Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking

CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.     

Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking

Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28相似文献   

Associations between Variation in CHRNA5-CHRNA3-CHRNB4, Body Mass Index and Blood Pressure in the Northern Finland Birth Cohort 1966

Background

The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation.

Methodology/Principal Findings

We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by −1.21 (95% CI −2.01, −0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of −0.38 (−0.68, −0.08) kg/m² per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing.

Conclusions

Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.     

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.     

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.     

Combined effect between CHRNB3–CHRNA6 region gene variant (rs6474412) and smoking in psoriasis vulgaris severity

Background

Many factors associated with causing psoriasis have been reported, such as the genetic and environmental factors. Smoking is one of the well-established environmental risk factors for psoriasis and also associated with the disease severity. In addition, several studies of psoriasis and psoriatic arthritis have documented gene–environment interactions involving smoking behavior. Although gene polymorphisms on nicotinic acetylcholine receptor subunits CHRNB3–CHRNA6 region gene have been found to correlate with smoking behavior and lung cancer susceptibility in Chinese Han population, the combined effect between the smoking-related genetic variants and smoking behavior on psoriasis vulgaris (PV) has been unreported.

Objective

To evaluate the combined effect of the smoking-related (rs6474412-C/T) polymorphism on CHRNB3–CHRNA6 region gene and smoking behavior on PV risk and clinic traits in Chinese Han population.

Methods

A hospital-based case–control study including 672 subjects (355 PV cases and 317 controls) was conducted. The variant of rs6474412 was typed by SNaPshot Multiplex Kit (Applied Biosystems Co., USA).

Results

The higher body mass index (BMI ≥ 25), smoking behavior and alcohol consumption were risk factors for PV, and the estimated ORs were 1.55 (95% CI, 1.09–2.29), 1.74 (95% CI, 1.22–2.49) and 1.81 (95% CI, 1.25–2.62) respectively. The smoking patients had more severe conditions than non-smokers (OR = 1.71, 95% CI, 1.08–2.70, P = 0.020). The alleles and genotypes of rs6474412 were not associated with risk of PV, but the combined effect of rs6474412 genotype (TT) and smoking behavior increased severity of PV (OR = 5.95; 95% CI, 1.39–25.31; P < 0.05; adjusted OR = 2.20; 95% CI, 1.55–3.14; P < 0.001).

Conclusions

Our results demonstrate that the combined effect of rs6474412-C/T polymorphism in smoking-related CHRNB3–CHRNA6 region gene and smoking behavior may not confer risk to PV, but may have impact on PV severity in Chinese Han population.     

The association of idiopathic recurrent pregnancy loss with polymorphisms in hemostasis-related genes

Recurrent pregnancy loss (RPL) is a complex, multifactorial condition. Inherited thrombophilia is the leading cause of thromboembolism and is associated with an increased risk of RPL. The aims of the current study were to investigate the effects of polymorphisms in hemostasis-related genes antithrombin (SERPINC1), thrombomodulin (THBD), tissue factor pathway inhibitor (TFPI), factor V, factor II and annexin A5 (ANXA5), involved in reproductive failure in 94 RPL cases with two or more consecutive pregnancy losses prior to 20 weeks of pregnancy and 169 healthy controls who had at least one term delivery and no history of pregnancy loss. The genotypes of SERPINC1 G786A, THBD C1418T, TFPI T-33C, factor V G1628A, factor II A19911G and ANXA5 G76A were assayed by the Sequenom MassARRAY system. Genotype and allele frequencies for SERPINC1 (rs2227589), TFPI (rs8176592), factor V (rs6020), factor II (rs3136516) and ANXA5 (rs113588187) in cases and controls were similar. The distribution of THBD C1418T allele showed significant differences between RPL cases and healthy controls (odds ratio (OR): 1.58, 95%, confidence interval (CI): 1.05–2.39, P = 0.027). In univariate logistic regression analyses, carriers of THBD 1418T allele (CT + TT) had an increased risk of RPL (OR: 1.83, 95%, CI: 1.10–3.06, P = 0.020). This indicated that THBD 1418T allele was associated with increasing the risk of RPL.     

Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.     

Association between microRNA-146a, -499a and -196a-2 SNPs and non-small cell lung cancer: a case–control study involving 2249 subjects

MicroRNA (miR) acts as a negative regulator of gene expression. Many literatures have suggested that miRs may be involved in the process of cell proliferation, inflammation, oxidative stress, energy metabolism and epithelial–mesenchymal transition. Thus, miRs may be implicated in the occurrence of non-small cell lung cancer (NSCLC). In the current investigation, we included 2249 subjects (1193 NSCLC patients and 1056 controls) and designed a study to identify the relationship of miR-146a rs2910164 C/G, -499a rs3746444 A/G and -196a-2 rs11614913 T/C with the risk of NSCLC. The risk factors (e.g., body mass index (BMI), sex, smoking, drinking and age) was used to adjust the odds ratios (ORs) and 95% confidence intervals (CIs). After conducting a power value assessment, we did not confirm that the miR-single nucleotide polymorphisms (SNPs) genotypic distributions were different in NSCLC cases and controls. However, the association of miR-196a-2 rs11614913 with a decreased risk of NSCLC was identified in the female subgroup (adjusted P=0.005, power = 0.809 for TC vs. TT, and adjusted P=0.004, power = 0.849 for CC/TC vs. TT). In addition, gene–gene interaction analysis showed that rs11614913 TC/3746444 AA and rs11614913 CC/rs3746444 AA could also reduce the susceptibility to NSCLC (rs11614913 TC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.001, power = 0.912 and rs11614913 CC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.003, power = 0.836). In conclusion, in overall comparisons, we did not confirm that the rs2910164, rs3746444, and rs11614913 SNPs genotypic distributions were different in NSCLC cases and controls. However, this case–control study demonstrates that miR-196a-2 rs11614913 may be a protective factor for the development of NSCLC among female patients.     

Association of CHRNA5-A3-B4 Variation with Esophageal Squamous Cell Carcinoma Risk and Smoking Behaviors in a Chinese Population

Background

CHRNA5-A3-B4, the gene cluster encoding nicotinic acetylcholine receptor subunits, is associated with lung cancer risk and smoking behaviors in people of European descent. Because cigarette smoking is also a major risk factor for esophageal squamous cell carcinoma (ESCC), we investigated the associations between variants in CHRNA5-A3-B4 and ESCC risk, as well as smoking behaviors, in a Chinese population.

Methods

A case-control study of 866 ESCC patients and 952 healthy controls was performed to study the association of polymorphisms (rs667282 and rs3743073) in CHRNA5-A3-B4 with cancer risk using logistic regression models. The relationships between CHRNA5-A3-B4 polymorphisms and smoking behaviors that can be quantified by cigarettes smoked per day (CPD) and pack-years of smoking were separately estimated with Kruskal-Wallis tests among all 840 smokers.

Results

CHRNA5-A3-B4 rs667282 TT/TG genotypes were associated with significantly increased risk of ESCC [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.03 – 1.69, P = 0.029]. The increased ESCC risk was even higher among younger subjects (≤60 years) (OR = 1.44, 95% CI = 1.04 – 1.98, P = 0.024). These effects were not found in another polymorphism rs3743073. No evident association between the two polymorphisms and smoking behaviors was observed.

Conclusions

These results support the hypothesis that CHRNA5-A3-B4 is a susceptibility gene cluster for ESCC. The relationship between CHRNA5-A3-B4 and smoking behaviors in a Chinese population needs further investigation.     

Chromosome 15q25 (CHRNA3-CHRNB4) Variation Indirectly Impacts Lung Cancer Risk in Chinese Males

Introduction

Recently, genome-wide association studies (GWAS) in Caucasian populations have identified an association between single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 nicotinic acetylcholine receptor subunit gene cluster on chromosome 15q25, lung cancer risk and smoking behaviors. However, these SNPs are rare in Asians, and there is currently no consensus on whether SNPs in CHRNA5-A3-B4 have a direct or indirect carcinogenic effect through smoking behaviors on lung cancer risk. Though some studies confirmed rs6495308 polymorphisms to be associated with smoking behaviors and lung cancer, no research was conducted in China. Using a case-control study, we decided to investigate the associations between CHRNA3 rs6495308, CHRNB4 rs11072768, smoking behaviors and lung cancer risk, as well as explore whether the two SNPs have a direct or indirect carcinogenic effect on lung cancer.

Methods

A total of 1025 males were interviewed using a structured questionnaire (204 male lung cancer patients and 821 healthy men) to acquire socio-demographic status and smoking behaviors. Venous blood samples were collected to measure rs6495308 and rs11072768 gene polymorphisms. All subjects were divided into 3 groups: non-smokers, light smokers (1–15 cigarettes per day) and heavy smokers (>15 cigarettes per day).

Results

Compared to wild genotype, rs6495308 and rs11072768 variant genotypes reported smoking more cigarettes per day and a higher pack-years of smoking (P<0.05). More importantly, among smokers, both rs6495308 CT/TT and rs11072768 GT/GG had a higher risk of lung cancer compared to wild genotype without adjusting for potential confounding factors (OR = 1.36, 95%CI = 1.09–1.95; OR = 1.11, 95%CI = 1.07–1.58 respectively). Furthermore, heavy smokers with rs6495308 or rs11072768 variant genotypes have a positive interactive effect on lung cancer after adjustment for potential confounding factors (OR = 1.13, 95%CI = 1.01–3.09; OR = 1.09, 95%CI = 1.01–3.41 respectively). However, No significant associations were found between lung cancer risk and both rs6495308 and rs11072768 genotypes among non-smokers and smokers after adjusting for age, occupation, and education.

Conclusion

This study confirmed both rs6495308 and rs11072768 gene polymorphisms association with smoking behaviors and had an indirect link between gene polymorphisms and lung cancer risk.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

Combinations of cytokine gene network polymorphic markers as potential predictors of myocardial infarction

With the intent to identify informative predictors of myocardial infarction (MI) development in an ethnically homogenous group of Russian men after MI (255 subjects) and in a corresponding control group (257 subjects), an analysis of genotype frequency distribution for polymorphic DNA markers (SNP) rs16944 (?511C>T, IL1B gene), rs1800796 (?572G>C, IL6 gene), rs1800872 (?592C>A, IL10 gene), rs3212227 (1159A>C, IL12B gene), rs1800629 (?308G>A, TNF), rs909253 (252A>G, LTA), rs767455 (36A>G, TNFRSF1A) was conducted. Using the Monte Carlo method and a Markov chain (APSampler), allele combinations associated both with decreased and increased MI risk were revealed. The most significant results were obtained for IL6*C/C (P = 3 × 10^?4, OR = 6.3 CI 2.37–16.75), LTA*A + IL6*G/G (FDR = 2.3 × 10^?4, OR = 0.25 CI 0.14–0.46), LTA*G/G + IL12B*A/A (FDR = 0.0053, OR = 4.92 CI 1.8–13.33), TNF*G + LTA*G/G + TNFRSF1A*A (FDR = 0.013, OR = 4.38, CI 1.6–12.01), TNFRSF1A*G + IL10*A/A + IL12B*C (FDR = 0.016, OR = 8.79, CI 2.17–35.63), TNF*G + LTA*G/G + IL10*C (FDR = 0.0105, OR = 3.54 CI 1.55–8.09).     

Association of Ghrelin Gene Polymorphisms and Serum Ghrelin Levels with the Risk of Hepatitis B Virus-Related Liver Diseases in a Chinese Population

Background

The functions of ghrelin (GHRL) include anti-inflammatory effects, reduction of the fibrogenic response, protection of liver tissue, and regulation of cell proliferation. Genetic variations in the GHRL gene may play an important role in the development of chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Therefore, we investigated whether GHRL gene polymorphisms and its serum levels are associated with hepatitis B virus (HBV)-related diseases risk in a Chinese population.

Methods

176 patients with CHB, 106 patients with HBV-related LC, 151 patients with HBV-related HCC, and 167 healthy controls were recruited in the study. Genotyping of GHRL rs26311, rs27647, rs696217, and rs34911341 polymorphisms were determined with the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing. The serum GHRL concentrations were determined using enzyme-linked immunosorbent assay (ELISA).

Results

Binary logistic regression analyses adjusting for gender and age revealed that a significant increased risk of LC was found in the GHRL rs26311 GC genotype and combined GC+CC genotypes when compared with the GG genotype (GC vs. GG: OR = 1.671, 95% CI = 1.013–2.757, P = 0.044; GC+CC vs. GG: OR = 1.674, 95% CI = 1.040–2.696, P = 0.034). In subgroup analysis by gender, binary logistic regression analyses adjusting for age showed that the GHRL rs26311 C allele and combined GC+CC genotypes were associated with a significantly increased risk to LC in males (C vs. G OR = 1.416, 95% CI = 1.017–1.972, P = 0.040; GC+CC vs. GG: OR = 1.729, 95% CI = 1.019–2.933, P = 0.042). In addition, we found significant decreased serum GHRL levels in LC patients compared with the healthy controls. However, there was no significant association of the GHRL rs26311 polymorphism with serum GHRL levels in LC patients.

Conclusions

These observations suggest that the GHRL rs26311 polymorphism is associated with an increased risk to HBV-related LC, especially in men. We also found an inverse association of serum GHRL levels with LC.     

人染色体8p11(CHRNB3-CHRNA6)区域基因多态性与中国汉族人群肺癌易感性的相关性

为探讨人染色体8p11(CHRNB3-CHRNA6)区域基因多态性与中国汉族人群肺癌遗传易感性之间的关系,文章采用病例-对照研究,对784例肺癌患者和782例性别、年龄、籍贯频数与之相匹配的健康对照中该区域6个标签SNP位点进行基因分型,并统计分析其基因型频率分布与肺癌易感性的关系,以及吸烟在其中的影响。结果发现rs16891561位点TT基因型在60岁以上人群(校正OR=0.42,95%CI=0.20-0.88;P=0.022)、女性人群(校正OR=0.34,95%CI=0.13-0.87;P=0.025)、非吸烟人群中(校正OR=0.32,95%CI=0.13-0.79;P=0.013)对肺癌发生具有保护效应;rs4236926位点TT基因型在60岁以上人群(校正OR=0.48,95%CI=0.23-0.99;P=0.048)、非吸烟人群(校正OR=0.32,95%CI=0.13-0.80;P=0.014)中对肺癌发生具有保护效应,这两种保护效应主要是与腺癌相关。对这两个位点进行累积效应分析发现,含有3~4个变异等位基因型的非吸烟者罹患肺癌的风险显著降低(校正OR=0.29,95%CI=0.11-0.71;P=0.007),并且,含有3~4个变异等位基因型的个体累计吸烟量("包-年"平均数=13.2)与其他个体相比显著降低。由此可见人染色体8p11(CHRNB3-CHRNA6)区域基因多态性与中国汉族人群肺癌易感性和吸烟行为相关。     

Polymorphisms in <Emphasis Type="Italic">VEGF-A</Emphasis> are associated with COPD risk in the Chinese population from Hainan province

In this study, we examined and validated how common variants contribute to susceptibility to chronic obstructive pulmonary disease (COPD) in the Han Chinese population. Here, we genotyped 18 nucleotide polymorphisms and evaluated their association with COPD using chi-square test and genetic model analysis (246 COPD patients and 350 controls), and found three SNPs that might cause a predisposition to COPD. Both rs3025030 and rs3025033 are located on chromosome 6 in VEGF-A. We found one risk allele ‘C’ from rs3025030 and another ‘G’ from rs3025033 using the log-additive model (OR 1.40; 95% CI 1.05–5.96; P = 0.022), (OR 1.38; 95% CI 1.03–1.84; P = 0.03). We also found another risk allele ‘A’ of rs9296092 in gene region ZBTB9-BAK1 by the allele model (OR 2.63; 95% CI 1.27–5.45; P = 0.0078), (adjusted OR 3.53; 95% CI 1.12–11.11; P = 0.031). We found a risk haplotype ‘CG’ associated with the risk of COPD (OR 1.39; 95% CI 1.04–1.86; P=0.028). Our results when compared with previous studies showed significant association between VEGF-A polymorphism and COPD. We also identified rs9296092 as a risk factor for COPD.     

Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population

NBS1 plays important roles in maintaining genomic stability as a key DNA repair protein in the homologous recombination repair pathway and as a signal modifier in the intra-S phase checkpoint. We hypothesized that polymorphisms of NBS1 are associated with hepatic cancer (HCC) risk. The NBS1 rs1805794 C/G polymorphism has been frequently studied in some cancers with discordant results, but its association with HCC has not been investigated. Moreover, studies of the 3'UTR variant rs2735383 have not touched upon HCC. This study examined the contribution of these two polymorphisms to the risk of developing HCC in a Chinese population. NBS1 genotypes were determined in 865 HCC patients and 900 controls and the associations with risk of HCC were estimated by logistic regression. Compared with the rs1805794 GG genotype, the GC genotype had a significantly increased risk of HCC (adjusted odds ratios [OR]=1.41; 95% confidence interval [CI]=1.11-1.80), the CC carriers had a further increased risk of HCC (OR=2.27; 95% CI=1.68-3.14), and there was a trend for an allele dose effect on risk of HCC (p<0.001). Also, we found that the risk effect of rs1805794 CC+CG was more pronounced in HCC patients that drank (OR=2.28, 95% CI=1.55-3.29 for drinkers; OR=1.31, 95% CI=1.00-1.77 for nondrinkers). However, there was no significant difference in genotype frequencies of rs2735383 G/C site between cases and controls. These findings suggest that rs1805794 C/G polymorphism in NBS1 may be a genetic modifier for developing HCC.     

Fibroblast growth factor receptor 4 polymorphisms and coronary artery disease: a case control study

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in vascular system. FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to coronary artery disease (CAD) in the Chinese population. We identified three polymorphisms in the FGFR4 gene, rs351855G/A (Gly388Arg), rs145302848C/G and rs147603016G/A, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 658 CAD cases and 692 healthy controls. Results showed that frequencies of GA genotype, AA genotype and A allele in rs351855 (Gly388Arg) polymorphism were significantly lower in CAD patients than in controls [odds ratio (OR) = 0.79, 95 % confidence intervals (CI) 0.62-0.99, P = 0.042; OR = 0.58, 95 % CI 0.41-0.81, P = 0.002; and OR = 0.77, 95 % CI 0.66-0.90, P = 0.001, respectively]. The rs147603016GA genotype and A allele also showed lower numbers in CAD cases (OR = 0.58, 95 % CI 0.36-0.93, P = 0.025; and OR = 0.59, 95 % CI 0.40-0.95, P = 0.028). The rs145302848C/G polymorphism did not show any correlation with CAD. Haplotype analysis revealed that the prevalence of ACG haplotype (rs351855, rs145302848 and rs147603016) was significantly decreased in CAD patients (P = 0.002). Our data suggested that the FGFR4 rs351855G/A (Gly388Arg) and rs147603016G/A polymorphisms could act as protective factors against CAD in the Chinese population and indicated that a single gene polymorphism could have diverse functions in different diseases.     

Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia

Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000–2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29–0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17–4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08–0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08–0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.