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1.  Mouthwash Use in General Population: Results from Adult Dental Health Survey in Grampian, Scotland 
ABSTRACT
Objectives
The purpose of this study was to determine the pattern of mouthwash use and to investigate the associated factors in general population.
Material and Methods
An Adult Dental Health Survey was conducted on 3,022 residents of Grampian region of Scotland (adjusted participation rate 58.2%). Participants received a questionnaire consisting of questions on oral health and behavioural factors.
Results
The majority of participants (38.1%) have never used mouthwash, 17.5% used mouthwash less than once a month, 19.4% used mouthwash once every few days and 25.1% used mouthwash daily.
Prevalence of use decreased with age (P < 0.001). Woman were more likely to use mouthwash than men (P = 0.004). Mouthwash use decreased with decrease in the level of deprivation (P < 0.001). Never-smokers were less likely to use mouthwash (40.3%) compared to smokers (53.1%) or those who stopped smoking (46.5%) (P < 0.001). Mouthwash was used by smaller proportion of people drinking alcohol on daily basis (36.6%), than by abstainers (42.2%) (P = 0.012).
There was a positive relationship between flossing or brushing pattern and mouthwash use (P < 0.001). There was statistically significant relationship between mouthwash use and reasons for the last dental visit (P = 0.009).
When compared to healthy individuals, mouthwash was used by higher proportion of people reporting that they had gum disease (P = 0.001), ulcers (P = 0.001), oral infections or swelling (P = 0.002) or other problems (P = 0.025).
Conclusions
Mouthwash use in general population is associated with socio-demographic, health and behavioural factors.
doi: 10.5037/jomr.2010.1402
PMCID: PMC3886070  PMID: 24421979
mouthwashes; oral hygiene; dental plaque; epidemiology; dental health survey; population groups.
2.  Systematic Review on the Incidence of Bisphosphonate Related Osteonecrosis of the Jaw in Children Diagnosed with Osteogenesis Imperfecta 
ABSTRACT
Objectives
To conduct a systematic review of epidemiological literature to determine the incidence of bisphosphonate related osteonecrosis of the jaw occurring either spontaneously or after dental surgery, in children and adolescents diagnosed with osteogenesis imperfecta.
Material and Methods
MEDLINE, HMIC and EMBASE were used to search for English-language articles published from 1946 - 2013. Inclusion criteria consisted of population based studies of children and adolescents (24 years and younger) diagnosed with osteogenesis imperfecta, only studies which included a dental examination, and patients treated with intravenous bisphosphonates were included. Articles were excluded if patients had any other co-morbidity which could affect osteonecrosis of the jaw, and those which treated patients with oral bisphosphonates only.
Results
Five studies consisting of four retrospective cohort studies and one case series were identified. Study populations ranged from 15 to 278 patients and number of subjects with osteogenesis imperfecta ranged from 15 to 221. Mean duration of intravenous bisphosphonate use ranged from 4.5 to 6.8 years. All patients were clinically examined and no patients were found to have osteonecrosis of the jaw.
Conclusions
There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta. More prospective studies on bisphosphonate use in osteogenesis imperfecta needs to be carried out.
doi:10.5037/jomr.2013.4401
PMCID: PMC3904727  PMID: 24478911
osteonecrosis; jaw; osteogenesis imperfecta; children; bisphosphonates.
3.  Patient perceptions regarding benefits of single visit scale and polish: a randomised controlled trial 
BMC Oral Health  2013;13:50.
Background
Single visit scale and polish is frequently carried out in dental practices however there is little evidence to support (or refute) its clinical effectiveness. The purpose of this research was to compare patient-reported outcomes between groups receiving a scale and polish at 6-, 12-, and 24-month intervals. Outcomes recorded included participants’ subjective assessment of their oral cleanliness; the perceived importance of scale and polish for oral health and aesthetics; and frequency at which this treatment is required.
Methods
A practice-based randomised control trial was undertaken, with a 24-month follow-up period. Participants were healthy adults with no significant periodontal disease (BPE codes <3) randomly allocated to three groups to receive scale and polish at 6-, 12-, or 24-month intervals. Patient-reported outcomes were recorded at baseline and follow-up. Oral cleanliness was reported using a 5-point scale and recorded by examiners blinded to trial group allocation. A self-completed questionnaire enabled participants to report perceived importance of scale and polish (5-point scale), and required frequency of treatment (6-point scale). The main hypothesis was that participants receiving 6-monthly scale and polish would report higher levels of oral cleanliness compared to participants receiving scale and polish at 12- and 24-month intervals.
Results
369 participants were randomised: 125 to the 6-month group; 122 to the 12-month group; and 122 to the 24-month group. Complete data set analysis was carried out to include 107 (6-month group), 100 (12-month group) and 100 (24-month group) participants. Multiple imputation analyses were conducted where follow-up data was missing. The difference in the proportions of participants reporting a 'high’ level of oral cleanliness at follow-up was significant (Chi-squared P = 0.003): 52.3% (6-month group), 47.0% (12-month group) and 30.0% (24-month group). Scale and polish was thought to be important by the majority in each group for keeping mouths clean and gums healthy, whitening teeth, and preventing bad breath and tooth decay; there were no statistically significant differences between groups at follow-up. Most participants at follow-up thought that the frequency of scale and polish should be “every 6 months” or more frequently: 77.9% (6-month group), 64.6% (12-month group), 71.7% (24-month group); differences between groups were not statistically significant (Chi squared P = 0.126). The results suggest that participants in the 24-month trial group were more likely to choose a scale and polish interval of “once a year” or less frequently (OR 2.89; 95% CI 1.36, 6.13).
Conclusions
The majority of healthy adults regarded 6-monthly single-visit scale and polish as being beneficial for their oral health. Receiving the treatment at different frequencies did not alter this belief; and those with the longest interval between scale and polish provision perceived that their mouth was less clean. In the absence of a strong evidence base to support (or refute) the effectiveness of single-visit scale and polish, the beliefs and preferences of patients regarding scale and polish may be influential drivers for maintaining provision of this treatment.
doi:10.1186/1472-6831-13-50
PMCID: PMC3851473  PMID: 24090395
Practice-based RCT; Routine scale and polish; Patient-reported outcomes
4.  Pharmacological and Other Interventions for Head and Neck Cancer Pain: a Systematic Review 
ABSTRACT
Objectives
Pain is a common complication in head and neck cancer. The aim of this paper is to evaluate the evidence from randomised control trials investigating pharmacological and non-pharmacological methods of pain management in head and neck cancer.
Material and Methods
Medline, Embase and the Cochrane library databases were searched. Squamous cell carcinomas of the head and neck excluding nasopharyngeal and salivary gland cancers were included. The limits were "human" and "randomised clinical trials". A quality assessment was carried out.
Results
13 studies were included with a total of 644 participants. The primary outcome for most of these papers was pain control post-treatment. Levels of bias varied between the studies. Majority (12 out of the 13 studies) reported intervention to be superior to the control or standard therapy in pain management. Only 46% of the studies were carried out on an intention to treat basis. Two studies reported high dropout rates, with one at 66%.
Conclusions
There is insufficient evidence from randomised clinical trials to suggest an optimal pharmacological intervention for head and neck cancer pain post-treatment. Further high quality randomised clinical trials should be conducted to develop an optimal management strategy for head and neck cancer pain.
doi:10.5037/jomr.2012.3401
PMCID: PMC3886097  PMID: 24422019
head and neck neoplasms; postoperative pain; opioid analgesics; pain measurement; systematic review.
5.  Can Alcohol Intake from Mouthwash be Measured in Epidemiological Studies? Development and Validation of Mouthwash Use Questionnaire with Particular Attention to Measuring Alcohol Intake from Mouthwash 
ABSTRACT
Objectives
The purpose of this study was to develop and validate the mouthwash use questionnaire to determine the lifetime exposure to alcohol from mouthwash and verify that it was suitable for use in general population.
Material and Methods
Data were available from three consecutive studies, all collecting information on mouthwash use. In addition, supermarkets and online stores were screened for the brands of mouthwash they sold. Alcohol content of mouthwash was identified from various sources, including laboratory measurements. Alcohol-containing mouthwash use was converted to glasses of wine equivalent.
Results
Mouthwash was used by 62% of the participants, and the main benefits reported were refreshment of bad breath (75%), elimination of bacteria (68%) and reduction of plaque formation (47%). Majority mouthwashes used by the participants contained alcohol (61%). Life-time exposure from alcohol in mouthwash was relatively small for most of the study participants: 79% had rinsed for less than one year with alcohol equivalent of one glass of wine per day. There was substantial agreement in mouthwash reporting between different occasions (Kappa > 0.62).
Conclusions
The questionnaire can be used to investigate mouthwash use in the general population and to measure alcohol intake from mouthwash.
doi:10.5037/jomr.2012.3301
PMCID: PMC3886086  PMID: 24422013
mouthwashes; oral health; oral cancer; alcohols; epidemiology; questionnaires.
6.  Head and Neck Cancer Pain: Systematic Review of Prevalence and Associated Factors 
ABSTRACT
Objectives
Pain is a major symptom in patients with cancer; however information on head and neck cancer related pain is limited. The aim of this review was to investigate the prevalence of pain and associated factors among patients with HNC.
Material and Methods
The systematic review used search of MEDLINE, EMBASE and CINAHL databases to December 2011. Cancers of the oral mucosa, oropharynx, hypopharynx and larynx were included in this review with pain as main outcome. The review was restricted to full research reports of observational studies published in English. A checklist was used to assess the quality of selected studies.
Results
There were 82 studies included in the review and most of them (84%) were conducted in the past ten years. Studies were relatively small, with a median of 80 patients (IQR 44, 154). The quality of reporting was variable. Most studies (77%) used self-administered quality of life questionnaires, where pain was a component of the overall scale. Only 33 studies reported pain prevalence in HNC patients (combined estimate from meta-analysis before (57%, 95% CI 43% - 70%) and after (42%, 95% CI 33% - 50%) treatment. Only 49 studies (60%) considered associated factors, mostly tumour- or treatment-related.
Conclusions
The study has shown high levels of pain prevalence and some factors associated with higher levels of pain. There is a need for higher quality studies in a priority area for the care of patients with head and neck cancer.
doi:10.5037/jomr.2012.3101
PMCID: PMC3886092  PMID: 24422003
cancer; head and neck cancer; pain; epidemiology; prevalence; review.
7.  Clinical outcomes of Single-Visit oral Prophylaxis: A practice-based randomised controlled trial 
BMC Oral Health  2011;11:35.
Background
Practice-based general dental practitioners routinely provide "scale and polish" or "oral prophylaxis" to patients attending their practices. Despite its routine provision, there is no evidence to support the clinical effectiveness of single-visit scale and polish, nor the frequency at which it should be provided. A recent systematic review recommended that future trials investigating scale and polish should involve dental practice patients.
Methods
A practice-based parallel randomised controlled trial with 24-month follow-up was conducted. Healthy adults (Basic Periodontal Examination [BPE] codes <3) were randomly assigned to 3 groups (6-month, 12-month, or 24-month interval between scale and polish). The primary outcome was gingival bleeding with the hypothesis that 6-monthly scale and polish would result in lower prevalence than 12-month or 24-month frequency. Follow-up measurements were recorded by examiners blinded to the allocation. 125, 122 and 122 participants were randomised to the 6-month, 12-month and 24-month groups respectively. Complete data set analyses were conducted for 307 participants: 107, 100, and 100 in the 6-month, 12-month and 24-month groups respectively. Chi-square test and ANOVA were used to compare treatment groups at follow-up. Logistic regression and ANCOVA were used to estimate the relationship between outcome and treatment group, adjusted for baseline values. Multiple imputation analyses were also carried out for participants with incomplete data sets.
Results
Prevalence of gingival bleeding at follow-up was 78.5% (6-month), 78% (12-month) and 82% (24-month) (p = 0.746). There were no statistically significant differences between groups with respect to follow-up prevalence of plaque and calculus. Statistically significant differences detected in the amount (millimetres) of calculus were too small to be clinically significant. Seventeen (4.6%) participants were withdrawn from the trial to receive additional treatment.
Conclusions
This trial could not identify any differences in outcomes for single-visit scale and polish provided at 6, 12 and 24 month frequencies for healthy patients (with no significant periodontal disease). However, this is the first trial of scale and polish which has been conducted in a general practice setting and the results are not conclusive. Larger trials with more comprehensive measurement and long-term follow up need to be undertaken to provide a firm evidence base for this intervention. This trial informs the design of future practice-based trials on this subject.
doi:10.1186/1472-6831-11-35
PMCID: PMC3280181  PMID: 22204658
8.  Sequence Variants and the Risk of Head and Neck Cancer: Pooled Analysis in the INHANCE Consortium 
Previous molecular epidemiological studies on head and neck cancer have examined various single nucleotide polymorphisms (SNPs), but there are very few documented associations. In the International head and neck cancer epidemiology (INHANCE) consortium, we evaluated associations between SNPs in the metabolism, cell cycle, and DNA repair pathways and the risk of head and neck cancer. We analyzed individual-level pooled data from 14 European, North American, Central American, and Asia case–control studies (5,915 head and neck cancer cases and 10,644 controls) participating in the INHANCE consortium. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for SNP effects, adjusting for age, sex, race, and country. We observed an association between head and neck cancer risk and MGMT Leu84Phe heterozygotes (OR = 0.79, 95% CI = 0.68–0.93), XRCC1 Arg194Trp homozygotes Arg/Arg (OR = 2.3, 95% CI = 1.1–4.7), ADH1B Arg48His homozygotes Arg/Arg (OR = 2.7, 95% CI = 1.9–4.0), ADH1C Ile350Val homozygotes Ile/Ile (OR = 1.2, 95% CI = 1.1–1.4), and the GSTM1 null genotype (OR = 1.1, 95% CI = 1.0–1.2). Among these results, MGMT Leu84Phe, ADH1B Arg48His, ADH1C Ile350Arg, and the GSTM1 null genotype had fairly low false positive report probabilities (<20%). We observed associations between ADH1B Arg48His, ADH1C Ile350Arg, and GSTM1 null genotype and head and neck cancer risk. No functional study currently supports the observed association for MGMT Leu84Phe, and the association with XRCC1 Arg194Trp may be a chance finding.
doi:10.3389/fonc.2011.00013
PMCID: PMC3356135  PMID: 22655231
SNP; head and neck cancer; INHANCE
9.  A methodology to establish a database to study gene environment interactions for childhood asthma 
Background
Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).
Methods
Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.
Results
To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.
Conclusions
It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.
doi:10.1186/1471-2288-10-107
PMCID: PMC3019209  PMID: 21134251
10.  Third Molar Removal and Orofacial Pain: a Population-Based Survey 
ABSTRACT
Objectives
The aim of the current study was to investigate whether there was a relationship between a history of third molar removal and the prevalence of orofacial pain in a sample of the general population.
Material and methods
A survey was conducted in South East Cheshire, United Kingdom (81% participation rate). Information was collected using postal questionnaires (n = 1510) and dental records (n = 809).
Results
Participants who reported third molar extractions were more likely to report orofacial pain (RR = 1.29; 95% confidence interval [CI] 1.01 - 1.65). Participants with a more recent history of extractions (< 8 years ago) as recorded in dental records were more likely to report orofacial pain compared to those who had all third molar present (RR = 1.91; 95% CI 1.10 - 3.32).
Conclusions
This research suggests that self-reported third molar removal is linked to self-reported orofacial pain, however evidence from one study is not sufficient to give an unequivocal answer.
doi:10.5037/jomr.2010.1304
PMCID: PMC3886054  PMID: 24421974
orofacial pain; third molar; wisdom tooth; tooth extraction; epidemiology.
11.  Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study 
Objective To see if the mortality risk among women who have used oral contraceptives differs from that of never users.
Design Prospective cohort study started in 1968 with mortality data supplied by participating general practitioners, National Health Service central registries, or both.
Setting 1400 general practices throughout the United Kingdom.
Participants 46 112 women observed for up to 39 years, resulting in 378 006 woman years of observation among never users of oral contraception and 819 175 among ever users.
Main outcome measures Directly standardised adjusted relative risks between never and ever users for all cause and cause specific mortality.
Results 1747 deaths occurred in never users of oral contraception and 2864 in ever users. Compared with never users, ever users of oral contraception had a significantly lower rate of death from any cause (adjusted relative risk 0.88, 95% confidence interval 0.82 to 0.93). They also had significantly lower rates of death from all cancers; large bowel/rectum, uterine body, and ovarian cancer; main gynaecological cancers combined; all circulatory disease; ischaemic heart disease; and all other diseases. They had higher rates of violent deaths. No association between overall mortality and duration of oral contraceptive use was observed, although some disease specific relations were apparent. An increased relative risk of death from any cause between ever users and never users was observed in women aged under 45 years who had stopped using oral contraceptives 5-9 years previously but not in those with more distant use. The estimated absolute reduction in all cause mortality among ever users of oral contraception was 52 per 100 000 woman years.
Conclusion Oral contraception was not associated with an increased long term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral contraception usage and background risk of disease.
doi:10.1136/bmj.c927
PMCID: PMC2837145  PMID: 20223876
12.  Using Prior Information from the Medical Literature in GWAS of Oral Cancer Identifies Novel Susceptibility Variant on Chromosome 4 - the AdAPT Method 
PLoS ONE  2012;7(5):e36888.
Background
Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS.
Methods
We developed a method that searches through PubMed abstracts for pre-assigned keywords and key concepts, and uses this information to assign prior probabilities of association for each single nucleotide polymorphism (SNP) with the phenotype of interest - the Adjusting Association Priors with Text (AdAPT) method. Association results from a GWAS can subsequently be ranked in the context of these priors using the Bayes False Discovery Probability (BFDP) framework. We initially tested AdAPT by comparing rankings of known susceptibility alleles in a previous lung cancer GWAS, and subsequently applied it in a two-phase GWAS of oral cancer.
Results
Known lung cancer susceptibility SNPs were consistently ranked higher by AdAPT BFDPs than by p-values. In the oral cancer GWAS, we sought to replicate the top five SNPs as ranked by AdAPT BFDPs, of which rs991316, located in the ADH gene region of 4q23, displayed a statistically significant association with oral cancer risk in the replication phase (per-rare-allele log additive p-value [ptrend] = 2.5×10−3). The combined OR for having one additional rare allele was 0.83 (95% CI: 0.76–0.90), and this association was independent of previously identified susceptibility SNPs that are associated with overall UADT cancer in this gene region. We also investigated if rs991316 was associated with other cancers of the upper aerodigestive tract (UADT), but no additional association signal was found.
Conclusion
This study highlights the potential utility of systematically incorporating prior knowledge from the medical literature in genome-wide analyses using the AdAPT methodology. AdAPT is available online (url: http://services.gate.ac.uk/lld/gwas/service/config).
doi:10.1371/journal.pone.0036888
PMCID: PMC3360735  PMID: 22662130
13.  A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers 
Background
Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35).
Methods
In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies.
Results
rs16969968 was again associated with UADT cancers in women (OR=1.21, 95% confidence interval(CI)=1.08–1.36, P=0.001) and a similar lack of observed effect in men (OR=1.02, 95%CI=0.95–1.09, P=0.66) (P-heterogeneity=0.01). In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR=1.22, 95%CI=1.12–1.34, P=7×10−6) but not males (OR=1.02, 95%CI=0.97–1.08, P=0.35) (P-heterogeneity=6×10−4). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P-heterogeneity=0.86).
Conclusions
This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.
Impact
Further research is warranted to elucidate the mechanisms underlying these observations.
doi:10.1158/1055-9965.EPI-10-1008
PMCID: PMC3070066  PMID: 21335511
genetic variants; 15q25; nicotinic acetylcholine receptor; upper aerodigestive tract cancers; cigarettes per day
14.  Correction: A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium 
McKay, James D. | Truong, Therese | Gaborieau, Valerie | Chabrier, Amelie | Chuang, Shu-Chun | Byrnes, Graham | Zaridze, David | Shangina, Oxana | Szeszenia-Dabrowska, Neonila | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Bucur, Alexandru | Bencko, Vladimir | Holcatova, Ivana | Janout, Vladimir | Foretova, Lenka | Lagiou, Pagona | Trichopoulos, Dimitrios | Benhamou, Simone | Bouchardy, Christine | Ahrens, Wolfgang | Merletti, Franco | Richiardi, Lorenzo | Talamini, Renato | Barzan, Luigi | Kjaerheim, Kristina | Macfarlane, Gary J. | Macfarlane, Tatiana V. | Simonato, Lorenzo | Canova, Cristina | Agudo, Antonio | Castellsagué, Xavier | Lowry, Ray | Conway, David I. | McKinney, Patricia A. | Healy, Claire M. | Toner, Mary E. | Znaor, Ariana | Curado, Maria Paula | Koifman, Sergio | Menezes, Ana | Wünsch-Filho, Victor | Neto, José Eluf | Garrote, Leticia Fernández | Boccia, Stefania | Cadoni, Gabriella | Arzani, Dario | Olshan, Andrew F. | Weissler, Mark C. | Funkhouser, William K. | Luo, Jingchun | Lubiński, Jan | Trubicka, Joanna | Lener, Marcin | Oszutowska, Dorota | Schwartz, Stephen M. | Chen, Chu | Fish, Sherianne | Doody, David R. | Muscat, Joshua E. | Lazarus, Philip | Gallagher, Carla J. | Chang, Shen-Chih | Zhang, Zuo-Feng | Wei, Qingyi | Sturgis, Erich M. | Wang, Li-E | Franceschi, Silvia | Herrero, Rolando | Kelsey, Karl T. | McClean, Michael D. | Marsit, Carmen J. | Nelson, Heather H. | Romkes, Marjorie | Buch, Shama | Nukui, Tomoko | Zhong, Shilong | Lacko, Martin | Manni, Johannes J. | Peters, Wilbert H. M. | Hung, Rayjean J. | McLaughlin, John | Vatten, Lars | Njølstad, Inger | Goodman, Gary E. | Field, John K. | Liloglou, Triantafillos | Vineis, Paolo | Clavel-Chapelon, Francoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | González, Carlos A. | Quirós, J. Ramón | Martínez, Carmen | Navarro, Carmen | Ardanaz, Eva | Larrañaga, Nerea | Khaw, Kay-Tee | Key, Timothy | Bueno-de-Mesquita, H. Bas | Peeters, Petra H. M. | Trichopoulou, Antonia | Linseisen, Jakob | Boeing, Heiner | Hallmans, Göran | Overvad, Kim | Tjønneland, Anne | Kumle, Merethe | Riboli, Elio | Välk, Kristjan | Voodern, Tõnu | Metspalu, Andres | Zelenika, Diana | Boland, Anne | Delepine, Marc | Foglio, Mario | Lechner, Doris | Blanché, Hélène | Gut, Ivo G. | Galan, Pilar | Heath, Simon | Hashibe, Mia | Hayes, Richard B. | Boffetta, Paolo | Lathrop, Mark | Brennan, Paul
PLoS Genetics  2011;7(4):10.1371/annotation/9952526f-2f1f-47f3-af0f-1a7cf6f0abc1.
doi:10.1371/annotation/9952526f-2f1f-47f3-af0f-1a7cf6f0abc1
PMCID: PMC3084181
15.  Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals 
Background Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.
Methods We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.
Results Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96–1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39–2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23–1.38, P = 1 × 10–18), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19–1.35, P = 5 × 10–13). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01–1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.
Conclusions This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.
doi:10.1093/ije/dyp288
PMCID: PMC2913450  PMID: 19776245
Lung cancer; nicotine dependence; smoking quantity; UADT cancer
16.  A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium 
McKay, James D. | Truong, Therese | Gaborieau, Valerie | Chabrier, Amelie | Chuang, Shu-Chun | Byrnes, Graham | Zaridze, David | Shangina, Oxana | Szeszenia-Dabrowska, Neonila | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Bucur, Alexandru | Bencko, Vladimir | Holcatova, Ivana | Janout, Vladimir | Foretova, Lenka | Lagiou, Pagona | Trichopoulos, Dimitrios | Benhamou, Simone | Bouchardy, Christine | Ahrens, Wolfgang | Merletti, Franco | Richiardi, Lorenzo | Talamini, Renato | Barzan, Luigi | Kjaerheim, Kristina | Macfarlane, Gary J. | Macfarlane, Tatiana V. | Simonato, Lorenzo | Canova, Cristina | Agudo, Antonio | Castellsagué, Xavier | Lowry, Ray | Conway, David I. | McKinney, Patricia A. | Healy, Claire M. | Toner, Mary E. | Znaor, Ariana | Curado, Maria Paula | Koifman, Sergio | Menezes, Ana | Wünsch-Filho, Victor | Neto, José Eluf | Garrote, Leticia Fernández | Boccia, Stefania | Cadoni, Gabriella | Arzani, Dario | Olshan, Andrew F. | Weissler, Mark C. | Funkhouser, William K. | Luo, Jingchun | Lubiński, Jan | Trubicka, Joanna | Lener, Marcin | Oszutowska, Dorota | Schwartz, Stephen M. | Chen, Chu | Fish, Sherianne | Doody, David R. | Muscat, Joshua E. | Lazarus, Philip | Gallagher, Carla J. | Chang, Shen-Chih | Zhang, Zuo-Feng | Wei, Qingyi | Sturgis, Erich M. | Wang, Li-E | Franceschi, Silvia | Herrero, Rolando | Kelsey, Karl T. | McClean, Michael D. | Marsit, Carmen J. | Nelson, Heather H. | Romkes, Marjorie | Buch, Shama | Nukui, Tomoko | Zhong, Shilong | Lacko, Martin | Manni, Johannes J. | Peters, Wilbert H. M. | Hung, Rayjean J. | McLaughlin, John | Vatten, Lars | Njølstad, Inger | Goodman, Gary E. | Field, John K. | Liloglou, Triantafillos | Vineis, Paolo | Clavel-Chapelon, Francoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | González, Carlos A. | Quirós, J. Ramón | Martínez, Carmen | Navarro, Carmen | Ardanaz, Eva | Larrañaga, Nerea | Khaw, Kay-Tee | Key, Timothy | Bueno-de-Mesquita, H. Bas | Peeters, Petra H. M. | Trichopoulou, Antonia | Linseisen, Jakob | Boeing, Heiner | Hallmans, Göran | Overvad, Kim | Tjønneland, Anne | Kumle, Merethe | Riboli, Elio | Välk, Kristjan | Voodern, Tõnu | Metspalu, Andres | Zelenika, Diana | Boland, Anne | Delepine, Marc | Foglio, Mario | Lechner, Doris | Blanché, Hélène | Gut, Ivo G. | Galan, Pilar | Heath, Simon | Hashibe, Mia | Hayes, Richard B. | Boffetta, Paolo | Lathrop, Mark | Brennan, Paul | Horwitz, Marshall S.
PLoS Genetics  2011;7(3):e1001333.
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
Author Summary
We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.
doi:10.1371/journal.pgen.1001333
PMCID: PMC3060072  PMID: 21437268

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