Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men

PurposeTranslesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.MethodsWe evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case–control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.ResultsCarriers of the G allele of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR) = 0.62, 95% confidence interval (CI): 0.44–0.89), comparing with those carrying the C allele, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR = 0.47, 95% CI: 0.25–0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533–rs5744724) haplotype had decreased risk of lung cancer (OR = 0.69, 95% CI: 0.49–0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygote of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard radio (HR) 1.54 (95% CI: 1.12–2.12) and 1.44 (95% CI: 1.06–1.97) respectively.ConclusionsOur findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.     

Polymorphisms of CHRNA5-CHRNA3-CHRNB4 Gene Cluster and NSCLC Risk in Chinese Population

AIM: To explore the potential association between single-nucleotide polymorphisms (SNPs) and haplotypes of the CHRNA5-CHRNA3-CHRNB4 gene cluster and the non-small cell lung cancer (NSCLC) susceptibility in never-smoking Chinese. METHODS: A case-control study was conducted with 200 NSCLC patients and 200 healthy controls, matched on age and sex. Five SNPs distributed in CHRNA5-CHRNA3-CHRNB4 gene cluster were selected for genotyping. The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age. RESULTS: For CHRNA3 rs578776 status, data were available in 199 NSCLC patients and 199 controls. The G/G homozygote in CHRNB4 rs7178270 had a reduced risk of developing NSCLC (OR = 0.553; 95% CI = 0.309–0.989; P = .0437), especially squamous cell carcinoma (SQC) (OR = 0.344; 95% CI = 0.161–0.732; P = .0043), compared with those who carry at least one C allele (C/C and C/G). The polymorphisms of rs578776, rs938682, rs17486278, and rs11637635 were not significantly different between controls and cases or between controls and histologic subgroups, adenocarcinoma and SQC, respectively. CONCLUSIONS: In our study, we found that the SNP of CHRNB4 rs7178270 is significantly associated with reduced risk of NSCLC, especially with reduced risk of SQC in never-smoking Chinese population.     

CYP3A4 genetic variants are associated with susceptibility of non-small cell lung cancer in a Shaanxi Han population

PurposeLung cancer (LC) is one of the fastest-growing malignant tumors in the world in terms of morbidity and mortality. CYP3A4 plays a crucial role in the occurrence of LC. Little is known about the contribution of CYP3A4 polymorphisms for non-small cell lung cancer (NSCLC) risk. This study aimed to explore the correlation of CYP3A4 genetic variants (rs3735451, rs4646440, rs35564277, and rs4646437) with NSCLC risk.MethodsFour single nucleotide polymorphisms (SNPs) were genotyped by Agena MassARRAY in this case-control study (507 NSCLC patients and 505 controls) among a Shaanxi Han population. Hardy-Weinberg equilibrium (HWE) of each SNP in controls was evaluated by exact test. The association of CYP3A4 polymorphisms with NSCLC risk was explored by calculating odds ratios (OR) and 95% confidence intervals (CI) using logistic regression analysis with adjustment for age and gender.ResultsOur research revealed that rs4646440 was significantly associated with an increased risk of NSCLC (OR 2.64, p = .005), while rs4646437 played a protective role in NSCLC risk (OR 0.48, p = 4.00 × 10⁻⁷). Stratified analyses indicated that rs4646440 significantly enhanced the susceptibility of NSCLC in BMI > 24 kg/m², non-smokers and non-drinkers (OR 14.29, p = .012; OR 1.56, p = .023; OR 1.67, p = .031, respectively). Besides, we observed that rs3735451 exhibited an increased risk of NSCLC in BMI > 24 kg/m² (OR 2.47, p = .030), whereas rs4646437 had a reduced risk of NSCLC in BMI ≤ 24 kg/m² (OR 0.47, p = 5.17 × 10⁻⁵). We also found that rs35564277 was considered as a protective factor of NSCLC in non-smokers (OR 0.50, p = .032).ConclusionOur study indicated that CYP3A4 genetic variants were associated with NSCLC susceptibility in a Shaanxi Han population.     

Vitamin D receptor polymorphism and colorectal cancer-specific and all-cause mortality

BackgroundThe vitamin D receptor (VDR) gene is present in colorectal cancer (CRC) cells and its genetic variants have been associated with an increased risk of CRC. The association with colorectal cancer prognosis remains widely unexplored.Methods1397 colorectal cancer patients participating in two cancer cohorts (ESTHER II and VERDI) and in a population-based case–control study (DACHS) were followed for 5 years. Unadjusted and adjusted hazard ratios for all-cause mortality (469 events) and CRC-specific mortality (336 events) were estimated for VDR variants rs731236 (TaqI), rs2228570 (FokI), rs11568820 (Cdx2), and rs1989969 (VDR-5132).ResultsNo association was found between VDR polymorphism and CRC specific and all-cause mortality. Adjusted hazard ratios ranged from 0.79 (95% CI 0.57–1.12) to 1.14 (95% CI 0.89–1.46) for CRC-specific mortality and from 0.89 (95% CI 0.67–1.18) to 1.22 (95% CI 0.99–1.50) for all-cause mortality. All 95% confidence intervals included the null value.ConclusionsOur findings do not support the hypothesis that the common VDR gene variants investigated in this study are of clinical relevance with respect to CRC prognosis.     

HapMap-based study identifies risk sub-region on chromosome 19q13.3 in relation to lung cancer among Chinese

Background: Chromosome 19q13.3 has been identified as one of the regions that associate with cancer risk in previous studies. Methods: We systematically examined the 70.772 kb region comprising four genes on chromosome 19q13.3 among Chinese using the haplotype-tagging SNP (htSNP) approach and the HapMap platform. The study involved 339 lung cancer cases and 358 non-cancer controls. Two htSNPs (rs1046282 and rs735482) captured most of the common haplotypes of CD3EA and the combined effects of sixteen htSNPs provided high coverage of common haplotypes of ERCC2, PPP1R13L, CD3EAP and ERCC1. Results: Both carriers of variant CC genotype [adjusted OR (95% CI) = 1.28 (1.02–1.60), P = 0.04] and variant C-allele among >20 years’ smokers [OR (95% CI) = 2.13 (1.24–3.67), P = 0.006] for CD3EAP rs735482 were at increased risk of lung cancer. Four haplotype blocks of strong linkage disequilibrium were identified. The haplotype ERCC2 rs3916874^G and rs238415^C [OR (95% CI) = 1.26 (1.02–1.57), P = 0.03] in block 1 and the haplotype PPP1R13L rs4803817^A, CD3EAP rs1046282^T, rs735482^C, ERCC1 rs3212980^A, rs3212964^G [OR (95% CI) = 3.56 (1.55–8.18), P = 0.005] in block 3 were associated with lung cancer risk. MDR (multifactor dimensionality reduction) analysis demonstrated the best significant model of two-attributes containing smoking duration and rs2298881 in ERCC1 (P = 0.004–0.005) and suggested that the effects of high-order interactions among smoking duration and ERCC2, PPP1R13, ERCC1 htSNPs could modulate lung cancer risk. Conclusions: HapMap-based study of 19q13.3 identified that genetic variation of CD3EAP and two loci were associated with lung cancer risk and interaction of smoking duration and genetic variants was the strongest predictor of lung cancer risk in a Chinese population.     

Genetic Variation in BCL2 3′-UTR Was Associated with Lung Cancer Risk and Prognosis in Male Chinese Population

Objectives

Bcl-2 is a critical apoptosis inhibitor with established carcinogenic potential, and can confer cancer cell resistance to therapeutic treatments by activating anti-apoptotic cellular defense. We hypothesized that genetic variants of BCL2 gene may be associated with lung cancer susceptibility and prognosis.

Methods

Three selected tagSNPs of BCL2 (rs2279115, rs1801018, and rs1564483) were genotyped in 1017 paired male Chinese lung cancer cases and controls by TaqMan assay. The associations of these variants with risk of lung cancer and overall survival of 242 male advanced non-small-cell lung cancer (NSCLC) patients were separately investigated.

Results

Compared with the BCL2 3′UTR rs1564483GG genotype, the rs1564483GA, AA, and GA+AA genotypes were associated with significantly decreased susceptibilities of lung cancer in male Chinese (adjusted OR = 0.78, 0.73, and 0.76, P = 0.016, 0.038, and 0.007, respectively), while rs1564483A allele has a inverse dose-response relationship with lung cancer risk (P _trend = 0.010). These effects were more evident in the elders, smokers, and subjects without family history of cancer (P _trend = 0.017, 0.043 and 0.005, respectively). Furthermore, advanced NSCLC males carrying BCL2 rs1564483 GA+AA genotypes had significantly longer median survival time (Long-rank P = 0.036) and decreased death risk (adjusted HR = 0.69, P = 0.027) than patients with rs1564483GG genotype. These effects were more obvious in patients with smoking, stage IIIA, and in patients without surgery but underwent chemotherapy or radiotherapy (adjusted HR = 0.68, 0.49, 0.67, 0.69, 0.50, respectively, all P<0.05).

Conclusion

The BCL2 3′UTR rs1564483A allele was associated with a decreased lung cancer risk and better survival for advanced NSCLC in male Chinese, which may offer a novel biomarker for identifying high-risk population and predicting clinical outcomes.     

REV3L,a Promising Target in Regulating the Chemosensitivity of Cervical Cancer Cells

REV3L, the catalytic subunit of DNA Polymerase ζ (Polζ), plays a significant role in the DNA damage tolerance mechanism of translesion synthesis (TLS). The role of REV3L in chemosensitivity of cervical cancer needs exploration. In the present study, we evaluated the expression of the Polζ protein in paraffin-embedded tissues using immunohistochemistry and found that the expression of Polζ in cervical cancer tissues was higher than that in normal tissues. We then established some cervical cancer cell lines with REV3L suppression or overexpression. Depletion of REV3L suppresses cell proliferation and colony formation of cervical cancer cells through G₁ arrest, and REV3L promotes cell proliferation and colony formation of cervical cancer cells by promoting G₁ phase to S phase transition. The suppression of REV3L expression enhanced the sensitivity of cervical cancer cells to cisplatin, and the overexpression of REV3L conferred resistance to cisplatin as evidenced by the alteration of apoptosis rates, and significantly expression level changes of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax). Our data suggest that REV3L plays an important role in regulating cervical cancer cellular response to cisplatin, and thus targeting REV3L may be a promising way to alter chemosensitivity in cervical cancer patients.     

Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk

Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10⁻¹⁰) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10⁻⁶) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10⁻⁵ and P = 5.65×10⁻³). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk.     

A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling

BackgroundThe classical protein tyrosine phosphatases (PTPs) have been widely reported to be associated with various human malignancies including colorectal cancer (CRC). However, there are few comprehensive analyses of the association between the classical PTP genes and CRC risk.MethodsFirst, a bioinformatics analysis was performed to identify missense variants within the classical PTP gene family. Second, exome-wide association data and an independent population study were conducted to evaluate effects of candidate variants on CRC risk. Finally, functional assays based on signaling pathways were applied to uncover the potential pathogenic mechanism.ResultsWe identified that PTPN12 rs3750050 G allele presented a 19% increase the risk of CRC, with an OR of 1.19 (95% CI = 1.09–1.30, P = 1.015×10⁻⁴) under an additive model in the combined analysis. Furthermore, biochemical assays illustrated that rs3750050 could impair the inhibitory effect of PTPN12 on Ras/MEK/ERK signaling by impeding SHC dephosphorylation, increase the expression of cyclin D1 and ultimately lead to aberrant cell proliferation, thus contributing to CRC pathogenesis.ConclusionOur study highlights that PTPN12 rs3750050 could increase CRC risk by modifying Ras/MEK/ERK signaling. This work provides a novel insight into the roles of genetic variants within PTP genes in the pathogenesis of CRC.     

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients. Further, we evaluated the potential associations of these genes with subsequent BM development. Lung cancer cell lines stably transfected with ATG16L1: rs2241880 (T300A) were established. Mouse models of brain metastasis were developed using cells transfected with ATG16L1–300T or ATG16L1–300A. ATG10: rs10036653 and ATG16L1: rs2241880 were significantly associated with a decreased risk of BM (respective hazard ratios [HRs]=0.596, 95% confidence interval [CI] 0.398–0.894, P = 0.012; and HR = 0. 655, 95% CI 0.438–0.978, P = 0.039, respectively). ATG12: rs26532 was significantly associated with an increased risk of BM (HR=1.644, 95% CI 1.049–2.576, P = 0.030). Invasion and migration assays indicated that transfection with ATG16L1–300T (vs. 300A) stimulated the migration of A549 cells. An in vivo metastasis assay revealed that transfection with ATG16L1–300T (vs. 300A) significantly increased brain metastasis. Our results indicate that genetic variations in autophagy-related genes can predict BM and that genome analysis would facilitate stratification of patients for BM prevention trials.     

NOD1 and NOD2 Genetic Variants in Association with Risk of Gastric Cancer and Its Precursors in a Chinese Population

BackgroundGenetic variants of nucleotide-binding oligomerization domain-containing protein (NOD) may influence the outcome of Helicobacter pylori (H. pylori) infection and gastric carcinogenesis. To explore genetic variants of NOD1 and NOD2 in association with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, China.MethodsTagSNPs of NOD1 and NOD2 were genotyped by Sequenom MASS array in 132 GCs, and 1,198 subjects with precancerous gastric lesions, and were correlated with evolution of gastric lesions in 766 subjects with follow-up data.ResultsAmong seven tagSNPs, NOD1 rs2709800 and NOD2 rs718226 were associated with gastric lesions. NOD1 rs2709800 TG genotype carriers had a decreased risk of intestinal metaplasia (IM, OR: 0.53; 95% CI: 0.31–0.92), while NOD2 rs718226 G allele (AG/GG) showed increased risks of dysplasia (DYS, OR: 2.96; 95% CI: 1.86–4.71) and GC (OR: 2.35; 95% CI: 1.24–4.46). Moreover, an additive interaction between rs718226 and H. pylori was found in DYS or GC with synergy index of 3.08 (95% CI: 1.38–6.87) or 3.99 (95% CI: 1.55–10.22), respectively. The follow-up data indicated that NOD2 rs2111235 C allele (OR: 0.52; 95% CI: 0.32–0.83) and rs7205423 G allele (OR: 0.56; 95% CI: 0.35–0.89) were associated with decreased risk of progression in H. pylori-infected subjects.ConclusionsNOD1 rs2709800, NOD2 rs718226, rs2111235, rs7205423 and interaction between rs718226 and H. pylori infection may be related to risk of gastric lesions.     

A Panel of Genetic Polymorphism for the Prediction of Prognosis in Patients with Early Stage Non-Small Cell Lung Cancer after Surgical Resection

Background

This study was conducted to investigate whether a panel of eight genetic polymorphisms can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection.

Materials and Methods

We selected eight single nucleotide polymorphisms (SNPs) which have been associated with the prognosis of lung cancer patients after surgery in our previous studies. A total of 814 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the eight SNPs with overall survival (OS) and disease-free survival (DFS) was analyzed.

Results

The eight SNPs (CD3EAP rs967591, TNFRSF10B rs1047266, AKT1 rs3803300, C3 rs2287845, HOMER2 rs1256428, GNB2L1 rs3756585, ADAMTSL3 rs11259927, and CD3D rs3181259) were significantly associated with OS and/or DFS. Combining those eight SNPs, we designed a prognostic index to predict the prognosis of patients. According to relative risk of death, a score value was assigned to each genotype of the SNPs. A worse prognosis corresponded to a higher score value, and the sum of score values of eight SNPs defined the prognostic index of a patient. When we categorized the patients into two groups based on the prognostic index, high risk group was significantly associated with worse OS and DFS compared to low risk group (aHR for OS = 2.21, 95% CI = 1.69–2.88, P = 8.0 x 10⁻⁹, and aHR for DFS = 1.58, 95% CI = 1.29–1.94, P = 1.0 x 10⁻⁵).

Conclusions

Prognostic index using eight genetic polymorphisms may be useful for the prognostication of patients with surgically resected NSCLC.     

Genetic Variants in Inflammation-Related Genes Are Associated with Radiation-Induced Toxicity Following Treatment for Non-Small Cell Lung Cancer

Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10–3.39), rs5275 (HR:1.58, 95% CI:1.09–2.27), and rs689470 (HR:3.38, 95% CI:1.09–10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31–0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14–7.63 and HR:3.23, 95% CI:1.03–10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events.     

The effect of CYP3A4 genetic variants on the susceptibility to chronic obstructive pulmonary disease in the Hainan Han population

PurposeGenetic polymorphisms act a crucial role in chronic obstructive pulmonary disease (COPD) progression. This study aimed to investigate the correlation between CYP3A4 variants and COPD risk.MethodsWe carried out a case-control study of 821 individuals (313 patients and 508 healthy subjects) to identify the correlation of CYP3A4 SNPs with COPD risk in the Hainan Han population. The association was evaluated by Odds ratios (OR) and 95% confidence intervals (CI).ResultsOur study showed that rs4646437 polymorphism was related to a significantly increased susceptibility to COPD (OR 1.45, 95% CI = 1.10–1.90, p = 0.008). Stratified analyses indicated that rs4646437 polymorphism was significantly related to an increased risk of COPD in males (OR 1.95, 95% CI = 1.19–3.20, p = 0.008). However, rs4646440 played a protective role in females (OR 0.54, 95% CI = 0.31–0.93, p = 0.024). Rs4646437 was found to significantly improve the risk of COPD in smokers (OR 1.67, 95% CI = 1.12–2.48, p = 0.011). While rs4646440 had a significantly lower susceptibility to COPD in non-smokers (OR 0.64, 95% CI = 0.45–0.90, p = 0.010). Haplotype analysis revealed that A_rs4646440T_rs35564277 haplotype of CYP3A4 was found to increase the risk of COPD in non-smokers (OR 1.71, 95% CI = 1.04–2.82, p = 0.034).ConclusionOur result gives a new understanding of the association between CYP3A4 gene and COPD in the Hainan Han population.     

Association of Genetic Markers in the BCL-2 Family of Apoptosis-Related Genes with Endometrial Cancer Risk in a Chinese Population

BackgroundIn vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies.ResultsSignificant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all). For SNPs rs17759659 and rs7243091 (minor allele for both: G), the associations were independent. The odds ratio was 1.27 (95% CI: 1.04–1.53) for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21–2.73) for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed.ConclusionGenetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women.     

Role of Nicotine Dependence on the Relationship between Variants in the Nicotinic Receptor Genes and Risk of Lung Adenocarcinoma

Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four ‘control’ genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10⁻¹⁰ and 1.1×10⁻¹⁰, respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.     

A novel major histocompatibility complex locus confers the risk of premature coronary artery disease in a Chinese Han population

Several novel loci have been proved to be associated with coronary artery disease and/or myocardial infarction risk by genome-wide association studies, however, the available coronary artery disease risk variants explain only a small proportion of the predicted genetic heritability of the disease. Recently, a novel coronary artery disease locus on chromosome 6p21.3 in the major histocompatibility complex was identified in an European population. We hereby investigated whether this single nucleotide polymorphisms (rs3869109) confers the risk of premature coronary artery disease in a Chinese Han population. A total of 422 patients were studied including 210 cases with coronary stenosis ≥50 % or previous myocardial infarction (male <55 years and female <65 years) and 212 controls without documented coronary artery disease. Ligase detection reaction was performed to detect rs3869109. The 3 genotypes AA, AG, and GG were present in rs3869109. There were significant differences between the control and premature coronary artery disease groups in the frequencies of the rs3869109 variants and alleles (all P < 0.05). The distribution of 3 genotypes and alleles at rs3869109 does not differ between women and men (all P > 0.05). There was a significant association between rs3869109 genotypes and the severity of premature coronary artery disease (P = 0.038). Multivariate logistic regression showed that carriers with AG and GG genotypes at rs3869109 have a higher risk of premature coronary artery disease than carriers of AA genotype (odds ratio [OR] 1.997, 95 % CI: 1.166–3.419, P = 0.012; OR 1.695, 95 % CI: 1.044–2.752, P = 0.033; respectively). Our results indicate that the rs3869109 variants are associated with premature coronary artery disease in a Chinese Han population, suggesting this genetic risk marker is useful in early coronary artery disease risk prediction.