MiRNA-146a rs2910164 Confers a Susceptibility to Digestive System Cancer: A Meta-Analysis Involving 59,098 Subjects.

BACKGROUND: MicroRNA (miR)-146a might participate in the occurrence of malignant tumor. The aim of the current investigation was to evaluate the relationship of microRNA-146a (miR-146a) rs2910164 C > G locus to the development of digestive system cancer (DSC). METHODS: We retrieved publications from PubMed, China Biology Medicine and EMBASE databases up to August 29, 2019. Finally, 56 independent case-control studies with 59,098 participants were included. The strength of the relationship between rs2910164 locus and a risk of DSC was assessed. The power value was also calculated in this study. RESULTS: We identified a correlation of rs2910164 locus in miR-146a with DSC development in dominant model (P = .035; power value = 0.994). MiR-146a rs2910164 locus was also identified to be correlated with a risk of DSC in Asians (GG/CG vs. CC: P = .033; power value = 0.989). Sensitivity analysis revealed that any individual study could not alter the final decision. In our study, no significant bias was found among these included studies (P > .1). The results of heterogeneity analysis suggested that small sample size (<1000 subjects), colorectal carcinoma, Asians, gastric carcinoma, esophageal squamous cell carcinoma, hepatocellular cancer, hospital-based study and high-quality score (≥7.0) subgroups contributed the heterogeneity to our findings. Galbraith radial plot determined that eleven outliers contributed to the main heterogeneity. CONCLUSION: In summary, this meta-analysis highlights that rs2910164 locus might be implicated in the risk of DSC. More studies are, therefore, needed to confirm our results.

Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic-to-pulmonary shunt.

Recent studies indicated that osteopontin (OPN) was involved in the genesis and progression of pulmonary arterial hypertension (PAH); however, its role in congenital heart disease-associated PAH (CHD/PAH) remains unknown. Our results showed that OPN was increased in lungs and plasma of patients with Eisenmenger syndrome; moreover, OPN and αVß3-integrin expression levels were augmented in rat lungs exposed to systemic-to-pulmonary shunt. Cell culture assay demonstrated that distal pulmonary arterial smooth muscle cells (PASMCs) from rat lungs suffering from volume and pressure overload exhibited enhanced proliferation compared with those from healthy rats. Mechanical stretch (20% at 1 Hz) increased OPN expression and activated ERK1/2 and protein kinase B (Akt) signal pathway in distal PASMCs from healthy rats. Interestingly, OPN enhanced the proliferation and migration of PASMCs while blocking αVß3-integrin with neutralizing antibody LM609 or Arg-Gly-Asp peptidomimetic antagonist cyclo(Ala-Arg-Gly-Asp-3-aminomethylbenzoyl) (XJ735), rectified the proliferative and migratory effects of OPN, which were partially mediated via ERK1/2 and Akt signaling pathways. Furthermore, surgical correction of systemic-to-pulmonary shunt, particularly XJ735 supplementation after surgical correction of systemic-to-pulmonary shunt, significantly alleviated the pulmonary hypertensive status in terms of pulmonary hemodynamic indices, pulmonary vasculopathy, and right ventricular hypertrophy. In summary, OPN alteration in lungs exposed to systemic-to-pulmonary shunt exerts a deteriorative role in pulmonary vascular remodeling through modulating the proliferation and migration of PASMCs, at least in part, via ανß3-ERK1/2 and ανß3-Akt signaling pathways. Antagonizing OPN receptor ανß3-integrin accelerated the regression of pulmonary vasculopathy after surgical correction of systemic-to-pulmonary shunt, indicating a potential therapeutic strategy for patients with CHD/PAH.-Meng, L., Liu, X., Teng, X., Gu, H., Yuan, W., Meng, J., Li, J., Zheng, Z., Wei, Y., Hu, S. Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic-to-pulmonary shunt.

Natural variation in the promoter of rice calcineurin B-like protein10 (OsCBL10) affects flooding tolerance during seed germination among rice subspecies.

Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland (Up221, flooding-intolerant) and lowland (Low88, flooding-tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding-tolerant type (T-type) or a flooding-intolerant type (I-type). The OsCBL10 T-type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I-type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding-tolerant rice cultivars containing the OsCBL10 T-type promoter have shown lower Ca2+ flow and higher α-amylase activities in comparison to those in flooding-intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild-type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade.

Exome Array Analysis Identifies Variants in SPOCD1 and BTN3A2 That Affect Risk for Gastric Cancer.

BACKGROUND & AIMS: Several genetic variants have been associated with gastric cancer risk, although these account for only a fraction of cases of gastric cancer. We aimed to identify low-frequency and other genetic variants that determine gastric cancer susceptibility. METHODS: We performed exome array analysis of DNA in blood samples from 1113 patients with gastric cancer, collected at hospitals from 2006 to 2010 in China, and 1848 individuals without cancer (controls) undergoing physical examinations. Among 71,290 variants analyzed (including 25,784 common variants), 24 variants were selected and replicated in an analysis of DNA in blood samples from 4687 additional cases of gastric cancer and 5780 controls. We compared expression of candidate genes in tumor vs normal gastric tissues using data from TCGA and performed functional annotation analyses. An immortalized human gastric epithelial cell line (GES1) and 7 human gastric cancer lines were used to express transgenes, knock down gene expression (with small interfering RNAs), disrupt genes (using the CRISPR/Cas9 system), or assess expression of reporter constructs. We measured cell proliferation, colony formation, invasion, and migration, and assessed growth of xenograft tumors in nude mice. RESULTS: A low-frequency missense variant rs112754928 in the SPOC domain containing 1 gene (SPOCD1; encoding p.Arg71Trp), at 1p35.2, was reproducibly associated with reduced risk of gastric cancer (odds ratio, 0.56; P = 3.48 × 10-8). SPOCD1 was overexpressed in gastric tumors, and knockout of SPOCD1 reduced gastric cancer cell proliferation, invasive activity, and migration, as well as growth of xenograft tumors in nude mice. We also associated the variant rs1679709 at 6p22.1 with reduced risk for gastric cancer (odds ratio, 0.80; P = 1.17 × 10-13). The protective allele rs1679709-A correlated with the surrounding haplotype rs2799077-T-rs2799079-C, which reduced the enhancer activity of this site to decrease expression of the butyrophilin subfamily 3 member A2 gene (BTN3A2). BTN3A2 is overexpressed in gastric tumors, and deletion of BTN3A2 inhibited proliferation, migration, and invasion of gastric cancer cells. CONCLUSIONS: We have associated variants at 1p35.2 and 6p22.1 with gastric cancer risk, indicating a role for SPOCD1 and BTN3A2 in gastric carcinogenesis.

Hsa-mir-499 rs3746444 T/C Polymorphism is Associated with Increased Risk of Coronary Artery Disease in a Chinese Population.

BACKGROUND: Coronary artery disease (CAD) is a complex disease resulting from a combination of environmental and genetic factors. We hypothesized that polymorphisms hsa-mir-499 rs3746444 T/C, IRAK1 rs3027898 C/A and RANKL rs7984870 C/G might contribute to CAD susceptibility. METHODS: We studied the association between the three polymorphisms and the risk of CAD in a Chinese population using 435 CAD patients and 480 controls. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to perform the genotyping, and the differences were analysed. RESULTS: When the hsa-mir-499 rs3746444 TT homozygote genotype was used as the reference group, the TC, CC or TC/CC genotypes were associated with a significantly increased risk of CAD [TC vs. TT: adjusted odds ratio (OR) 1.41, 95% confidence interval (CI) 1.02-1.94, p = 0.04; CC vs. TT: adjusted OR 3.14, 95% CI 1.77-5.56, p < 0.001; CC/TC vs. TT: adjusted OR 1.68, 95% CI 1.25-2.26, p < 0.001). In the recessive model, when the hsa-mir-499 rs3746444 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased risk of CAD (adjusted OR 2.87, 95% CI 1.63-5.04, p < 0.001). Risk factors such as diabetes mellitus (DM), hypertension, smoking and low high-density ipoprotein cholesterol (HDL-c) were also associated with a significantly increased risk for CAD. Logistic regression analyses revealed that IRAK1 rs3027898 C/A and RANKL rs7984870 C/G polymorphisms were not associated with risk of CAD. CONCLUSIONS: These findings suggested that the functional polymorphism hsa-mir-499 rs3746444 T/C is associated with CAD susceptibility.

Forkhead box A1 (FOXA1) tagging polymorphisms and esophageal cancer risk in a Chinese population: a fine-mapping study.

Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of esophageal cancers. Besides environmental risk factors, genetic factors such as single-nucleotide polymorphisms (SNPs) play an important role in ESCC carcinogenesis. We performed a hospital-based case-control study to evaluate the Forkhead-box protein A1 (FOXA1) rs12894364 C > T, rs2145146 C > A and rs7144658 T > C tag SNPs in the risk of developing ESCC. We recruited 629 ESCC cases and 686 controls. Genotypes were determined using ligation detection reaction. Logistic regression analyses revealed that the three FOXA1 SNPs were not associated with ESCC risk. However, there was significantly decreased ESCC risk associated with the FOXA1 rs12894364 C > T and rs2145146 C > A polymorphisms among older patients. There was significantly increased ESCC risk associated with the FOXA1 rs7144658 T > C polymorphism among male patients. This study demonstrates an association between FOXA1 polymorphisms and ESCC susceptibility. Additional larger studies are required to confirm our findings.

Long noncoding RNAs POLR2E rs3787016 C/T and HULC rs7763881 A/C polymorphisms are associated with decreased risk of esophageal cancer.

Worldwide, rates of esophageal cancer have been keeping highly in recent decades. Genetic variants in multiple cellular pathways might play an important role in altering risk of esophageal carcinoma. In this study, long noncoding RNAs (lncRNAs) functional single nucleotide polymorphisms (SNPs) were investigated in Chinese Han populations. We have genotyped the ANRIL rs2151280 T/C, POLR2E rs3787016 C/T, and HULC rs7763881 A/C SNPs in 380 esophageal squamous cell carcinoma (ESCC) cases and 380 cancer-free controls. POLR2E rs3787016 C/T was associated with a significantly decreased risk for ESCC (CT vs. CC: OR 0.62, 95 % CI 0.44-0.87, P = 0.005; adjusted OR 0.62, 95 % CI 0.44-0.87, P = 0.005). The other SNP, HULC rs7763881, also showed a suggestive association (AC vs. AA: OR 0.70, 95 % CI 0.50-0.98, P = 0.037; adjusted OR 0.69, 95 % CI 0.49-0.97, P = 0.031). ANRIL rs2151280 T/C SNP was not associated with risk of ESCC. In the future, larger studies with other ethnic populations, tissue-specific biological characterization, and detailed individual information should be undertaken to validate current findings.

p21, p53, TP53BP1 and p73 polymorphisms and the risk of gastric cardia adenocarcinoma in a Chinese population.

Gastric cardia adenocarcinoma (GCA) is one of the most common malignant tumors and among the leading causes of cancer-related death. Genetic factors might play an important role in GCA carcinogenesis. Here, we performed a hospital-based case-control study to evaluate the effect of functional p21, p53, TP53BP1 and p73 single nucleotide polymorphisms (SNPs) on the risk of GCA. The study included 330 GCA cases and 608 controls. Genotypes were determined using the ligation detection reaction (LDR) method. The p21 rs1059234 TT, p21 rs3176352 GC/CC, p21 rs762623 GA and TP53BP1 rs560191 CC genotypes were associated with the risk of GCA, and a genotype combination effect was observed. After Bonferroni correction, the association remained significant for TP53BP1 rs560191 G > C, whereas the remaining four SNPs showed no association between the polymorphisms and GCA risk in all comparison models. Further large replication studies are needed to confirm the present findings.

Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population.

OBJECTIVE: To investigate the association between gastric cardia adenocarcinoma (GCA) and ten functional single nucleotide polymorphisms (SNPs), including TP53BP1 rs560191 G>C, CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A, and six C1orf10/CRNN variants. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs. METHODS: Two hundred and forty-three GCA cases and 476 controls were enrolled in this study. A custom-by-design 48-Plex SNPscan(TM) Kit was used to determine their genotypes. RESULTS: When the TP53BP1 rs560191 GG homozygote genotype was used as the reference group, the GC genotype was associated with a significantly increased risk of GCA. The CC genotype was not associated with the risk of GCA compared with the GG genotype. None of the CASP8 rs1035142 G>T, CASP7 rs3127075 G>C, CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls. CONCLUSIONS: The results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility. However, the statistical power of our study was limited. Large, well-designed studies and further functional investigations are needed to confirm our findings.

Genetic variants at 8q24 are associated with risk of esophageal squamous cell carcinoma in a Chinese population.

Esophageal cancer and gastric cancer have shared risk factors and inherited susceptibility. Recent genome-wide association studies have identified multiple genetic loci associated with gastric cancer risk, which may also involve in the development of esophageal cancer. Herein, we evaluated the relationship of gastric cancer risk-related variants at 1q22, 3q13.3, 5p13.1, and 8q24 with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population with a case-control study (2139 cases and 2273 controls). We found that the T allele of rs2294008, an intronic variant of the PSCA gene at 8q24 that was previously associated with an increased risk of gastric cancer, was inversely associated with a decreased risk of ESCC (odds ratio = 0.90; 95% confidence interval, 0.81-0.99; P = 0.034). Of interest, the association of rs2294008 with ESCC was consistent with that observed in esophageal adenocarcinoma and ESCC in Caucasian populations. However, no significant associations were observed for the other three variants at 1q22 (rs4072037), 3q13.31 (rs9841504), and 5p13.1 (rs13361707). Our findings suggest that the susceptibility locus of PSCA at 8q24 may be a double-edged sword, as modulator between the carcinogenesis processes of stomach and esophagus.

Interleukin 15 receptor alpha rs2228059 A > C polymorphism decreased risk of gastric cardiac adenocarcinoma in a Chinese population.

Gastric cardiac adenocarcinoma (GCA) is one of the common malignant tumors in the world and has a high incidence in China. Both environmental risk factors and genetic factors might play an essential role in the GCA carcinogenesis. We performed a hospital-based case-control study to evaluate the genetic effects of interleukin 15 (IL15) and IL15 receptor alpha (IL15RA) functional single nucleotide polymorphisms (SNPs) on the pathogenesis of GCA. A total of 243 GCA cases and 476 controls were enrolled in this study. The genotypes were determined using a custom-by-design 48-Plex SNPscan(TM) Kit. When the IL15RA rs2228059 AA homozygote genotype was used as the reference group, the CC genotype was correlated with a significantly decreased risk for GCA (CC vs. AA: adjusted OR = 0.61, 95 % CI = 0.37-0.98, p = 0.042). Our results revealed that functional variant IL15RA rs2228059 A > C might attenuate individual's risk of GCA. However, there was no significant association between the other five IL15 SNPs and GCA susceptibility. This present study demonstrated that IL15RA rs2228059 A > C polymorphism might modify GCA susceptibility. The results were based on a limited sample size; future larger studies with more rigorous designs are warranted to validate our findings.

The variant interleukin 1f7 rs3811047 G>A was associated with a decreased risk of gastric cardiac adenocarcinoma in a Chinese Han population.

To investigate the association between gastric cardiac adenocarcinoma (GCA) and six functional single nucleotide polymorphisms (SNPs) including interleukin 1A (IL1A) rs1800587 C>T, IL1B rs16944 G>A, IL1f7 rs3811047 G>A, IL3 rs40401 C>T, IL3 rs2073506 G>A, and IL7Rα rs6897932 A>G. We performed a hospital-based case-control study to evaluate the genetic effects of these SNPs. A total of 243 GCA cases and 476 controls were enrolled in this study. A custom-by-design 48-Plex SNPscan(TM) kit was used to determine the genotypes. The IL1f7 rs3811047 G>A polymorphism was significantly associated with a decreased risk of GCA either in the single locus analyses or the recessive genetic model. However, there was no significant association between the other five SNPs and GCA risk. These results elucidated that the functional polymorphism, IL1f7 rs3811047 G>A, might contribute to GCA susceptibility. However, the statistical power of our study was limited, large well-designed studies and further functional investigations are needed to confirm our findings.

Variant alleles of VEGF and risk of esophageal cancer and lymph node metastasis.

CONDENSED ABSTRACT: The variant alleles of the functional polymorphisms, VEGF -2578 C > A, -1498 T > C and +936 C > T, were not associated with risk of esophageal cancer and lymph node metastasis. Compared with the most common haplotype, C-2578T-1498C+936, the A-2578C-1498C+936 haplotype was associated with a borderline significantly increased risk of esophageal cancer. C-2578C-1498C+936 and A-2578T-1498T+936 haplotypes were associated with significantly increased risk of esophageal cancer. Vascular endothelial growth factor (VEGF) is a potent stimulator for angiogenesis. It has been implicated in the growth and metastasis of esophageal cancer. Three functional single nucleotide polymorphisms (SNPs) of VEGF (-2578 C > A, -1498 T > C and +936 C > T) are known to be related to VEGF expression. We conducted a case-control study to evaluate the effects of these three functional SNPs on the development of esophageal cancer and lymph node metastasis. A total of 497 cases and 380 controls were analyzed. Genotypes were determined by matrix assisted laser desorption/ionization time-of-flight mass spectrometry and direct sequence methods. The variant alleles of the functional polymorphisms VEGF -2578 C > A, -1498 T > C and +936 C > T SNPs were not associated with esophageal cancer risk. These VEGF genotypes were not associated with the risk of esophageal cancer after stratification. Furthermore, no association was observed between VEGF -2578 C > A, -1498 T > C and +936 C > T polymorphisms and lymph node metastasis. Compared with the most common haplotype C-2578T-1498C+936, the A-2578C-1498C+936 haplotype was associated with a borderline significantly increased risk of esophageal cancer. C-2578C-1498C+936 and A-2578T-1498T+936 haplotypes were associated with significantly increased risk of esophageal cancer. Variants in the functional polymorphisms of VEGF may not contribute to esophageal cancer and lymph node metastasis susceptibility. VEGF A-2578C-1498C+936, C-2578C-1498C+936 and A-2578T-1498T+936 haplotypes may be associated with increased risk of esophageal cancer. However, our results were obtained with a limited sample size and therefore this is a preliminary conclusion. Validation by a larger study with more diverse ethnic populations is needed.

Interleukin 17A rs3819024 A>G polymorphism is associated with an increased risk of gastric cardia adenocarcinoma in a Chinese population.

Gastric cardia adenocarcinoma (GCA) is one of the most common malignant tumors. In addition to environmental risk factors, genetic factors might play an important role in GCA carcinogenesis. To evaluate the association between polymorphisms in the interleukin 17A (IL17A) gene on the development of GCA, we conducted a hospital-based case-control study. A total of 243 GCA cases and 476 controls were recruited and their genotypes were determined using a custom-by-design 48-Plex SNPscan™ Kit. IL17A rs3819024 A > G polymorphism was found to be associated with the increased risk of GCA. When the IL17A rs3819024 AA homozygote genotype was used as the reference group, the AG genotype was associated with a significantly increased risk of GCA (AG versus AA: adjusted OR = 1.53, 95% CI = 1.05-2.23, p = 0.026). However, there was no significant association between five other SNPs and GCA. Stratified analyses indicated that a significantly increased risk of GCA associated with the IL17A rs3819024 A > G polymorphism was evident among male patients, patients who drank alcohol or those who never smoked. These findings indicated that functional polymorphism IL17A rs3819024 A > G might contribute to GCA susceptibility. Future larger studies with more rigorous study designs are required to confirm the current findings.

Decoy receptor 3 polymorphisms are not associated with the risk of esophageal cancer in a Chinese population.

Esophageal cancer (EC) is the sixth most common cancer worldwide, and esophageal squamous-cell carcinoma (ESCC) accounts for more than 90% of ECs. We hypothesized that genetic factors might play an important role in ESCC carcinogenesis. We conducted a hospital-based case-control study to evaluate the association between two single nucleotide polymorphisms of decoy receptor 3 (DcR3), namely, rs2297441 G > A and rs2257440 T > C, on the ESCC risk. In all, 629 ESCC cases and 686 controls were included. Genotypes were determined using the ligation detection reaction method. When the DcR3 rs2297441 GG homozygote genotype was used as the reference group, the GA genotype showed no association with the ESCC risk (GA versus GG: adjusted OR = 1.11, 95% CI = 0.88-1.40, p = 0.396); similarly, even the TT genotype showed no association with the ESCC risk (AA versus GG: adjusted OR = 0.80, 95% CI = 0.55-1.18, p = 0.268). Logistic regression analyses revealed that the DcR3 rs2257440 T > C polymorphism was not associated with the ESCC risk. DcR3 rs2297441 G > A and DcR3 rs2257440 T > C polymorphisms may not contribute to the ESCC risk, and additional, larger studies are required to confirm our results.

NQO1 rs1800566 C>T polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population.

BACKGROUND. Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of esophageal cancers. Genetic factors may play an important role in the carcinogenesis of ESCC. METHODS. We conducted a hospital-based case-control study to evaluate functional NAD(P)H: quinone oxidoreductase 1 (NQO1) rs1800566 C>T and NQO2 rs2070999 G>A single-nucleotide polymorphisms on the risk of ESCC. A total of 629 patients with ESCC and 686 controls were recruited for this study. The genotypes were determined using the ligation detection reaction method. RESULTS. When the NQO1 rs1800566 CC homozygote genotype was used as the reference group, the TT genotype was associated with a significantly decreased risk of ESCC. In the recessive model, when the NQO1 rs1800566 CC/CT genotypes were used as the reference group, the TT homozygote genotype was associated with a 31% decreased risk of ESCC. A significantly decreased risk of ESCC was evident in patients with the NQO1 rs1800566 C>T polymorphism among females, those of a younger age (<63 years), those who had never smoked, those who consumed alcohol and those who did not. There was no association found between the NQO2 rs2070999 G>A polymorphism and ESCC risk. CONCLUSION. The NQO1 rs1800566 TT genotype was associated with a decreased risk of ESCC in a Chinese population. The association was evident among female patients, younger patients, patients who had never smoked, patients who consumed alcohol and those who did not. These findings need to be confirmed by repeating the study in a larger cohort of patients.

IL-15 receptor alpha rs2228059 A>C polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Esophageal cancer is very aggressive; genetic polymorphisms may explain in part the individual differences in esophageal cancer susceptibility. We conducted a hospital based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs) in the interleukin (IL)-15 and IL-15 receptor alpha (IL-15RA) gene on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscan(TM) kit. The IL-15RA rs2228059 A>C polymorphism was associated with a decreased risk of ESCC in a recessive genetic model; However, there was no significant association between the other five SNPs and ESCC risk. Stratified analyses indicated a significantly decreased risk of ESCC associated with the IL-15RA rs2228059 A>C polymorphism was evident among male, older, non-smoker, and non-drinker patients. These findings indicated that the functional polymorphism, IL-15RA rs2228059 A>C, might contribute to ESCC susceptibility. However, the statistical power of our study was limited because of the moderate sample size and absence of a validation cohort. Large well-designed studies are warranted to confirm our findings.

Caspase8 rs1035142 G>T polymorphism was associated with an increased risk of esophageal cancer in a Chinese population.

Esophageal cancer is one of the ten most common cancers in the world and has poor prognosis. Apoptosis is considered a fundamental component in cancer pathogenesis. We conducted a hospital-based case-control study to evaluate the genetic effects of 16 apoptosis associated single nucleotide polymorphisms (SNPs) on esophageal cancer development. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. Genotypes were determined using a custom-by-design 48-Plex SNPscan™ Kit. The caspase8 (CASP8) rs1035142 G>T polymorphism was associated with increased risk of ESCC by heterozygote comparison, homozygote comparison, a dominant genetic model and a recessive genetic model. However, no significant association was detected between the other 15 SNPs and ESCC risk. Stratified analyses indicated a significantly increased risk of ESCC associated with CASP8 rs1035142 G>T polymorphism was evident among all subgroups. These findings indicated that the functional polymorphism CASP8 rs1035142 G>T might contribute to ESCC susceptibility.

Polymorphisms of VEGF, TGFß1, TGFßR2 and conotruncal heart defects in a Chinese population.

Genetic variants may determine susceptibility of congenital heart disease (CHD). To evaluate the impact of transforming growth factor-ß1 (TGFß1), TGFß receptor II (TGFßR2) and vascular endothelial growth factor (VEGF) polymorphisms on conotruncal heart defects susceptibility, we genotyped six functional polymorphisms TGFß1 rs1800469 C>T, TGFßR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T in a hospital based case-control study of 244 conotruncal heart defects cases and 136 non-CHD controls in a Chinese population. Logistic regression analyses revealed that if the TGFß1 rs1800469 CC homozygote genotype was used as the reference group, subjects carrying the CT variant heterozygote had a significant 0.48-fold decreased risk of conotruncal heart defects [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.30-0.88], subjects carrying the TT variant homozygote had a significant 0.47-fold decreased risk of conotruncal heart defects (OR 0.53; 95% CI 0.28-1.00). In stratification analyses, the TGFß1 rs1800469 C>T genotype was associated with a decreased risk for tetralogy of fallot in homozygote comparisons (OR 0.47; 95% CI 0.22-0.99), a decreased risk for transposition of great artery in the dominant genetic model (OR 0.49; 95 % CI 0.28-0.87) and heterozygote comparisons (OR 0.45; 95% CI 0.24-0.83). Our findings suggest that TGFß1 rs1800469 C>T polymorphism was significantly associated with decreased risk of conotruncal heart defects. TGFßR2 rs3087465 G>A, VEGF -2578C>A, -1498T>C, -634G>C and +936C>T polymorphisms may not play a role in the susceptibility of conotruncal heart defects.

Interleukin-6 receptor rs7529229 T/C polymorphism is associated with left main coronary artery disease phenotype in a Chinese population.

Left main coronary artery disease (LMCAD) is a particular severe phenotype of coronary artery disease (CAD) and heritability. Interleukin (IL) may play important roles in the pathogenesis of CAD. Although several single nucleotide polymorphisms (SNPs) identified in IL related genes have been evaluated for their roles in inflammatory diseases and CAD predisposition, the investigations between genetic variants and CAD phenotype are limited. We hypothesized that some of these gene SNPs may contribute to LMCAD phenotype susceptibility compared with more peripheral coronary artery disease (MPCAD). In a hospital-based case-only study, we studied IL-1A rs1800587 C/T, IL-1B rs16944 G/A, IL-6 rs1800796 C/G, IL-6R rs7529229 T/C, IL-8 rs4073 T/A, IL-10 rs1800872 A/C, and IL-10 rs1800896 A/G SNPs in 402 LMCAD patients and 804 MPCAD patients in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and ligation detection reaction (LDR) method. When the IL-6R rs7529229 TT homozygote genotype was used as the reference group, the CC or TC/CC genotypes were associated with the increased risk for LMCAD (CC vs. TT, adjusted odds ratio(OR)=1.46, 95% confidence interval (CI)=1.02-2.11, p=0.042; CC+TC vs. TT, adjusted OR=1.31, 95% CI=1.02-1.69, p=0.037). None of the other six SNPs achieved any significant differences between LMCAD and MPCAD. The present study suggests that IL-6R rs7529229 T/C functional SNP may contribute to the risk of LMCAD in a Chinese population. However, our results were limited. Validation by a larger study from a more diverse ethnic population is needed.