| According to latest global cancer statistics,there were approximately 18.1 million new cancer cases and 9.6 million cancer deaths in 2018.About 2.1 million lung cancer cases were diagnosed(11.6% of the total cancer cases),and the number of lung cancerrelated death was 1.77 million(18.4% of the total cancer deaths).The incidence(17.1%)and mortality rates(21.7%)of lung cancer in China were much higher than the recent global statistics.The social and economic burden from the high morbidity and mortality of lung cancer prompts us to explore the risk factors,which is necessary to conduct primary prevention intervention.Genetic and environmental factors were regarded as the most familiar risk factors of lung cancer.The previous published genome-wide association study(GWAS)of lung cancer had reported the genetic locus on chromosome 5p15.33,6p21.3,and 15q25 were risk causal regions for lung cancer among Europeans and Americans.Since indoor activities occupy most of the time in human life,it is of great importance to explore the association of indoor air pollution(IAP)with health issues.The main chemical components of IAP induced by solid biomass fuels combustion and cooking oil fumes are polycyclic aromatic hydrocarbons(PAHs),particulate matter(PM),and nitrogen dioxide(NO2),which have been reported to be positively associated with lung cancer risk.Previous epidemiological studies mainly concerned about the adverse effect of solid fuel burning and cooking oil fumes on incident risk of lung cancer and most of them were case-control studies.There were few studies focusing on the interactive and combined effect of IAP,especially daily cooking duration,with genetic polymorphisms on lung cancer incidence.In the Dongfeng-Tongji(DFTJ)cohort study,a total of 38925 retired staffs from Dongfeng motor corporation(DMC)were recruited in 2013.Their baseline demographic characteristics,lifestyles,and cooking related data at baseline were gathered from the standardized questionnaire that were performed face to face by welltrained investigators.The anthropometric data,such as weight and height,were measured by trained examiners.The confirmation of new incident lung cancers and diagnosis date were based on medical insurance records and death registry from the health-care system of DMC and local centers for disease control(CDC).Among these participants,5178 subjects were genotyped by using the Illumina Infinium Omni Zhong Hua-8 Bead Chip.We aimed to evaluate the effects of daily cooking duration and their combine effects with genetic polymorphisms on lung cancer incidence in this prospective study.The study contains the following two parts:Part I Association between daily cooking duration and incident risk of lung cancer: results from a prospective cohort studyObjective: Since indoor activities occupy most of the time in human life,it is of great importance to explore the association of indoor air pollution(IAP)with health issues.IAP induced by indoor solid fuels burning and cooking oil fumes had been proved to be a risk factor for lung cancer,but fewer longitudinal studies concerned about the effects of daily cooking duration.People are more likely to expose to indoor cooking oil fumes or solid fuels combustion with longer daily cooking duration.In this study,we conducted a prospective cohort study to investigate the association between daily cooking duration and incident risk of lung cancer.Methods: We recruited 38295 retired staffs from Dongfeng motor corporation(DMC)in 2013.Of these subjects,who had previous history of cancer(n = 2194),had missing(n = 448)or outlier information of cooking(n = 96,including 9 with cooking time ? 10 hours per day,69 with housework time ? 10 hours per day,and 18 with cooking frequency ? 5 per day)were excluded.Additionally,until the end of 2016,the new incident cases with the other cancer types except lung cancer were also excluded(n = 1689).Finally,the left 33868 employees were included in the further analysis.The baseline demographic characteristics of age,gender,marital status and education level;the lifestyles such as regular physical exercise,tobacco smoking status,alcohol drinking status,medical history of benign lung diseases,family history of cancer and daily household work duration;and the information of cooking related exposure data such as daily cooking duration,per capita house area,and resident floor were gathered from the standardized questionnaire.The BMI is defined as the body mass divided by the square of height.The participants were classified into not cooking subjects and daily cooking subjects.According to the daily cooking duration,we further classified the daily cooking subjects into 3 subgroups: daily cooking with ? 1 hour,> 1 h and ? 2 hours,and > 2 hours per day(h/day).The confirmation of new incident lung cancers and diagnosis date were based on medical insurance records and death registry from the health-care system of DMC and local CDC.Among all 33868 participants,261 new incident lung cancer cases were identified until the end of 2016.We used multivariable Cox regression model to evaluate the association of daily cooking duration with lung cancer incidence and calculated the hazard ratio(HR)and their 95% confidence interval(95%CI),with adjustment for age(continuous variable),gender(male,female),marital status(married and unmarried/separated/divorced/widowed),education level(high school and above,middle school,and primary school),smoking status(never,ever),alcohol drinking status(never,ever),regular exercise status(yes,no),BMI(< 24 kg/m2,? 24 kg/m2),family history of cancer(yes,no),the benign lung disease history(yes,no),per capita housing area(including ? 25.68m2,(25.68,33.50)m2,(33.50,40.50)m2 and > 40.50m2),daily housework duration(? 1 h/day,1-2 h/day and > 2 h/day),and resident floor(continuous variable).Results: Compared with subjects without cooking,subjects with daily cooking duration >2 h/day had a significantly higher risk of lung cancer [HR(95%CI)= 2.05(1.20,3.53),Ptrend = 0.011].Particularly,the above association was greatly enhanced among non-smokers [HR(95%CI)= 3.15(1.28,7.77),Ptrend = 0.002] and non-alcohol drinkers [HR(95%CI)= 3.36(1.57,7.19),Ptrend = 0.003].However,the above associations were not significant among ever smokers and ever alcohol drinkers.Besides,when we cross-classified all participants by dichotomous smoking and alcohol drinking status,we found that the association of daily cooking duration > 2h/day with lung cancer incidence was largely enhanced among subjects neither smoking nor alcohol drinking [HR(95%CI)= 3.54(1.33,9.43),Ptrend = 0.005].Conclusion: Longer daily cooking duration was associated with increased risk of lung cancer,especially among non-smokers and non-alcohol drinkers with daily cooking duration > 2h/day.This study added new cohort study evidence that daily cooking duration,a new indicator of cooking related pollution exposure,was a potential risk factor for lung cancer.Part II The combined effects of daily cooking duration and genetic polymorphism on the incident risk of lung cancerObjective: Previous genome-wide association studies had reported many lung cancer associated SNPs,such as rs2736100 and rs2853677 in TERT(5p15.33)and rs2395185 in human leukocyte antigen-DRB9(HLA-DRB9)(6p21.32)].But few studies had explored their combined effects of IAP,especially daily cooking duration on lung cancer incidence.In the results of Part I,we found that daily cooking duration > 2 h/day was significantly associated with lung cancer incidence.In this part,we aimed to evaluate the associations between genetic polymorphisms and incident risk of lung cancer,and then to explore their combined effects with daily cooking duration on incident risk of lung cancer in the cohort study.Methods: Based on the 33868 participants included in Part 1,5178 subjects(including 209 incident lung cancer and 4969 control subjects)were genotyped by using the Illumina Infinium Omni Zhong Hua-8 Bead Chip.We identified 123 reported single nucleotide polymorphisms(SNPs)from the GWAS Catalog database(P < 5×10-8).Finally,15 SNPs with comparatively integrated genotyping data,minimum allele frequency(MAF)> 0.1,and Hardy Weinberg equilibrium(HWE)> 0.05 were selected to be tested in our study.We used the multivariable Cox regression models to evaluate the associations of 15 selected SNPs with lung cancer incidence,with adjustment for age,gender,marital status,education level,smoking status,alcohol drinking status,regular exercise status,BMI,family history of cancer,and the benign lung disease history.The combined effects of the positive SNPs with daily cooking duration were further explored on lung cancer incidence.Results: Fifteen lung cancer-related SNPs reported in GWAS were described as followings: rs10937405(3q28,TP63),rs2736100(5p15.33,TERT),rs2853677(5p15.33,TERT),rs4975616(5p15.33,CLPTM1L),rs31489(5p15.33,CLPTM1L),rs380286(5p15.33,CLPTM1L),rs3999544(6p22.2,HIST1H4H),rs149949(6p22.1, OR2B7P),rs2395185(6p21.32,HLA-DRB9),rs3817963(6p21.32,BTNL2),rs1056562(11q23.3,MPZL2),rs12296850(12q23.1,NR1H4),rs3813565(15q25.1,CHRNB4),rs8040868(15q25.1,CHRNA3)and rs7216064(17q24.2,BPTF).Individuals carrying rs3999544(6p22.2,HIST1H4H)TT genotypes had 2.81-fold increased risk of lung cancer compared with rs3999544 CC carriers.However,there was no significant effect of rs3999544 CT+TT on lung cancer incidence [HR(95%CI)= 0.88(0.60,1.28)].Two SNPs(rs2395185 and rs3817963)which both located at 6p21.3 were associated with lung cancer risk.Compared with the rs2395185 GG carriers,subjects carrying rs2395185 GT+TT genotypes had a 47% increased risk of lung cancer [HR(95%CI)= 1.47(1.08,2.01)].There was a significant combined effect between rs2395185 and daily cooking duration on lung cancer incidence [GT+TT& > 1 h/day vs.GG without cooking,adjusted HR(95%CI)= 2.36(1.01,5.51)].Compared with the rs3817963 TT genotype carriers,participants with rs3817963 TC+CC genotypes had a 1.34-fold increased risk of lung cancer [HR(95%CI)= 1.34(1.00,1.78)].There were significant combined effects between rs3817963 TC+CC genotype and daily cooking duration with > 1 h/day on lung cancer incidence [HR(95%CI)= 2.20(1.10,4.42)].Conclusions: We found significant associations of two SNPs rs2395185 and rs3817963 at 6p21.3 with higher risk of lung cancer.There were significant combined effects between these two variants and daily cooking duration on lung cancer incidence.These results could provide new epidemiological evidence for the combined effect of environment-gene on lung cancer incidence. |
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