Replication of results of genome-wide association studies on lung cancer susceptibility loci in a Korean population

Background and objective: Genome‐wide association studies (GWAS) have identified the three chromosomal regions, 5p15, 6p21 and 15q25, as being associated with lung cancer risk in European populations. This study was performed to confirm these associations in Korean patients with lung cancer. Methods: The genotypes at rs2736100, rs402710, rs401681 and rs31489 at 5p15, rs9295740 at 6p22, which is in extensive linkage disequilibrium with the 6p21 region, as well as rs2036534 and rs6495309 at 15q25, were determined in 1094 patients with lung cancer and 1100 healthy control subjects, who were frequency matched for age and gender. Results: The single‐nucleotide polymorphisms (SNP) at 5p15 (rs2736100, adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.03–1.67, P = 0.025; rs402710, aOR 0.82, 95% CI 0.69–0.98, P = 0.025; rs401681, aOR 0.82, 95% CI 0.69–0.98, P = 0.026) and at 15q25 (rs2036534, aOR 0.75, 95% CI 0.61–0.93, P = 0.01; rs6495309, aOR 0.81, 95% CI 0.65–1.00, P = 0.052) were significantly associated with lung cancer risk. The magnitude of the effect was similar to that reported in previous studies, and the association was in the same direction. The effect of SNP in the 5p15 region on the risk of lung cancer was significant only for adenocarcinoma. The two SNP in the 15q25 region were significantly associated with lung cancer risk in ever‐smokers and in patients with squamous‐cell carcinoma. However, there was no association between the SNP at 6p22 and lung cancer risk. Conclusions: The association between SNP in the 5p15 and 15q25 regions and the risk of lung cancer was confirmed in a Korean population.     

Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI‐EBI Catalog of published genome‐wide association studies

We conducted a hypothesis‐free cross‐trait analysis for waist‐to‐hip ratio adjusted for body mass index (WHR_adjBMI) loci derived through genome‐wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHR_adjBMI single‐nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross‐trait associations between WHR_adjBMI SNPs and other traits through the NHGRI‐EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHR_adjBMI SNPs. We found 160 WHR_adjBMI SNPs and 3675 proxy SNPs. Cross‐trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes‐related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross‐trait associations were found for triglycerides (n = 10), high‐density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHR_adjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHR_adjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.     

Tag single nucleotide polymorphisms of alcohol‐metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis

Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol‐metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital‐based case–control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age‐ and gender‐matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14–5.80] and 2.59 [1.79–3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21–113.29] and 70.08 [33.65–145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08–2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24–2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis.     

Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case‐cohort study

A number of single nucleotide polymorphisms (SNP) have been linked to higher risk of venous thromboembolism (VTE). We investigated the VTE risk associated with SNPs in the GP6 (rs1613662), SERPINC1 (rs2227589), F11 (rs2036914 and rs2289252), FGG (rs2066865), and F12 (rs1801020) genes. In F11, the CC genotype for rs2036914 and the CT and TT genotypes for rs2289252 were associated with a significantly higher VTE risk. A trend toward a thrombogenic effect was observed for the risk alleles of the GP6 and FGG SNPs. Risk estimates were unaffected by adjustments for blood type and F5 rs6025 (Factor V Leiden) mutation.     

Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy. A "New" BPD has been characterized in preterm infants that may begin in utero, and then progress post-natally, resulting in arrested lung development and alveolar hypoplasia. Foundations for this "New" BPD may be derived from pro-inflammatory genes including tumor necrosis factor-alpha (TNFalpha). The hypothesis of the current study is that single nucleotide polymorphisms (SNPs) of the pro-inflammatory TNFalpha gene place preterm infants at increased risk for BPD. Preterm infants (105 in number) with birthweights 相似文献   

Association of ADAM33 gene polymorphisms with asthma in a Chinese population

Background and Aim: Asthma is a very common disease involving genetic and environmental factors. A disintegrin and metalloproteinase 33 (ADAM33) has been one of the most exciting candidate genes for asthma since its first association with the disease in the white population. Recently, studies on the association of ADAM33 gene polymorphisms with the risk of asthma have been controversial. We therefore focused on testing the hypothesis that either single‐nucleotide polymorphisms (SNPs) of the ADAM33 gene may be associated with asthma risk. The aim of this study was to evaluate the potential relationship between polymorphisms of ADAM33 and asthma in a Han population in China. Methods: A case control study was conducted in a Han population of eastern Chinese population. A total of 329 asthma patients and a control group of 316 healthy volunteers were recruited for this study. Four polymorphic sites (F+1, S2, T2 and V4) were selected for genotyping. Genotypes were determined by the allele‐specific polymerase chain reaction with fluorescence melting curves and DNA sequencing method. Data were analysed using the chi‐squared test software. Results: Statistically significant differences in the distributions of the S2 site between patients and controls were observed (χ2 = 7.140, P < 0.05). Conclusion: These preliminary results suggest an association between ADAM33 polymorphisms S2 C/G and asthma in a Chinese Han population. The SNPs (F+1 C/T, T2 G/A and V4 C/G) of the ADAM33 gene may be the causal variants in asthma disease, but the strength of this evidence is limited by our small sample size. Please cite this paper as: Chi X, Wang L, Wang J, Li Q, Wang X, Wang J and Xiao W. Association of ADAM33 gene polymorphisms with asthma in a Chinese population. Clin Respir J 2013; 7: 16–20.     

Single nucleotide polymorphisms of the factor IX gene for linkage analysis in the southern Chinese population

Carrier detection and prenatal testing for haemophilia B in Oriental populations have been hampered by the lack of informative markers within the factor IX (FIX) gene. We detected a T/C nucleotide variation at nucleotide 32770 in the poly-A region of the FIX gene in the mother of a haemophilia B child. Analysis of 139 unrelated alleles revealed a heterozygosity rate of 0.193, thus offering an additional marker for linkage analysis. Together with two other polymorphic sites (5' MseI and 3' HhaI) found in Chinese and Thai populations, these polymorphisms were useful in 66% of the families studied.     

Genetic variants associated with predisposition to prostate cancer and potential clinical implications

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.     

A variant in microRNA-196a2 is not associated with susceptibility to and progression of colorectal cancer in Chinese

Background: MicroRNAs (miRNAs) are small non‐coding RNAs with regulatory functions as tumour suppressors and oncogenes. Although single nucleotide polymorphism (SNP) in miRNA regions have been reported to be rare and unlikely to be functionally important, recent evidence suggested that rs11614913 SNP in miR‐196a2 was associated with the susceptibility of lung cancer, breast cancer, congenital heart disease and shortened survival time of non‐small‐cell lung cancer. Aims: The aim of this study was to investigate the association between this genetic variant and the risk and/or progression of colorectal cancer (CRC). Methods: A total of 126 CRC patients and 407 healthy controls was periodically enrolled. DNA was extracted from blood specimens, and miR‐196a2 polymorphism was genotyped by polymerase chain reaction–ligation detection reaction (PCR–LDR). Results: Although the frequency of CC homozygotes or miR‐196a2C allele‐containing genotypes (CT and CC) was lower in CRC patients than in the healthy controls, no significant association between miR‐196a2 polymorphism and the risk of CRC was found. The frequency of the ‘C’ allele in CRC patients was also not significantly lower than in healthy controls. In a subsequent analysis of the association between this polymorphism and the progression of CRC, there was still no significant difference in both genotype and allelic frequency. Conclusions: Our results suggest that miR‐196a2 polymorphism is not associated with both an increased risk and progression of CRC in Chinese.     

Association of interleukin‐13 C‐1112T and G+2044A polymorphisms with asthma: A meta‐analysis

Background and objective: Polymorphisms in the IL13 gene have been reported to be associated with susceptibility to asthma. However, a number of studies have shown inconsistent results. A meta‐analysis was performed to investigate whether polymorphisms in the IL13 gene were associated with the risk of asthma. Methods: Searches were performed of the Medline and Chinese National Knowledge Infrastructure (CNKI) databases, covering all papers published up to 31 August 2010. A recently proposed logistic regression‐based method for meta‐analysis of case–control genetic association studies was used to analyse pooled data. All statistical analyses were performed using stata version 10.0 software. Results: The IL13 C‐1112T and G+2044A polymorphisms were investigated in 10 and 14 studies, respectively. The summary estimates suggested that both these polymorphisms were associated with susceptibility to asthma. Carriers of the IL13 ?1112T allele had a 38.9% increased risk of asthma compared with homozygotes (?1112CC) (odds ratio (OR) 1.389, 95% confidence interval (CI): 1.103–1.749). Carriers of the IL13+2044A allele had a 40.0% increased risk of asthma compared with homozygotes (+2044GG) (OR 1.400, 95% CI: 1.137–1.724). In a subgroup analysis by ethnicity, the IL13 ?1112T allele was associated with an increased risk of asthma among Caucasians (OR 1.629, 95% CI: 1.255–2.113) but not among Asians, and the IL13+2044A allele was associated with an increased risk of asthma among Asians (OR 1.436, 95% CI: 1.101–1.873) but not among Caucasians. Conclusions: This meta‐analysis indicated that the IL13 C‐1112T and G+2044A polymorphisms predispose to asthma. Further studies, including pooling of individual data to facilitate evaluation of gene–gene and gene–environment interactions between these IL13 gene polymorphisms and asthma susceptibility, are recommended.