Original Article Association of Heat Shock 70 Protein 1B Gene Polymorphisms and the Susceptibility to Asthma in Pediatric Patients

Int J Clin Exp Med 2017;10(5):8243-8252 www.ijcem.com /ISSN:1940-5901/IJCEM0048145

Original Article Association of heat shock 70 protein 1B gene polymorphisms and the susceptibility to asthma in pediatric patients

Ying Liu, Hong Zhang

Department of Pediatrics, Tianjin Union Medicine Centre, No. 130 Jieyuan Road, Hongqiao District, Tianjin 300121, China Received January 4, 2017; Accepted January 27, 2017; Epub May 15, 2017; Published May 30, 2017

Abstract: Background: Childhood asthma and wheezing are very common, especially in those born preterm. Genetic and environmental factors are associated with developing asthma and wheezing. Epidemiological data show that obesity could increase the risk of asthma, and insulin resistance, or metabolic syndrome are an important risk factor for obesity asthma. Some studies identified some sites within the heat shock protein (HSP)-B gene region 1267 polymorphism was associated insulin resistance or metabolic disorders, while this site was closely related to asthma. But no research was performed to evaluate the influence of HSPA1B 1276A/G polymorphism on metabolic syndrome in pediatric asthma patients. Methods: Here, we recruited 246 pediatric asthma patients, who were separated into pediatric asthma patients with MetS or without MetS groups and 224 matched healthy controls from Tianjin Province to evaluate the influence of HSPA1B 1276A/G polymorphism on metabolic syndrome in pediatric asthma patients. Single nucleotide polymorphism of HSPA1B 1276 locus was genotyped using PCR-RFLP. Some biochemical variables were also determined. Results: Our results showed that the genotypic and allelic frequency of rs1061581 did not show significant difference between pediatric asthma patients and normal controls. However, the frequency of G allele was significantly higher in asthma group with MetS (21.36%) than in controls (14.71%) (P = 0.022; OR = 0.667; 95% CI = 0.407-0.916). After analyzing the relationship between biochemical features of patients and genotype of HSPA1B 1276A/G, we found levels of LDL cholesterol, fasting insulin, and HOMA-IR were significantly higher in the asthmatic patients carrying the GA and GG genotypes than in the carriers of AA genotype of rs1061581 (P = 0.031, P = 0.021, P = 0.041, respectively). Conclusion: Thus, Our data suggested that HSPA1B 1276A/G variation was related to metabolic phenotype in pediatric asthma patients. Furthermore, we first identified HSPA1B 1276G allele was the risk factor for pediatric asthma patients with MetS in Tianjin population, China.

Keywords: Pediatric asthma patients, metabolic syndrome, insulin resistance, HSPA1B gene, polymorphism

Introduction the genes involved in asthma are still unknown and are likely to be numerous. To date, numer- Asthma is a chronic allergic disorder of the ous risk genes have been reported to be as- airways that is characterized by inflammatory sociated with asthma susceptibility in various infiltrates in the bronchial walls, airway hyper- populations. One of the candidate susceptible responsiveness (AHR) and reversible airway ob- genes that have been intensely investigated is struction [1, 2]. Currently, the global prevalen- heat shock 70 protein (HSP-70) [5-23]. ce of asthma is 1%-18%, with the number of pediatric asthma patients around 300 million, Heat shock proteins, which function mostly as and the incidence of this disease is on the molecular chaperones, participate in the fold- rise. The overall prevalence of asthma in China ing and assembly of newly synthesized pro- is 1%, but in children is up to 3%, with both in- teins in cells, facilitate protein transport to sub- creasing. It is believed to be a multifactorial cellular compartments, and are involved in the disease whereby genetic factors contribute to refolding of damaged proteins. HSP-70 family is its etiology and/or clinical severity [3, 4]. While, one of the most conserved families. In humans, HSPA1B gene and pediatric asthma patients there are 13 different genes encoding HSPA informed consents conforming to the tenets of proteins including HSPA1A, HSPA1B, HSPA1L, the Declaration of Helsinki were obtained from HSPA2, HSPA4, HSPA4L, HSPA5, HSPA6, HS- each participant prior to the study. PA7, HSPA8, HSPA9, HSPA12A and HSPA14. The HSPA1A and HSPA1B genes were shown Participants to encode an identical product which is the major heat inducible HSPA protein [24]. Several A total of 246 patients with pediatric asthma polymorphisms in the region of HSPA1B have patients (Age from 0-9 years old), defined ac- been associated with different HSPA1B ex- cording to the criteria of the Global Initiative pression levels. Of these, the HSPA1B 1267A> for Asthma (GINA), and 224 matched healthy G (also referred to as rs1061581) is the best controls were enrolled in this study from the studied. It involves the substitution of a gua- Tianjin People’s Hospital pulmonology outpa- nine (G) by an adenine (A) and is associated tient clinic. All subjects are Han Chinese. Re- with an increase in HSPA1B expression levels spiratory symptoms and medications were as- [25-28]. Up to now, a lot of studies of genetic sessed in detail and pulmonary function tests epidemiology have assessed the association of were performed in a standard fashion using HSPA1B gene polymorphisms and risk of asth- electronic spirometer (MIR), for every subject. ma in different populations, but conflicting re- The inclusion criteria for controls were as fol- sults were obtained due to the heterogeneity lows: no symptoms or history of asthma or of the genetic background among populations. other pulmonary diseases; no symptoms or Furthermore, this support the need for replica- history of atopy; negative skin prick test re- tion studies among all ethnic groups. sults with a battery of common aeroallergens; and absence of first-degree relatives with a Metabolic syndrome (MetS) which was firstly history of asthma or atopy; without autoim- described by Reaven as syndrome X, is a major mune or inflammatory disease. public challenge worldwide [29, 30]. The main components of the syndrome are obesity, insu- All the subjects’ height and weight were mea- lin resistance (IR), hypertension, and dyslipid- sured by the same person using the same emia. There is agreement that MetS causes equipment. Body mass index was calculated pro-inflammatory and thrombogenic state, le- by dividing body weight to height square (kg/ 2 ading to late-onset diabetes mellitus and car- m ). Biochemical features, including total cho- diovascular diseases with increased mortality lesterol (TC), triglycerides (TG), low-density li- and morbidity. Recently, a great deal of epide- poprotein cholesterol (LDL), and high-density miological data show that obesity and insulin lipoprotein cholesterol (HDL) were collected for resistance can increase the risk of asthma [31- further study. 34]. Its mechanism is unclear. Several studies Diagnosis of metabolic syndrome have confirmed that HSPA1B 1276A/G polymorphisms are associated with insulin resis- For the diagnosis of metabolic syndrome, mo- tance or metabolic disorders. dified Chinese Diabetes Society (CDS) diagnostic criteria were used. The CDS definition for Taken together the association of HSPA1B MetS required impaired glucose tolerance plus gene polymorphisms and asthma, the aim of two of the following three disorders: obesity the present study was to investigate whether (waist-to-hip ratio ≥0.9 cm in men or ≥0.85 cm SNP in HSPA1B 1276A/G, rs1061581 is asso- in women), dyslipidemia (triglyceride level ≥1.7 ciated with metabolic syndrome in pediatric mmol/L and/or HDL cholesterol level ≤1.03 asthma patients and further explore the pa- mmol/L in men or ≤1.29 mmol/L in women), thogenesis of asthma complicated by meta- and high blood pressure (systolic blood pres- bolic syndrome. sure ≥140 mmHg and/or diastolic blood pres- Subjects and methods sure ≥90 mmHg). Glucose concentration was determined using the glucose oxidase method, Ethics statement and insulin concentration was determined using a radioimmunoassay (Diagnostic Products The Medical Ethics Committee of the Tianjin Corp, Los Angeles, CA). To assess insulin resis- People’s Hospital approved this study. Written tance, homeostasis model assessment of insu-

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Table 1. Anthropometric and biochemical data of pa- facturer’s instructions (New England tients and healthy controls BioLabs, Ipswich, MA). The -308G allele Characteristic Asthma Control P-value contains an NcoI restriction site not present in the -308A allele; thus, in Mets [n (%)] 150 (61.29) 50 (22.81) <0.001 the presence of the -308G allele, the Hypertension [n (%)] 96 (38.71) 37 (16.23) <0.001 PCR product (107 bp) is cut into 2 frag- BMI (kg/m2) 24.25±1.98 22.34±1.01 <0.001 ments of 80 and 27 bp in length [36]. Fasting insulin (sun/mL) 14.8±8.2 8.1±7.1 <0.001 Fasting glycemia (mmol/L) 6.14±1.24 4.21±0.74 <0.001 Assay of serum HSPA1B levels HOMA-IR 3.9±2.3 1.6±1.7 <0.001 The serum level of HSPA1B was de- Total cholesterol (mmol/L) 5.34±0.87 5.52±1.08 0.574 termined by ELISA Quantikine Human Triglycerides (mmol/L) 1.81±0.76 1.79±0.36 0.637 HSPA1B immunoassay kit (Biosource, HDL cholesterol (mmol/L) 1.03±0.48 1.29±0.45 0.067 USA). The lower limit of detection ranged LDL cholesterol (mmol/L) 3.02±1.41 2.65±1.26 0.059 from 4 to 6 pg/mL. Assay was carried HSPA1B (pg/ml) 53.21±3.84 27.93±6.50 <0.001 out according to the manufacturers’ in- MetS, Metabolic syndrome; BMI, Indicates body mass index; HDL, structions. High-density lipoprotein; LDL, Low-density lipoprotein. Statistical analysis lin resistance (HOMA-IR) index was calculated Data were statistically described in terms of as follows: [fasting insulin (μU/mL)] × [fasting mean ± standard deviation (SD), or frequencies glucose (mmol/L)]/22.5. The HOMA-IR index is (number of cases) and percentages as requir- a mathematical model designed by Mathews et ed depending on their distribution. The Hardy- al. [35]. Weinberg equilibrium (HWE) was assessed for each variation to identify the deviation. The Genotyping of SNP in HSPA1B 1276A/G, differences of the genotypes and alleles of rs1061581 HSPA1B 1276A/G between patients and normal controls were evaluated by using Pearson Genome DNA from whole blood cells of each Chi-square test. Exact test was used instead sample was extracted by using Blood Geno- when the expected frequency is less than 5. mic DNA Miniprep Kit (Axygen, USA) accord- The odds ratio (OR) and 95% confidence inter- ing to the manufacturer’s instructions. Geno- vals (95% CI) were calculated. Unpaired Stu- typing for the HSPA1B1276A/G polymorph- dent’s t test or Mann-Whitney tests were used isms in genomic DNA was performed using the for two-group comparisons. Because of skewed PCR and restriction fragment length polymor- distributions, log-transformed values for HDL phism (RFLP). The genomic region encompass- cholesterol, LDL cholesterol, insulin, HOMA-IR, ing the 1276A/G polymorphism was amplified and HSPA1B were used in analyses and back- using the following primers: forward 5’-ACAA- transformed for data presentation. Statistical GGCCCAGATTCACG-3’ and reverse 5’-TCCCTG- analysis of data was performed using the SP- CTCCGATTCCG-3’. Polymerase chain reaction SS software package 16.0 (SPSS Inc. USA). products were generated in a 10 μL reaction P-value less than 0.05 was considered statisti- volume containing 50 ng of genomic DNA, 1 × cally significant. PCR buffer, 2 mmol/L MgCl2, 0.2 mmol/L of each dNTP, 1 μmol/L of each primer, and 0.25 Results U of Taq DNA polymerase (Invitrogen Corpor- ation, Carlsbad, CA). Cycling conditions con- In this study, 246 asthmatic (106 males and sisted of an initial denaturation step at 94°C 140 females) and 224 controls (110 males for 5 minutes, followed by 35 cycles of dena- and 114 females) were screened for rs10615- turation at 94°C for 30 seconds, annealing at 81 polymorphisms using PCR-RFLP methods. 60°C for 30 seconds, and extension at 72°C The mean age of asthmatic patients was 6.48 for 30 seconds and a final elongation step at years, and mean age of matched controls was 72°C for 1 minute. Polymerase chain reaction 6.71 years. There were no significant differen- products were digested with 2 U of NcoI restric- ces between two groups with regarded to gen- tion enzyme at 37°C, according to the manu- der and age distribution. Table 1 showed the

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Table 2. Genotype and allele frequency of rs1061581 and Pearson’s chi-square test in pediatric asthmatic patients and normal control Patients (n = 246) Controls (n = 224) Genotype/Allele P-value OR (95% CI) HWE*P = 0.24 HWE P = 0.27 AA 163 185 0.611 0.905 (0.611-1.331) GA 76 37 0.073 0.822 (0.682-1.481) GG 7 2 0.126 4.560 (0.551-37.422) A 406 411 0.318 0.841 (0.594-1.181) G 90 41 *Chi-square test for deviation from the Hardy-Weinberg equilibrium (a value of P<0.001 was regarded as a deviation from the HWE).

Table 3. Genotype and allele frequency of rs1061581 and Pearson’s chi-square test in metabolic syndrome patients and normal control Patients (n = 200) Controls (n = 270) Genotype/Allele P-value OR (95% CI) HWE*P = 0.81 HWE P = 0.48 AA 130 217 0.558 0.861 (0.541-1.392) GA 62 49 0.928 1.257 (0.787-2.010) GG 8 2 0.351 3.356 (0.347-32.543) A 320 493 0.351 0.815 (0.524-1.267) G 80 46 *Chi-square test for deviation from the Hardy-Weinberg equilibrium (a value of P<0.001 was regarded as a deviation from the HWE). general characteristics of the studied subjects. 1581 between pediatric asthmatic patients The incidence of MetS in pediatric asthma and normal controls did not show significant group was about triple that of control (61.30% difference. vs 22.80%). Ninety-six (38.70%) patients in asthma group and 37 (16.21%) patients in con- On the basis of MetS criteria, the asthmatic trol group had Hypertension. Body mass index, patients were further subgrouped as pedia- glucose and insulin blood levels, HOMA-IR and tric asthma with MetS and pediatric asthma serum HSPA1B levels were significantly higher without MetS. As shown in Table 4, among the in pediatric asthma patients (P<0.001 for both pediatric asthmatic patients with MetS, the parameter). There were no differences in lipid GG genotype of the rs1061581 was found in panels between groups including total choles- 59.20% (88/150) of the cases, whereas the GA terol, triglycerides, LDL cholesterol, and HDL and AA were present in 36.85% (56/150) and cholesterol. 3.95% (6/150) of the asthmatic patients with MetS, respectively. In the pediatric asthmatic Firstly, the frequency of genotypes and alleles patients without MetS, the GG, GA and AA gen- of HSPA1B gene SNP rs1061581 was detected otypes were found in 78.12% (75/96), 20.81% in pediatric asthmatic patients and controls. (20/96) and 1.05% (1/96) of the cases, respec- HWE of rs1061581 in patients and controls tively. The frequency of G allele was significant- were listed in Table 2, and the results showed ly higher in asthma group with MetS (22.37%) allelic distribution of rs1061581 was not devi- than in controls (15.70%) (P = 0.022; OR = ated from HWE in both case and control popu- 0.645; 95% CI = 0.441-0.937). While asthmatic lations. The genotypic and allelic frequency of patients without MetS failed to show any such rs1061581 did not show significant difference difference (P = 0.16; OR = 1.445; 95% CI = between asthmatic patients and normal con- 0.863-2.467). trols. Then, Genotype and allele frequency of rs1061581 were detected in metabolic syn- In the patients with pediatric asthma, anthro- drome patients and normal control (Table 3). pometric and biochemical parameters were The genotypic and allelic frequency of rs106- analyzed according to the genotypes of rs106-

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Table 4. The comparison of genotype and allele frequency of HSPA1B site in pediatric asthmatic sub- groups and the control group Genotype (%) Allele (%) Groups (N) AA GA GG A G Pediatric with MetS (150) 88 (59.21) 56 (36.84) 6 (3.95) 232 (77.63) 68 (22.36) Pediatric without MetS (96) 75 (78.13) 20 (20.83) 1 (1.04) 170 (88.54) 22 (11.46) Controls (224) 187 (69.03) 37 (30.53) 2 (0.44) 381 (84.29) 71 (15.71) Control with Mets (52) 42 (80.77) 8 (15.38) 2 (3.84) 92 (88.47) 12 (11.54) Control without Mets (172) 145 (83.33) 27 (16.67) 0 286 (83.33) 29 (16.67)

Table 5. Anthropometic and biochemical parameters in studies have shown that high se- patients with asthma according to HSPA1B genotypes for rum HSPA1B level is linked to hy- 1276A/G polymorphisms perresponsiveness in asthma. Fur- Genotype thermore, the concentration of HS- Characteristic P-value PA1B was found to be elevated AA (n = 163) GA + GG (n = 83) in asthmatic airways and sputum. Fasting insulin (μU/mL) 11.15±3.64 15.78±8.31 0.021 HSPA1B has many effects relevant Fasting glycemia (mmol/L) 6.15±1.85 6.36±2.14 0.522 to the pathogenesis of asthma, in- HOMA-IR 2.63±0.69 4.25±2.37 0.041 cluding neutrophil release, epithe- Total cholesterol (mmol/L) 5.32±0.97 4.74±1.08 0.073 lial cell barrier permeability, macro- Triglycerides (mmol/L) 1.91±0.92 1.71±0.86 0.476 phage activation, recruitment of HDL cholesterol (mmol/L) 1.03±0.24 1.02±0.17 0.181 inflammatory infiltrates, effective- LDL cholesterol (mmol/L) 2.52±1.26 3.13±1.04 0.031 ness of the local and systemic inflammatory response, and am- plification of the effects of other 1581. For statistical purposes, the carriers of proinflammatory cytokines. Because secretion the A allele in the heterozygous and homozy- of cytokine is genetically regulated at the level gous states were treated together (Table 5). of transcription, and the linkage of HSPA1B We observed that the levels of LDL cholesterol polymorphisms with the genotype of asthma and insulin, and HOMA-IR were significantly has been demonstrated in accumulating stud- higher in the asthmatic patients carrying the ies [37-41]. GA and GG genotypes than in the carriers of AA genotype of rs1061581 (P = 0.028, P = HSPA1B gene is located in the class III region 0.021, P = 0.042, respectively). Furthermore, of the human major histocompatibility complex results revealed at among asthmatic patients, (MHC) on chromosome 6p21 [42, 43]. Among the rs1061581 GA and GG genotypes exhi- the several single nucleotide polymorphisms bited significantly higher serum HSPA1B le- (SNPs) identified in HSPA1B, HSPA1B rs106- vels than that of AA genotype (57.21±1.62 vs 1581 is the most extensively studied. The A 52.43±1.42, P<0.001). allele of this polymorphism can lead to high binding affinity of nuclear factors to the TNF Discussion promoter, resulting in a high level of transcription activity and secretion levels of HSPA1B. Genetic predisposition has been considered So, it was suggested to have a significant fun- as a crucial determinant in patients, and can- ctional effect [44]. A number of studies have didate genes have concentrated on leukotri- tried to determine whether the polymorphism ene-related genes. However, conflicting results of HSPA1B rs1061581 influences HSPA1B have been reported. Aron et al. suggested that expression, susceptibility to asthma, but no HSP70 overexpression in asthma was indepen- accordant result was obtained due to the het- dent on HSP gene polymorphisms, and Smith erogeneity of the genetic background among et al. reported that HSPA1A and HSPA1B do populations [45-47]. Whether genetic varia- not share common patterns of polymorphisms. tions of the HSPA1B rs1061581 conferred HSPA1B has important biological effects on susceptibility to asthmatic patients in Chinese airway inflammation and remodeling. Several was puzzled.

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In this study, we analyzed HSPA1B gene SNP In the patients with pediatric asthma, anthro- rs1061581 in 246 asthmatic patients and pometric and biochemical parameters were 224 matched controls from Tianjin, China. In analyzed under the genotypes of rs1061581. order to exclude the gender bias, the percent- We observed the levels of LDL cholesterol and age of males was extremely similar in patients insulin, and HOMA-IR content of GG + GA car- (43.54%, 108/246) and controls 49.56%, 112/ riers were higher than that of the AA carriers. 224). No difference was found in genotypic and This finding is in contrast with a study conduct- allelic frequency of rs1061581 between asth- ed by Chang et al., who reported an associ- matic patients and normal controls. This result ation between the pediatric pediatric asthma was in contrast with other previous studies patients and an insulin resistance state in that the HSPA1B rs1061581 polymorphism relation with the GG + GA genotypes of the was strongly associated with the risk of asth- rs1061581 polymorphism. HSPA1B suppress- ma. According to stratified analysis by ethni- es insulin induced tyrosine phosphorylation of city, Zhang et al. showed significant associa- insulin receptor and its substrates which may tions were showed in Asians, but not Cauca- affect insulin sensitivity. LDL cholesterol is sians. However, Silva et al. meta-analysis sug- sometimes referred to as bad cholesterol be- gested the positive association was shown in cause they can transport their content of fat West Asians and South Asians, but not in molecules into artery walls, attract macroph- East Asians. It is possible that different genetic backgrounds and environmental exposure ages, and thus drive atherosclerosis. LDL cho- may account for these differences [48]. lesterol pose a risk for cardiovascular disease when they invade the endothelium and be- Additionally, our results revealed asthmatic come oxidized, since the oxidized forms are subjects with genotypes carrying at least more easily retained by the proteoglycans [54- one G alles (GG and GA genotypes) exhibited 56]. A complex set of biochemical reactions significantly higher HSPA1B serum levels than regulates the oxidation of LDL particles, chiefly that of AA genotype. It has been shown previ- stimulated by presence of necrotic cell debris ously that individuals carrying the GG genotype and free radicals in the endothelium [57-59]. To have higher amounts of HSPA1B mRNA, and our knowledge, this is the first time to identify serum protein levels, than individuals with the that SNP rs1061581 in the HSPA1B confer- AA genotype. Similarly, Louis et al. reported red to IR and TBIL value in China pediatric asth- that cells stimulated with lipopolysaccharide, matic patients. All these results indicated that from individuals with the rs1061581 A allele, though the rs1061581 was not genetic suscep- expressed more HSPA1B than did the cells tible factor for asthmatic patients, it associated from individuals that were homozygous for the with clinical features such as serum LDL cho- G allele. lesterol and insulin [60-63]. HSPA1B rs1061581 polymorphism was sug- When the pediatric asthmatic patients were gested to have a significant functional effect, further subgrouped as asthma with MetS and with the G allele being associated with higher asthma without MetS according to diagnosis constitutive and inducible levels of transcrip- of MetS criteria, significant association was ob- tion for HSPA1B than the A allele [49]. The G allele of this polymorphism has been reported served between this polymorphism and asth- to be correlated with an increase in transcrip- matic patients with MetS susceptibility. While tion activity and secretion levels of HSPA1B asthmatic patients without MetS failed to show [25, 50]. The HSPA1B rs1061581 G allele leads any such difference. Due to the limited sample to high binding affinity of nuclear factors to the size in this study, we suggested more MetS pa- HSP70 promoter and gives a high level of gene tients with pediatric asthma should be collect- transcription. Several studies have shown that ed for further verification. To our knowledge, it high serum HSPA1B level is linked to hyper is the first time to verify SNP rs1061581 poly- responsiveness in asthma. In addition, HSPA1B morphism could impact on pediatric asthmatic was found in increased concentration in asth- patients with MetS in Chinese, and this result matic airways, in lavage fluid from asthmatic was partially consistent with high expression of lungs and induced sputum from subjects with HSPA1B mRNA and HSPA1B-stimulated genes severe pediatric asthma [22, 51-53]. in MetS patients [64-68].

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Therefore, Carrier of HSPA1B 1267A/G locus, [5] Ober C and Yao TC. The genetics of asthma high level of LDL-C and decrement in lung func- and allergic disease: a 21st century perspec- tion lead to insulin resistance. Thus, it results in tive. Immunol Rev 2011; 242: 10-30. an increased incidence of metabolic syndrome [6] Yang G, Chen J, Xu F, Bao Z, Yao Y and Zhou J. in asthmatic patients. So, people with asthma Association between tumor necrosis factor-al- carrying rs1061581 G allele should be early pha rs1800629 polymorphism and risk of intervention, such as reducing inflammation, asthma: a meta-analysis. PLoS One 2014; 9: e99962. weight control, improve insulin resistance, and [7] Srivastava P, Shafiq N, Bhasin DK, Rana SS, improve lung function. These measurements Pandhi P, Behera A, Kapoor R, Malhotra S and can effectively reduce the metabolic syndrome Gupta R. Differential expression of heat shock and atherosclerosis occurs, thereby reducing protein (HSP) 70-2 gene polymorphism in be- asthma, heart and cerebrovascular disease in- nign and malignant pancreatic disorders and cidence and mortality. its relationship with disease severity and com- plications. JOP 2012; 13: 414-419. Conclusions [8] Wang YZ, Zhou F and Wu YM. [Heat shock protein 70-2 gene +1267(G/A) polymorphism and In summary, though no any relationship be- susceptibility to lung cancer in Chinese Han tween genotypes and alleles in rs1061581 population]. Zhonghua Lao Dong Wei Sheng and asthma susceptibility was revealed, rs10- Zhi Ye Bing Za Zhi 2009; 27: 764-766. 61581 G allele increases insulin resistance [9] Li WQ, Wang CD, Lin JA, Chen YL, Wu T, Liu X and LDL cholesterol in pediatric asthmatic pa- and Chen RQ. [Relationship of heat shock pro- tients. Furthermore, we identified rs1061581 tein 70-2 gene polymorphism with hepatocel- was the risk factor for pediatric asthmatic pa- lular carcinoma]. Zhonghua Gan Zang Bing Za tients with MetS in Tianjin population. Zhi 2010; 18: 538-539. [10] Mir KA, Pugazhendhi S, Paul MJ, Nair A and Acknowledgements Ramakrishna BS. Heat-shock protein 70 gene polymorphism is associated with the severity We thank all the participants in this study. of diabetic foot ulcer and the outcome of surgi- This study was supported by Training Program cal treatment. Br J Surg 2009; 96: 1205-1209. Foundation for Talent of the Tianjin People’s [11] Gombos T, Forhecz Z, Pozsonyi Z, Janoskuti L Hospital (TIJN201224147). and Prohaszka Z. Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) Disclosure of conflict of interest gene polymorphism with disease severity in patients with chronic heart failure. Cell Stress None. Chaperones 2008; 13: 199-206. [12] Tosaka K, Mashima Y, Funayama T, Ohtake Y, Address correspondence to: Dr. Hong Zhang, De- Kimura I; Glaucoma Gene Research Group. partment of Pediatrics, Tianjin Union Medicine Cen- Association between open-angle glaucoma ter, No. 130 Jieyuan Road, Hongqiao District, Tianjin and gene polymorphism for heat-shock protein 300121, China. Tel: 86-022-82166395; Fax: 86- 70-1. Jpn J Ophthalmol 2007; 51: 417-423. 022-82166395; E-mail: [email protected] [13] Lin JA, Li WQ, Ye DF, Xue Y and Chen RQ. [The heat shock protein 70-2 gene +1267(A/ References G) polymorphism and susceptibility to ankylosing spondylitis in Chinese Han population]. [1] Cohn L, Elias JA and Chupp GL. Asthma: mech- Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2007; anisms of disease persistence and progres- 24: 574-575. sion. Annu Rev Immunol 2004; 22: 789-815. [14] Nam SY, Kim N, Kim JS, Lim SH, Jung HC [2] Misra RS. A review of the CD4+ T cell contribu- and Song IS. Heat shock protein gene 70-2 tion to lung infection, inflammation and repair polymorphism is differentially associated with with a focus on wheeze and asthma in the pe- the clinical phenotypes of ulcerative colitis diatric population. EC Microbiol 2014; 1: 4-14. and Crohn’s disease. J Gastroenterol Hepatol [3] Braman SS. The global burden of asthma. 2007; 22: 1032-1038. Chest 2006; 130: 4S-12S. [15] Lin JA, Ye DF, Zhu YY, Chen JM and Zheng WQ. [4] Koppelman GH and Nawijn MC. Recent ad- [Relationship between heat shock protein 70- vances in the epigenetics and genomics of hom gene polymorphism and ankylosing spon- asthma. Curr Opin Allergy Clin Immunol 2011; dylitis]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 11: 414-419. 2004; 21: 182-183.

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