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CLPTM1L Genetic Polymorphisms and Interaction with Smoking and Alcohol Drinking in Lung Cancer Risk a Case–Control Study in the Han Population from Northwest China

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CLPTM1L Genetic Polymorphisms and Interaction with Smoking and Alcohol Drinking in Lung Cancer Risk a Case–Control Study in the Han Population from Northwest China CLPTM1L Genetic Polymorphisms and Interaction With Smoking and Alcohol Drinking in Lung Cancer Risk A Case–Control Study in the Han Population From Northwest China Xiaojie Xun, MD, Huijuan Wang, PhD, Hua Yang, MD, Hong Wang, MD, Bo Wang, MD, Longli Kang, MD, PhD, Tianbo Jin, MD, PhD, and Chao Chen, PhD Abstract: Genetic variants of cleft lip and palate trans-membrane (Medicine 93(28):e289) 1-like (CLPTM1L) genes in the p15.33 region of chromosome 5 were previously identified to influence susceptibility to lung cancer. Abbreviations: CHB = Chinese Han Beijing, CIs = confidence We examined the association of single nucleotide polymorphisms intervals, CLPTM1L = cleft lip and palate trans-membrane 1 like, (SNPs) in CLPTM1L genes with lung cancer and explored their potential HWE = Hardy-Weinberg equilibrium, LAC = lung adenocarcinoma, effects on the relationship between environmental risk factors (smoking, LASC = lung adenosquamous carcinoma, LD = linkage drinking) and lung cancer in a Chinese Han population. disequilibrium, LOD = logarithm of the odds, LSCC = lung We genotyped 9 single nucleotide polymorphisms (SNPs) of squamous cell carcinoma, MAF = minor allele frequency, ORs = CLPTM1L in a case–control study with 228 lung cancer cases and odds ratios, SCLC = small-cell lung cancer, SNPs = single nucleotide 301 controls from northwest China. Odds ratios (ORs) and 95% polymorphisms. confidence intervals (CIs) were calculated by unconditional logistic regression. We identified that the minor alleles of rs451360, rs402710, and INTRODUCTION rs31484 in CLPTM1L were associated with a 0.52-fold, 0.76-fold, and s one of the most common malignant tumors, lung cancer 1 0.70-fold decreased risk of lung cancer in allelic model analysis, A causes the greatest number of cancer-related deaths . The respectively. In the genetic model analysis, we found rs402710 and incidence of lung cancer appears to result from a combination of rs401681 were associated with decreased lung cancer risk. Further factors, including genetic susceptibility of the individual and stratification analysis showed that rs380286 displayed a significantly risk factors in the environment. Lung cancer has the highest mortality rate, and it is the leading cause of cancer-related decreased lung cancer risk (OR ¼ 0.65, P ¼ 0.041) in the non-drinkers. 2,3 In addition, Haplotype ‘‘GTTATCTGT’’ was found to be associated deaths in urban China. Several genes at chromosomal locus 5p15.33, including with decreased lung cancer risk (OR ¼ 0.50, P ¼ 0.033). cleft lip and palate trans-membrane 1-like (CLPTM1L), were Our results verified that genetic variants of CLPTM1L contribute to found to be associated with lung cancer risk in recent genome- lung cancer susceptibility in the northwest Chinese Han population. Addi- wide association studies.4–8 CLPTM1L, also known as CRR9, tionally, we found that consumption of alcohol may interact with CLPT encodes an enzyme that may be associated with apoptosis.9 This M1L polymorphisms to contribute to overall lung cancer susceptibility. gene is expressed in cells of various tumor types, including lung tumor tissue, and is overexpressed in cisplatin-resistant Editor: Harry Burke. cell lines. Received: September 20, 2014; revised: October 28, 2014; accepted: October 29, 2014. In modern China, an increasing number of people have From the School of Life Sciences, Northwest University, Xi’an, China (XX, smoking and drinking habits. In the northwest China, drinking HJW, HY, TJ, CC); National Engineering Research Center for Miniaturized and smoking is very common. Previous studies have shown that DetectionSystems,Xi’an,China(HJW,HW,BW,TJ,CC);Key there are interactions between certain genes and environmental Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Tibet University for factors that increase the risk of lung cancer. But there are few Nationalities, Xianyang, Shaanxi, China (TJ, LK). studies reporting an interaction between CLPTM1L and Correspondence: Tianbo Jin, School of Life Sciences, Northwest environmental factors like drinking and smoking habits. There- University; National Engineering Research Center for Miniaturized fore, in this study, we aimed to determine the relationship Detection Systems; Key Laboratory of High Altitude Environment and CLPTM1L Genes Related to Diseases of Tibet Autonomous Region, School of between and lung cancer risk, as well as to explore Medicine, Tibet University for Nationalities, Mailbox: 386, #229 North the interaction between CLPTM1L and environmental factors. Taibai Road, Xi’an 710069, Shaanxi, China (e-mail: [email protected] Nine SNPs of CLPTM1L were genotyped to perform an associ- com), Chao Chen, School of Life Sciences, Northwest University; ation analysis in a case–control study of the northwest Chinese National Engineering Research Center for Miniaturized Detection Systems Mailbox: 386, #229 North Taibai Road, Xi’an 710069, Han population. Shaanxi, China (e-mail: [email protected]). Xiaojie Xun and Huijuan Wang Joint first authors. This work was supported by the National 863 High-Technology Research MATERIALS AND METHODS and Development Program (2012AA02A519). The authors have no conflicts of interest to report. Study Participants Copyright # 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. All patients and controls were members of the Han popu- This is an open access article distributed under the Creative Commons lation living in Xi’an city and nearby. The patients were Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recruited between January 2011 and February 2014 at the First ISSN: 0025-7974 Affiliated Hospital of the Medical College of Xi’an Jiaotong DOI: 10.1097/MD.0000000000000289 University. All patients were newly diagnosed with lung cancer Medicine Volume 93, Number 28, December 2014 www.md-journal.com | 1 Xun et al Medicine Volume 93, Number 28, December 2014 and were characterized histologically. None of the patients had smokers had at least 1 or more per day smoking and a period or previous history of other cancers, chemotherapy, or radiother- periods aggregated more than 6 months were defined as ever- apy. Patients who had comorbidity, such as diabetes mellitus, smokers; Never-smokers were defined as those who smoked hypertension, or any endocrine disorders were excluded. The less than 100 cigarettes in their lifetime (or before diagnosis for 301 controls were randomly selected from the individuals who cases) and former smokers as those who quit smoking at least received physical examination at First Affiliated Hospital 1 year before the time of the survey. The case information was during the same time period as the cases were recruited. The collected through consultation with treating physicians or by control group comprised unrelated healthy individuals who had review of medical charts. All of the participants signed informed no known medical illness or hereditary disorders and who were consent. The Human Research Committee of the First Affiliated not taking any medications. Control subjects were excluded if Hospital of Xi’an Jiaotong University and Northwest University they had <12 months of data before their index date or had miss for Approval of Research Involving Human Subjects approved information. Participants were chosen without restrictions of the use of human tissue in this study. age, gender, or disease stage. A total of 228 cases and 301 controls were included in the study. The basic characteristics of the participants (eg, gender, age, and pathology) are listed in Table 1. SNP Selection and Genotyping All 9 SNPs were previously published to be associated with lung cancer, with minor allele frequencies >5% in the HapMap Clinical Data and Demographic Information Chinese Han Beijing (CHB) population. The blood samples We used a standard epidemiological questionnaire to were collected into tubes containing ethylenediaminetetraacetic collect personal data through an in-person interview, including acid. After centrifugation, the samples were stored at À808C residential region, age, gender, smoking status, alcohol use, until analysis. DNAwas extracted from whole blood samples by education status, and family history of cancer. Patients were GoldMag-Mini Whole Blood Genomic DNA Purification Kit classified as alcohol drinkers if they consumed one or more (GoldMag Co. Ltd. Xi’an City, China) and DNA concentration drinks (Drinking alcohol intake calculated using standard units: was measured by NanoDrop 2000. The Multiplexed SNP one standard drink units ¼ 10 g of pure alcohol ¼ 0.5 two high MassEXTENDED assay was designed by Sequenom MassAR- spirits ¼ 1 two low spirits ¼ 355 mL beer ¼ 1.5 two wine ¼ 3 RAY Assay Design 3.0 Software.10 SNP genotyping was per- two wines.) per week, and as nondrinkers if they consumed less formed by Sequenom MassARRAY RS1000 using the standard than 1 drink per week or abstained from alcohol. All of the protocol.10 TABLE 1. General Characteristics of the Study Population Variables Cases N (%) Controls N (%) OR (95% CI) P value Age (years) Mean Æ SD 58.7 Æ 10 50.2 Æ 8.1 <0.001Ã 50 49 (21.5) 166 (55.1) 4.49 (3.04–6.63) <0.001y >50 179 (78.5) 135 (44.9) 60 126 (55.3) 270 (89.7) 7.05 (4.48–11.10) <0.001y >60 102 (44.7) 31 (10.3) 70 203 (89) 299 (99.3) 18.41 (4.31–78.59) <0.001y >70 25 (11) 2 (0.7) Sex Male 178 (78.1) 188 (62.5) 0.46 (0.32–0.69) <0.001y Female 50 (21.9) 113 (37.5) Smoking status smoking 165 (72.4) 91 (30.2) 5.82 (3.99–8.49) <0.001y nonsmoking 63 (27.6) 210 (69.8) Drinking status drinking 37 (16.2) 66 (21.9) 0.69 (0.44–1.08) 0.101y nondrinking 191 (83.8) 235 (78.1) Histology type SCLC 37 (16.2) LAC 73 (32) LSCC 80 (35.1) LASC 11 (4.8) Others 27 (32) Total 228 301 CI ¼ confidence interval; LAC ¼ lung adenocarcinoma; LASC ¼ lung adenosquamous carcinoma; LSCC ¼ lung squamous cell carcinoma; OR ¼ odds ratio; SCLC ¼ small-cell lung cancer.
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