Correlation analysis of gene polymorphisms and β-lactam allergy

Journal of Zhejiang University SCIENCE B, Jul 2015

A total of 64 patients with β-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between β-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4Rα, high-affinity immunoglobulin E-receptor β chain (FcεRIβ), interferon γ receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY® platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032–0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with β-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and β-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls.

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Correlation analysis of gene polymorphisms and β-lactam allergy

J Zhejiang Univ-Sci B (Biomed & Biotechnol) 1673-1581 Correlation analysis of gene polymorphisms and ?-lactam allergy* Jing LI 0 Xin-yue LIU 0 Lin-jing LI 0 Chong-ge YOU 0 Lei SHI 0 Shang-di ZHANG 0 Qian LIU 0 Jun WANG 0 Ze-jing LIU 0 Ting-hong LV 1 0 Centre of Laboratory Medicine, Lanzhou University Second Hospital , Lanzhou 730030, China) ( 1 School of Basic Medical Science, Lanzhou University , Lanzhou 730030 , China) 2 Project supported by the Natural Science Foundation of Gansu Province , China (Nos. 3ZS061-A25-084 and 1208RJZA192) , the Key Laboratory of Digestive System Tumors of Gansu Province, and the Fundamental Research Funds for the Central Universities (No. lzujbky-2011-t03-15), China ORCID: Xin-yue LIU A total of 64 patients with ?-lactam allergy and 30 control subjects were enrolled in a case-control study. This study is aimed to analyze the relationship between ?-lactam allergy and 10 single nucleotide polymorphisms (SNPs) in interleukin-10 (IL-10), IL-13, IL-4R?, high-affinity immunoglobulin E-receptor ? chain (Fc?RI?), interferon ? receptor 2 (IFNGR2), and CYP3A4, and within the Han Chinese population of Northwest China. Genotyping for the SNPs was conducted using the Sequenom MassARRAY? platform. SPSS 17.0 was employed to analyze the statistical data and SHEsis was used to perform the haplotype reconstruction and analyze linkage disequilibrium of SNPs of IL-10 and IL-13. The results showed that the genotype distribution of CYP3A4 rs2242480/CT differed significantly between case and control groups of males (P=0.022; odds ratio (OR)=0.167, 95% confidence interval (CI): 0.032-0.867). Further analysis showed that CCA, CCG, and TAA haplotypes of IL-10 had no significant correlation in patients with ?-lactam allergy. The correlation between CCT and CAC haplotypes of IL-13 and ?-lactam allergy needs to be further studied. The analysis did not reveal any differences in the distribution of others gene polymorphisms between cases and controls. Allergy; ?-Lactam; Interleukin (IL); Pharmacogenomics; Single nucleotide polymorphism (SNP) doi; 10; 1631/jzus; B1400309 Document code; A CLC number; R394; 6 - 1 Introduction ?-Lactams are widely used in clinical practice worldwide. However, it is difficult to prevent adverse reactions of the drug (Prematta et al., 2012; Torres et al., 2014) . Penicillin G presented the most serious allergic reactions with an incidence of 0.7%?10%, and anaphylactic shock with an incidence of 0.004%? 0.018%, within which there was a 10%?20% mortality rate. The incidence of skin rash as a result of using ampicillin is greater than 10%. Urticaria, angioneurotic edema, gastrointestinal reactions, and aplastic anemia are the most common allergic symptoms, which may lead to anaphylactic shock and death (Bousquet et al., 2009; Comte et al., 2012; Lee, 2014) . However, the mechanism of ?-lactam antibiotics inducing the allergic reactions remains unclear (Comte et al., 2012). The present study attempts to identify the underlying genetic mechanisms involved in the allergic reactions caused by ?-lactam antibiotics. The correlation between ?-lactam allergy and the single nucleotide polymorphisms (SNPs) of genes such as interleukin-10 (IL-10) rs1800871, IL-10 rs1800872, IL-10 rs1800896, IL-13 rs20541, IL-13 rs1881457, IL-13 rs1800925, IL-4R? rs1801275, high-affinity immunoglobulin E-receptor ? chain (Fc?RI?) rs569108, interferon ? receptor 2 (IFNGR2) rs9808753, and CYP3A4 rs2242480 was assessed within the Han Chinese population of Northwest China by performing multiplex polymerase chain reaction (PCR) using iPLEX single-base extension technology from Sequenom MassARRAY? (Bo?ao Biotechnology Co., Beijing, China) and matrix-assisted laser desorption/ ionization-time of flight (MALDI-TOF). The relationship between the haplotype and ?-lactam allergy was also further analyzed. This study provides data concerning the genetic diagnosis for patients with ?-lactam allergy, and further clarifies the relationship between pharmacogenomics and the efficacy and safety of drugs. These findings also provide evidence that several new genetic targets can be utilized in the diagnosis and prevention of the adverse drug reactions to antibiotics and that treatment can be provided for a specific target gene with polymorphic variation. 2 Materials and methods 2.1 Subjects The subjects for this study were recruited from the outpatient department of Lanzhou University Second Hospital (Lanzhou, China) between Jan. 2010 and Apr. 2013. The allergic work-up was performed according to the European Network for Drug Allergy guidelines (Torres et al., 2002; 2003). The case group had to have a history compatible with an immediate reaction to ?-lactam and with a positive result of skin tests. Skin tests were made with major and minor determinants of benzyl penicillin (penicilloyl-polylysine and minor determinant mixture (MDM) containing benzyl-penicillin, sodium benzyl-penicilloate, and benzyl-penicilloic acid at a final concentration of 1.5 mmol/L) (Torres et al., 2003; Gu?ant et al., 2015 ). The control group included the patients who presented negative skin test to ?-lactam and had no history of allergic, dermatologic, or respiratory diseases, or autoimmune diseases such as asthma, eczema, allergic rhinitis, and urticaria. All the subjects were selected from the Han Chinese population of Northwest China and matched for age, race, and gender. Of the 94 patients enrolled, 64 (33 males and 31 females) were included in the case group (mean age: (42.04?14.4) years) and 30 (15 males and 15 females) were included in the control group (mean age: (41.73?6.06) years). There was no significant differences in the average age or gender between the two groups (P=0.888). The study protocol and medical informed consent were approved by the ethical committee of Lanzhou University Second Hospital (Lanzhou, China). In accordance with the medical informed consent, 3 ml of whole blood was drawn in ethylene diamine tetraacetic acid (EDTA) tubes from all subjects, and was stored at ?20 ?C whilst awaiting analysis. 2.2 Genomic DNA extraction Genomic DNA was extracted from 200 ?l of venous blood anticoagulated with EDTA using the QuickGene DNA whole blood kit (Shenggong, Shanghai, China) as per the manufacturer?s instructions. All DNA samples were tested using the NanoDrop 2000 spectrophotometer (Thermo Scientific, USA) for evaluation of template quality and quantity, and then adjusted to a concentration of 20 ng/?l and stored at ?40 ?C. 2.3 Gene polymorphism analysis of the SNPs The following 10 SNPs of six genes that might increase the susceptibility to ?-lactam allergy were selected: IL-10 rs1800871, IL-10 rs1800872, IL-10 rs1800896, IL-13 rs20541, IL-13 rs1881457, IL-13 rs1800925, IL-4R? rs1801275, Fc?RI? rs569108, IFNGR2 rs9808753, and CYP3A4 rs2242480. The primers were synthesized by Invitrogen Co. (Shanghai, China; Table 1). The iPLEX? Gold Reagent kit (SEQUENOM Co., USA) was used for SNP genotyping. MassARRAY Nanodispenser RS1000 (SEQUENOM Co., USA) was used for chip spotting. MassARRAY Analyzer Compact (SEQUENOM Co., USA) was used for mass spectrometry detection and analysis. 2.4 Plex PCR Plex PCR was performed with a total volume of 5 ?l, and the reaction mixture contained 10 ng DNA, 0.5 U Hotstar Taq, 0.5 pmol of each primer, and 0.1 ?l of 25 mmol/L dNTP. The PCR reaction conditions were as follows: 94 ?C for 4 min; 45 cycles of 94 ?C for 20 s, 56 ?C for 30 s, and 72 ?C for 1 min; final 3 min extension at 72 ?C, and then kept at 4 ?C. 2.5 Purification of the PCR product Firstly, the remanent dNTP was removed by adding 0.5 U shrimp alkaline phosphatase (SAP) into the PCR product. The reaction mixture that contained 5 ?l PCR product and 2 ?l SAP buffer (0.5 U SAP, 0.17 ?l buffer) was incubated at 37 ?C for 20 min and 85 ?C for 5 min and then kept at 4 ?C. 2.6 Single-base extension and resin purification 3 Results In total, 7 ?l SAP-treated PCR product, 0.804 ?l primer mixture, 0.041 ?l iPLEX, and 0.2 ?l extension mixture were combined in an Eppendorf tube. The reaction conditions were as follows: 94 ?C for 30 s; 40 cycles of 94 ?C for 5 s, 52 ?C for 5 s, 80 ?C for 5 s, and 94 ?C for 5 s; and final 3 min extension at 72 ?C. Each extension product was purified using 6 mg Clean Resin (SEQUENOM Co., USA). 2.7 Chip spotting and mass spectrometric examination The purified product was examined by Spectro CHIP (SEQUENOM Co., USA). SpectroCHIP was analyzed by MALDI-TOF, and the results were exported using TYPER Version 4.0 (SEQUENOM Co., USA). 2.8 Statistical analysis All data were analyzed using statistical software SPSS 17.0. The relationships between the nine SNPs and ?-lactam allergy susceptibility were assessed using chi-square test for estimation of the odds ratio (OR) and 95% confidence interval (CI) for each SNP genotype. Hardy-Weinberg equilibriums of each SNP in the control group were tested using chi-square test. All the statistics were inspected using bilateral probability, and statistical significance was determined as being below the conventional level of P=0.05. Moreover, the online SHEsis software (http://analysis2.bio-x.cn/myAnalysis.php) (Shi and He, 2005) was used to analyze the linkage disequilibrium (LD) and haplotype construction. D' and r2 were calculated for LD analysis. 3.1 SNPs associated with ?-lactam allergy In order to increase statistical power, homozygous mutant genotypes were merged into heterozygous genotypes to conduct statistical analysis. For gender and age, no significant statistical difference was found between the trial group and the control group. The results showed that the nine SNPs such as rs1800871, rs1800872, rs1800896, rs20541, rs1881457, rs1800925, rs1801275, rs569108, and rs9808753 were not significantly correlated with ?-lactam allergy in the Han Chinese population of Northwest China between the case and control groups (P>0.05; Table 2). The rs2242480/CT genotype of CYP3A4 gene was significantly correlated with ?-lactam allergy in the male patients (P=0.022, OR=0.167, 95% CI: 0.032?0.867; Table 3). 3.2 LD analysis Three SNPs of IL-10 such as rs1800871, rs1800872, and rs1800896 were located at the promoter region of IL-10 (separation distance <100 bp). The LD analysis was performed to study the relationships between these three SNPs and ?-lactam allergy. For patients with ?-lactam allergy in the Han Chinese population of Northwest China, rs1800872 and rs1800871 showed complete linkage; rs1800896 and rs1800872, rs1800896 and rs1800871, respectively, showed strong linkage (Table 4). The LD analysis on three SNPs of IL-13 showed that rs1881457 and rs1800925 had strong linkage, rs1800925 and rs20541 had strong linkage. However, rs1881457 and rs20541 did not show LD (Table 5). Three SNPs of IL-10 and IL-13 exhibited LD. The haplotype was constructed to analyze the effect of the LD on ?-lactam allergy in the Chinese Han population of Northwest China. The SNPs such as rs1800871, rs1800872, and rs1800896 showed complete linkage. Three haplotypes were found in the three SNPs of IL-10 gene: CCA, CCG, and TAA, respectively. These haplotypes were observed in the case and control groups (F=0.895, 0.905, and 0.851, respectively). None of the three haplotypes correlated with ?-lactam allergy in the Han Chinese population of Northwest China (Table 6). Six haplotypes were observed in rs20541, rs1881457, and rs1800925 of IL-13. Four of them were observed in the case and control groups that included CAC, CCC, TAC, and TCT (F=0.069, 0.500, 0.928, and 0.238, respectively). Hence, these four haplotypes were not correlated with the ?-lactam allergy in the Han Chinese population of Northwest China. Among these six haplotypes, CCT was only observed in the control group (F=0.026). The F-value of CAC was a marginal value of 0.069 (Table 6). 4 Discussion 4.1 Relationship between genetic polymorphisms of T cell-related cytokine and ?-lactam allergy T cells play an important role in ?-lactam allergy. They are reported to be involved in various types of hypersensitivity (Kim et al., 2005; Rubio et al., 2010) . T helper (Th) 1 and Th2 cells are the two types of T cells. Th2 cells can be involved in immunoglobulin E (IgE)-mediated immediate hypersensitivity as they promote the secretion of cytokines such as IL-4, IL-5, IL-6, IL-10, and IL-13 (Palomares, 2013). IL-10 can inhibit the clonal expansion of Th0, Thl, and Th2 cells (Jiang, 2015) , and it plays an important role in the occurrence and development of allergy. This study selected rs1800871, rs1800872, and rs1800896, which directly affected the expression of IL-10. Apter et al. (2008) reported that there was no significant correlation between IL-10 genetic polymorphism and ?-lactam allergy. Guglielmi et al. (2006) suggested that IL-10 promoter and IL-4R? genetic polymorphisms were related to immediate ?-lactam allergy in female patients. The results of present study show that rs1800872 of IL-10 was not correlated with ?-lactam allergy in the Han Chinese population of Northwest China. Additionally, three types of haplotype, CCA, CCG, and TAA of IL-10, were not found to be correlated with ?-lactam allergy in the Han Chinese population. The study data were consistent with the findings of Apter et al. (2008) ; however, it was not consistent with that of Guglielmi et al. (2006) . The reason might be that because our SNP chip is based on Sequenom MassARRAY? technology which is used to perform high-throughput sequencing. The chip presented high sensitivity and specificity, so the results are more reliable. The researchers have utilized different technologies including classic sequencing and high-sensitive PCR. The threshold for the detection of gene expression might be further explored using such procedures. Guglielmi et al. (2006) and Apter et al. (2008) have proved that other important factors, such as race, region, and environmental conditions, can also influence the distribution of genotype. The IL-4R? gene was located on chromosome 16p11?16p12. It is a subunit that plays a key role in allergic disease by promoting the IgE production (Wu and Scheerens, 2014). The present study showed that the distribution frequency of rs1801275 of IL-4R? was not significantly different between the groups (P>0.05), and the same results were obtained when the patients were stratified by gender (P>0.05). IL-13 was mainly involved in the allergic reactions through inducing the B lymphocytes to secrete IgE antibodies (Ford et al., 2001) . IL-13 and IL-4 were isogenous, because of their chromosomal localization and the molecular composition of proteins. Additionally, the sharing receptor structure presented the same signal pathway, and it also demonstrated similar physiological functions. IL-13 can indirectly play a role in eosinophils by upregulating the expression of eotaxin, and the effect of IL-13 was greater than that of IL-4 (Levine and Wenzel, 2010) . The present study results showed that the distribution frequencies of three SNPs of IL-13 gene such as rs20541, rs1881457, and rs1800925 were not significantly different between the case and control groups (P>0.05). The same results were obtained when the patients were stratified by gender (P>0.05). Six haplotypes were constructed on these three SNPs of IL-13 gene, in which CCT was only one observed in the control group (F=0.026) but not in the case group. The F-value of CAC was 0.069. Therefore, the relationship between these two haplotypes and ?-lactam allergy in the Han Chinese population of Northwest China requires further study. 4.2 Relationship between ?-lactam allergy and other genetic polymorphisms The study of SNPs of Fc?RI? and IFNGR2 mainly focused on their relationships with allergic diseases such as asthma (Kim and Park, 2006; Sanak et al., 2007) and allergic rhinitis (Nagata et al., 2001), and was used to treat malignant tumors such as non-Hodgkin lymphoma (Purdue et al., 2007; Chen et al., 2011) and gastric cancer (Hou et al., 2007). IFNGR1 was reported to correlate with ?-lactam allergy, however, the relationship between SNP of IFNGR2 and ?-lactam allergy was not clear. The study showed that the SNPs of both Fc?RI? and IFNGR2 were not correlated with ?-lactam allergy. 4.3 Relationship between CYP3A4 gene polymorphism and ?-lactam allergy Cytochrome P450 is widely distributed across all living organisms including vertebrates, invertebrates, plants, fungi, and bacteria. It was one of the most widely distributed enzymes of phase I drug metabolism, and it presented the richest natural content and the broadest substrate spectrum. Furthermore, CYP is distributed in various organs and tissues of the human body. CYP3A subfamily was one of the major ratelimiting enzymes in drug metabolism (Gellner et al., 2001) . Four genotypes were involved in drug metabolism in humans including CYP3A4, CYP3A5, CYP3A7, and CYP3A43 (Gibson et al., 2002) . The correlation between the SNPs of CYP3A4 and ?-lactam allergy was not reported in the past, and we found that the rs2242480 of CYP3A4 gene was correlated to ?-lactam allergy in male patients. The frequency of genotype CT was significantly different between the case and control groups when compared with the wild-type gene CC (P=0.022; OR=0.167, 95% CI: 0.032?0.867). 5 Conclusions The study provides evidence about the genetic diagnosis for patients with ?-lactam allergy in the Han Chinese population of Northwest China. CYP3A4 polymorphism was found to correlate with ?-lactam allergy in male patients. The relationships between ?-lactam allergy and haplotypes CCT and CAC from rs20541, rs1881457, and rs1800925 of IL-13 need to be further studied using a larger sample. The roles of these sites in the pathogenesis of ?-lactam allergy require further clarification. Acknowledgements We appreciate the valuable comments from other members of our laboratories. Compliance with ethics guidelines Jing LI, Xin-yue LIU, Lin-jing LI, Chong-ge YOU, Lei SHI, Shang-di ZHANG, Qian LIU, Jun WANG, Ze-jing LIU, and Ting-hong LV declare that they have no conflict of interest. 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Jing Li, Xin-yue Liu, Lin-jing Li, Chong-ge You, Lei Shi, Shang-di Zhang, Qian Liu, Jun Wang, Ze-jing Liu, Ting-hong Lv. Correlation analysis of gene polymorphisms and β-lactam allergy, Journal of Zhejiang University SCIENCE B, 2015, 632-639, DOI: 10.1631/jzus.B1400309