wellcome Trust and the National Health Service Cardiovascular Research and Development Programme. The Patch II and Patch in Practice studies were supported by a Cancer Research UK programme grant.
Funding Information:
Wellcome Trust project (086684 to MRM) and a postdoctoral International Agency for Research on Cancer fellowship (to MNT).
Funding Information:
MRM is a member of the UK Centre for Tobacco Control Studies, a UK Clinical Research Collaboration Public Health Research Centre of Excellence. Funding from the Economic and Social Research Council, the British Heart Foundation, Cancer Research UK, the Department of Health and the Medical Research Council, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.
PY - 2012/5/16
Y1 - 2012/5/16
N2 - Background Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. Methods We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. Results Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10-6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10-11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). Conclusions Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
AB - Background Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. Methods We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. Results Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10-6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10-11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). Conclusions Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
UR - http://www.scopus.com/inward/record.url?scp=84861325364&partnerID=8YFLogxK
U2 - 10.1093/jnci/djs191
DO - 10.1093/jnci/djs191
M3 - Review article
C2 - 22534784
AN - SCOPUS:84861325364
SN - 0027-8874
VL - 104
SP - 740
EP - 748
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 10
ER -