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Polymorphisms of PRLHR and HSPA12A and Risk of Gastric and Colorectal Cancer in the Chinese Han Population

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Polymorphisms of PRLHR and HSPA12A and Risk of Gastric and Colorectal Cancer in the Chinese Han Population Su et al. BMC Gastroenterology (2015) 15:107 DOI 10.1186/s12876-015-0336-9 RESEARCH ARTICLE Open Access Polymorphisms of PRLHR and HSPA12A and risk of gastric and colorectal cancer in the Chinese Han population Qinghua Su1, Yuan Wang2, Jun Zhao1, Cangjian Ma1, Tao Wu1, Tianbo Jin3,4 and Jinkai Xu1* Abstract Background: Gastric and colorectal cancers have a major impact on public health, and are the most common malignant tumors in China. The aim of this research was to study whether polymorphisms of CHCHD3P1-HSP90AB7P, GRID1, HSPA12A, PRLHR, SBF2, POLD3 and C11orf93-C11orf92 genes are associated with the risk of gastric and colorectal cancers in the Chinese Han population. Methods: We genotyped seven single nucleotide polymorphisms (SNPs) from seven genes. We selected 588 patients with gastric cancer and 449 with colorectal cancer, along with 703 healthy controls. All these SNPs were evaluated using the χ2 test and genetic model analysis. Results: The genotype “A/T” of rs12413624 in PRLHR gene was associated with a decreased risk of colorectal cancer in allele model analysis [odds ratio (OR) = 0.81; 95 % confidence interval (CI) = 0.68–0.97; p = 0.018] and log-additive model analysis (OR = 0.81; 95 % CI = 0.66–0.98; p = 0.032). The genotype “A/G” of rs1665650 in HSPA12A gene was associated with a decreased risk of gastric cancer in overdominant model analysis (OR = 0.77; 95 % CI = 0.60–0.99; p =0.038). Conclusions: Our results provide evidence that variants of PRLHR gene are a protective factor in colorectal cancer and variants of HSPA12A gene are a protective factor in gastric cancer in the Chinese Han population. Background (10q25.3), rs12413624 (10q26.11), rs10500715 (11p15.4), Gastric and colorectal cancers are two of the most wide- rs3824999 (11q13.4) and rs3802842 (11q23.1) [4–7]. spread cancers worldwide [1]. Both gastrointestinal ma- The prolactin releasing hormone receptor (PRLHR), also lignancies are leading causes of cancer-related death in known as G-protein-coupled receptor 10, is the receptor East Asia, Eastern Europe, parts of Central and South for prolactin releasing peptide (PrRP). Numerous studies America. With improvements in the standard of living suggest digestive disease was associated with regulation of and changes in lifestyle, food and the environment, the feeding and a pivotal role of PrRP in the homeostatic regu- incidences of gastric and colorectal cancers are con- lation of feeding and energy balance [8]. Evidence from stantly increasing in China, where they are now the third our group has shown that central administration of PrRP most frequent malignancies [2, 3]. decreases feeding and body weight gain in rats and mice, In the present study, the low-risk susceptibility markers without causing adverse effects [9]. HSPA12A is a member were previously reported in genome-wide association of the heat shock protein (HSP) family and a common studies as being related to the risk of digestive system can- molecule within cells that act as a chaperone in conditions cer: rs10795668 (10p14), rs10788473 (10q23.1), rs1665650 of stress, including carcinogenesis [10]. Overexpression of HSPA12A might be associated with poor survival in hepa- tocellular carcinoma. There is a good correlation between * Correspondence: [email protected] Qinghua Su and Yuan Wang are joint first authors. the expression of HSPs and the resistance of cancer cells 1Department of General Surgery, the Second Affiliated Hospital, Xi’an to chemotherapy [11]. GRID1 gene encodes glutamate re- Jiaotong University School of Medicine, No. 157 West Fifth Road, Xi’an, ceptor δ1, a subunit of glutamate receptor channels that Shaanxi 710004, China Full list of author information is available at the end of the article mediate most of the fast excitatory synaptic transmission © 2015 Su et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Su et al. BMC Gastroenterology (2015) 15:107 Page 2 of 5 in the central nervous system and play key roles in synap- Statistical analysis tic plasticity [12]. SBF2 gene appears to influence the sort- The genotype frequencies of each SNP in the control ing and degradation of cell surface receptors, such as subjects were checked using the Hardy–Weinberg equilib- epidermal growth factor receptor, with resultant alter- rium (HWE). Power analysis was carried out using the ations in downstream signaling [4]. online calculator at http://sampsize.sourceforge.net/iface/ The aim of this study was to investigate the relationship s3.html. Data analysis was performed using SPSS version between CHCHD3P1-HSP90AB7P, GRID1, HSPA12A, 16.0 statistical package (SPSS, Chicago, IL, USA) and PRLHR, SBF2, POLD3,andC11orf93-C11orf92 genes and Microsoft Excel. P < 0.05 was considered to represent susceptibility to gastric and colorectal cancers in the statistical significance. Differences in the distribution Chinese Han population. were analyzed using logistic regression. The genotype frequencies of cases and controls were calculated using Methods a χ2 test [15, 16]. Odds ratios (ORs) and 95 % confidence Ethics statement intervals (CIs) were tested using unconditional logistic re- The protocol in this study conformed to the principles gression analysis with adjustment for age and gender [17]. of the Declaration of Helsinki and was ratified by the The allele, overdominant and log-additive models were Ethical Committee of the Second Affiliated Hospital, applied using PLINK software (http://pngu.mgh.harvar- Xi’an Jiaotong University School of Medicine, China. d.edu/purcell/plink/) to assess the association of SNPs with the risk of gastric and colorectal cancers. Study population We recruited 588 patients with gastric cancer and 449 Results with colorectal cancer between December 2010 and The 588 gastric cancer cases comprised 392 men and 196 November 2014 from the Department of General women with a mean age of 58.12 ± 11.66 years. The 449 ’ Surgery, the Second Affiliated Hospital, Xi an Jiaotong colorectal cancer cases comprised 260 men and 189 University School of Medicine. All of the study partici- women with a mean age of 59.09 ± 11.78 years. The 703 pants were from the Chinese Han population living in healthy controls comprised 396 men and 307 women with ’ the area of Xi an. Confirmed cases were patients who a mean age of 48.57 ± 9.43 years. We found no differences were newly diagnosed and histologically confirmed. Ac- between gender and age distribution. The characteristics cording to the recruitment and exclusion standards, we of the patients and controls are shown in Table 1. The surveyed the patients using a self-designed questionnaire primers of the seven selected SNPs are shown in Table 2, including demographic factors such as age, gender, and which were designed by Sequenom MassARRAY Assay education, and potential risk factors including smoking, Design 4.0 Software [14]. Seven SNPs in seven genes were dietary conditions, alcohol consumption, and family his- analyzed in this study. SNP ID, gene, HWE test results, tory of cancer [13]. The controls were 703 healthy indi- minor/major alleles, and MAF of cases and controls of all viduals who were selected from June 2011 to October the SNPs are shown in Table 3. The minor allele of each 2014 from the Medical Examination Center, Department SNP, a risk factor, was compared with the wild-type allele. ’ of General Surgery, the Second Affiliated Hospital, Xi an Further model association analyses used logistic Jiaotong University School of Medicine. The controls were tests including allele model, overdominant model and ’ all Chinese Han living in Xian city and surrounding area. log-additive model (Table 4). The genotype “A/T” of We excluded patients with chronic diseases of the kidneys, rs12413624 is associated with a decreased risk of heart, liver and brain. All participants gave signed in- colorectal cancer by allele model analysis (OR = 0.81; formed consent prior to participation in the study. 95 % CI = 0.68–0.97; p = 0.018) and log-additive model Genotyping We genotyped seven single nucleotide polymorphisms Table 1 Demographic characteristics of patients with gastric (SNPs) with minor allele frequency (MAF) > 5 % in seven and colorectal cancers, and controls a b genes in the HapMap Asian population. Genomic DNA Group (N) Age (years) Gender P value P value (male/female) was stored at −20 °C and was extracted from whole blood – Healthy controls 48.57 ± 9.43 396/307 –– by the phenol chloroform extraction method. Using an ex- (N = 703) traction kit (GoldMag, China), we isolated DNA from the Gastric cancer 58.12 ± 11.66 392/196 0.21 0.54 samples. DNA concentration was measured by spectrom- cases (N = 588) etry (DU530 UV/VIS spectrophotometer; Beckman Instru- Colorectal cancer 59.09 ± 11.78 260/189 0.32 0.25 ments, Fullerton, CA, USA). We designed the Multiplexed cases (N = 449) SNP Mass EXTEND assay using Sequenom MassARRAY aP value is based on the age versus healthy controls in the study Assay Design version 4.0 software [14]. bP value is based on the gender versus
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