Int J Clin Exp Pathol 2017;10(3):3510-3516 www.ijcep.com /ISSN:1936-2625/IJCEP0038921

Original Article Polymorphism of TNIP1 was associated with atherosclerotic ischemic stroke in southern Han Chinese but unrelated with telomere

Jianzhong Yu1, Dong Luo2, Feng Zhou1, Tianbo Jin3, Xiongfei Liang1, Dan Yu1

1Department of Neurology, Haikou Municipal Hospital, Affiliated Haikou Hospital of Xiangya Medical College of Central South University, Haikou, Hainan, China; 2Department of Neurology, School of Medicine, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China; 3School of Life Sciences, Northwest University, Xi’an, Shaanxi, China Received August 28, 2016; Accepted October 31, 2016; Epub March 1, 2017; Published March 15, 2017

Abstract: Objective: To evaluate the association between atherosclerotic ischemic stroke (AIS) and single-nucleo- tide polymorphisms (SNP) in TERT, TNIP1, OBFC1 in southern Chinese Han population. Methods: Sequenom MassARRY system was used to genotype 12 SNPs (rs10069690, rs2242652, rs2853677, rs2853676 in TERT; rs7708392, rs10036748, rs960709 in TNIP1; rs9325507, rs3814220, rs12765878, rs11191865, rs9420907 in OBFC1) in both atherosclerotic ischemic stroke patients (n=400) and healthy controls (n=399). Association analyses were performed in SNPstats platform in five genetic models (dominant, recessive, additive, codominant, overdominant). Analysis of allele frequencies and linkage disequilibrium were also conducted. Odd ratio (OR) and 95% confidence interval (95% CI) were adjusted for confounding factors (age, gender, past medical history, smoke, alcohol, blood lipid). Results: SNP rs7708392 was significantly associated with an increased risk of AIS after adjust- ment for above confounding factors in our population (heterozygous model P=0.04, OR=1.62, 95% CI 1.01-2.61 and overdominant model P=0.037, OR=1.64, 95% CI 1.03-2.62). None of the rest SNPs was observed to associate with AIS susceptibility in allele or any genetic model. No significant difference was found between the common hap- lotype in OBFC1 and TNIP1 and the risk of AIS. And there were no statistical significance between telomere length, serum lipid levels, hypertension, diabetes mellitus and rs7708392 genotype in the control group. Conclusion: TNIP1 rs7708392 polymorphism was first found to be associated with the occurrence of AIS, but the association may be independent of telomere, hypertension and diabetes mellitus. Further study should be conducted to confirm the association and to explore the role of this variant in the pathogenesis of AIS.

Keywords: SNP, stroke, cerebral infarction, TNIP1, TERT, OBFC1

Introduction tecting and maintaining genetic integrity and stability. Evidences suggested that shorter telo- Stroke is the second most common cause of mere length was associated with an increased death and leading cause of adult disability risk of age-related disease [4, 5], such as car- worldwide [1]. In China, the annual stroke mor- diovascular disease and ischemic stroke [6-10]. tality rate has become the first leading cause Telomere length shortening was considered to of death and adult disability over heart dise- be an indicator of the cumulative burden of ase [2]. Ischemic stroke (IS) accounts for about inflammation and oxidative stress [11]. Loss 62.4%-69.6% of all stroke cases [3]. Modifiable of A20, which binds with the protein risk factors including hypertension, metabolic (ABIN-1) encoded by the gene TNF α-induced disturbances, smoking, and obesity are the protein 3-interacting protein 1 (TNIP1), resulted most common of stroke. However, the genetic in inflammation and autoimmune responses risk factors involved in stroke remains elusive. with elevation of IL-6 [12, 13]. However, present studies mostly focused on the associations Telomeres consist of DNA-protein complexes between TNIP1 gene polymorphisms and sys- located at the end of the , pro- temic [13, 14]. An in vivo TNIP1 polymorphism and atherosclerotic ischemic stroke study indicated that ABIN-1 involved in the The case-control study protocol was appro- regulation of chronic inflammation and car- ved by the Clinical Research Ethics of Haikou diovascular disease [15]. Telomerase reverse Municipal Hospital. Written informed consent transcriptase protein (TERT) was considered was obtained from all the subjects or families as rate limiting catalytic subunit of telomerase participating in the present study. [16]. Cumulative studies confirmed that poly- morphisms of gene TERT were associated with A 3-5 ml sample of peripheral venous blood telomere-related diseases including cancers, was collected from each participant, and tem- myocardial infarction, and IS [4, 17-19]. Oligo- porarily stored at -20°C in the hospital central nucleotide/oligosaccharide binding fold con- lab. Then the further study was completed in taining 1 (OBFC1) codes for oligosaccharide- Northwest University (Xi’an city, Shaanxi prov- binding fold-containing protein 1 and is part ince, China). of CST complex, which is bind to the telo- meric 3’ overhang and plays an important role DNA isolation and genotyping assay in telomere maintenance [30]. Genomic DNA was taken with the GoldMag- Up to now, there were only few studies cond- Mini Purification Kit (GoldMag Co. Ltd. Xian city, ucted on the correlation between SNPs (rs- China) according to manufacturer’s protocols. 10069690, rs2242652, rs2853677, rs2853- DNA concentrations were qualified with the 676, rs10036748, rs960709, rs9325507, rs- NanoDrop 2000 (Thermo Scientific, Waltham, 3814220, rs12765878, rs11191865, rs7708- Massachusetts, USA). Genotype were perfor- 392 and rs9420907) and atherosclerotic isch- med on the Sequenom MassARRAY RS1000 emic stroke (AIS). Thus, this case-control study [22]. The results were managed and analyzed was designed to assess if these variants con- by Sequenom Typer 4.0 Software (Sequenom, ferred risk to AIS in southern Han Chinese, and Inc.). the possible relation with telomere. Telomere length measurement Materials and methods Real-time quantitative PCR (RT-PCR)-based Study population and sample collection method was used to calculate the relative From February 2015 to March 2016, athero- telomere length (RTL) in a LightCycler®480 sclerotic ischemic stroke patients were recr- QPCR System (Roche, Basel, Switzerland). RTL uited from the Department of Neurology of was the ratio between the copy number of Affiliated Haikou Hospital of Xiangya Medical telomere repeats (T) and a single-copy gene College of Central South University in Haikou copy number (S). city, Hainan province, China. The diagnostic criteria were defined as a sudden focal or Statistical analysis global disturbance of cerebral function caused by vascular occlusion over 24 hours or longer, Continuous variables were expressed as mean and further confirmed with computed tomo- ± standard deviation (SD) and categorical vari- graphy (CT) or magnetic resonance imaging ables were shown as counts. Hardy-Weinberg (MRI). Newly diagnosed and only LAA (large equilibrium (HWE) in control group was tested 2 vessel atherosclerosis) cases classified on by χ test. Kruskal-Wallis H test was used TOAST [21] (Trial of Org 10172 in Acute Stroke to assess the difference of telomere length Treatment) were included. Patients who had among genotype of rs7708392. Independent the following conditions were excluded: car- sample t test and Chi-square (χ2) tests were dioembolism, brain trauma, tumors, transient used to test for the differences of measure- ischemic attack, or cerebrovascular malforma- ment data and enumeration data between tion; and inflammatory disease, collagenosis, groups. The odds ratio (OR) and 95% confi- or severe heart, liver, renal diseases. At the dence interval (CI) were calculated on SNPS- same time, the controls were enrolled from the tats platform in five genomic models includ- health checkup center in the same hospital. ing dominant, co-dominant, additive, recessive, The exclusion criteria included subjects diag- and overdominant model. A two-sided P<0.05 nosed with any history of cerebrovascular and was considered to be statistically significant. cardiovascular disease. Data analyses were done by Microsoft Excel,

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Table 1. Characteristics and clinical features rs3814220, rs12765878, rs11191865, Characteristic Case Control P and rs9420907 were significantly diffe- rent in any model after adjustment for the Age (years) 66.8 ± 11.6 48.7 ± 11.1 <0.001 confounding factors between the AIS pati- Gender (male/female) 34.3 38.3 0.23 ents and the controls. Table 3 presented Cigarette smoking (%) 32.8 13.8 <0.001 the association of rs7708392 with the risk Alcohol (%) 17.3 10.5 0.006 of AIS in genetic models after adjustment DM (%) 23 5.3 <0.001 for gender, age, smoking, alcohol, diabetes Hypertension (%) 69.3 7.8 <0.001 history, hypertension history, BMI, TC, TG, BMI (kg/m2) 24.7 ± 3.8 23.8 ± 2.8 <0.001 HDL-C, and LDL-C. A statistically significant TC (mmol/l) 4.91 ± 1.2 5.18 ± 0.9 <0.001 difference was found in heterozygous (P= TG (mmol/l) 1.34 ± 0.9 1.49 ± 0.5 0.004 0.04, OR=1.62, 95% CI 1.01-2.61) and over- LDL-C (mmol/l) 2.92 ± 1.0 3.12 ± 0.7 0.001 dominant model (P=0.037, OR=1.64, 95% HDL-C (mmol/l) 1.28 ± 0.3 1.38 ± 0.5 0.001 CI 1.03-2.62). BMI, body mass index; DM, diabetes mellitus; TC, total choles- terol; TG, total triglyceride; HDL-C, high density lipoprotein-choles- Haplotypes and the risk of AIS terol; LDL-C, low density lipoprotein-cholesterol. For further investigation of the correlation between SNPs and risk of AIS, linkage dise- SPSS23.0 (SPSS Inc., Chicago, IL) and SNPS- quilibrium and haplotype analysis were con- tats platform. Linkage disequilibrium and hap- ducted for the SNPs within the same gene. lotype construction were analyzed on the hap- There was strong linkage disequilibrium am- loView software. ong rs10036748, rs7708392, rs960709 with- in TNIP and rs9325507, rs3814220, rs127- Results 65878, rs11191865 within OBFC1. The com- mon haplotype was shown in Table 4. How- Patient characteristics and clinical features ever, none of the haplotypes were associated with AIS susceptibility. A total of 400 atherosclerotic ischemic stroke patients and 399 healthy controls were inc- The rs7708392 genotype and telomere, se- luded in this present case-control study. The rum lipid levels distribution of demographic and clinical data were presented in Table 1. We observed dif- The association between rs7708392 geno- ferences in age, smoking, alcohol, history of type and telomere, serum lipid levels in con- diabetes mellitus (DM), history of hyperten- trol group was presented in Table 5. There sion, body mass index (BMI), total cholesterol was no statistical difference for relative telo- (TC), total triglyceride (TG), high density lipo- mere length among these three genotypes. No protein-cholesterol (HDL-C), low density lipo- difference was found for each lipid level, hyper- protein-cholesterol (LDL-C) between the case tension, and diabetes mellitus among them. and control group. Blood lipid in cases is lower Discussion than that in controls. No significant difference was presented in gender. We performed this case-control study to ass- ess the correlation between some polymor- The SNPs and the risk of AIS phisms in TERT, TNIP1 and OBFC1 and the risk of AIS in southern Chinese Han population. The detailed information about all SNPs inc- The results suggested that rs7708932 within luded in this study was shown in Table 2. There TNIP1 was associated with an increased risk of was no significant difference from HWE in ischemic stroke. None of the rest SNPs had a genotype frequencies in the control group for significant difference with AIS susceptibility. all SNPs. All the SNPs were not associated The haplotype analysis showed that none of with AIS in allele model. CC genotype was not the common haplotype in TNIP1 and OBFC1 observed for rs9420907 in both case and was associated with AIS risk. control group. None of the following SNPs: rs10069690, rs2242652, rs2853677, rs28- Atherosclerosis, which originated from endo- 53676, rs10036748, rs960709, rs9325507, thelial dysfunction, is a major cause of isch-

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Table 2. Candidate SNPs in this study MAF (%) HWE Alleles SNP Position Band Gene Case Control ORs 95% CIs P P A/B rs10069690 1279790 5p15.33 T/C TERT 0.14 0.15 0.88 0.67-1.17 0.39 1 rs2242652 1280028 5p15.33 A/G TERT 0.15 0.16 0.88 0.67-1.15 0.36 0.1 rs2853677 1287194 5p15.33 G/A TERT 0.38 0.41 0.89 0.73-1.09 0.24 0.54 rs2853676 1288547 5p15.33 T/C TERT 0.15 0.17 0.89 0.68-1.17 0.41 0.47 rs7708392 150457485 5q33.1 G/C TNIP1 0.25 0.23 1.09 0.87-1.38 0.44 0.33 rs10036748 150458146 5q33.1 C/T TNIP1 0.25 0.23 1.13 0.90-1.42 0.30 1 rs960709 150461049 5q33.1 A/G TNIP1 0.25 0.23 1.09 0.87-1.37 0.46 0.78 rs9325507 105645622 10q24.33 T/C OBFC1 0.35 0.37 0.93 0.75-1.13 0.41 0.59 rs3814220 105647300 10q24.33 G/A OBFC1 0.35 0.37 0.91 0.74-1.12 0.42 0.52 rs12765878 105669622 10q24.33 C/T OBFC1 0.35 0.37 0.93 0.75-1.13 0.45 0.52 rs11191865 105672842 10q24.33 A/G OBFC1 0.35 0.37 0.92 0.75-1.13 0.44 0.52 rs9420907 105676465 10q24.33 C/A OBFC1 0.02 0.01 2.42 0.85-6.89 0.09 1 A/B minor/major allele, SNP single nucleotide polymorphism, HWE Hardy-Weinberg equilibrium, MAF minor allele frequency, OR odd ratio, CI confidence interval.

Table 3. Association between rs7708392 and the risk of factors and atherosclerosis in rheu- atherosclerotic ischemic stroke in genetic models matoid arthritis and systemic lupus Model Genotype Control Case OR (95% CI) P# erythematosus [23, 24]. TINP1, a gene which codes for TNFAIP3-inte- Codominant C/C 236 224 1 racting protein-1 (ABIN-1), is a regu- G/C 135 152 1.62 (1.01-2.61) 0.04 latory molecule that stops signal G/G 25 24 0.87 (0.34-2.25) 0.83 way by several receptors, including Dominant C/C 236 224 1 TNF-alpha, TLR and PPAR [25]. Pre- G/C-G/G 160 176 1.48 (0.94-2.32) 0.09 vious studies had confirmed the Recessive C/C-G/C 371 376 1 variants in TINP1 gene were associ- G/G 25 24 0.73 (0.29-1.84) 0.5 ated with an increased risk of sys- Overdominant C/C-G/G 261 248 1 temic lupus erythematosus in Euro- G/C 135 152 1.64 (1.03-2.62) 0.037 pean, Chinese and Japanese popu- Log-additive ------1.22 (0.85-1.76) 0.28 lation [26]. Naveed Akbar, et al re- OR odd ratio, CI confidence interval.# adjusted for gender, age, smoking, ported that ABIN-1 was associated alcohol, diabetes history, hypertension history, body mass index, total cho- with cardiovascular disease in mice lesterol, total triglyceride, high density lipoprotein-cholesterol, low density [15]. However, up to now, there was lipoprotein-cholesterol. no report on the association bet- ween TINP1 polymorphisms and risk of AIS. Therefore, we conduc- Table 4. Haplotype frequencies and the risk of AIS ted the disease association bet- Gene Haplotype Case Freq Control Freq OR (95% CI) p ween three variants rs10036748, TNIP1 T-C-G 0.75 0.76 1 rs7708392, rs960709 and the risk C-G-A 0.25 0.22 1.25 (0.86-1.81) 0.25 of IS. The results showed that rs- OBFC1 G-T-A-C-A 0.63 0.62 1 7708392 was associated with an A-C-G-T-A 0.35 0.37 0.90 (0.65-1.24) 0.52 increased risk of IS in heterozygous and overdominant model. For explo- G-T-A-C-C 0.02 0.006 1.64 (0.24-11.05) 0.61 ration of the possible reason, we AIS atherosclerotic ischemic stroke, Freq frequency, OR odd ratio, CI confidence interval. P adjusted for gender, age, smoking, alcohol, diabetes also performed the association an- history, hypertension history, body mass index, total cholesterol, total triglyc- alysis between rs7708392 geno- eride, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol. type and hypertension, blood lipid levels and diabetes mellitus in the control group. However, none of emic stroke, especially in the carotid and intra- them showed a significant difference among cranial arteries. Evidence manifested the asso- them. Although the difference disappeared ciation among vascular function, inflammation after Bonferroni correction, this polymorphism

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Table 5. Genotype of rs7708392 and telomere, hypertension, diabetes mellitus and serum lipid in controls Genotype n Telomere (M) HBP (%) DM (%) HDL LDL TG TC CC 236 1.08 17.8 6.4 5.22 ± 0.89 3.13 ± 0.74 1.49 ± 0.52 5.22 ± 0.89 GC 135 1.12 13.3 6.9 1.38 ± 0.53 3.11 ± 0.71 1.52 ± 0.60 5.18 ± 0.81 GG 24 1.15 20 12 1.31 ± 0.54 3.10 ± 0.64 1.42 ± 0.46 4.94 ± 0.77 p 0.56 0.47 0.56 0.76 0.94 0.68 0.3 M median, HBP hypertension, DM diabetes mellitus, TC total cholesterol, TG triglyceride, HDL-C high-density lipoprotein choles- terol, LDL-C low-density lipoprotein cholesterol. was still a potential target in developing athe- association with the risk of AIS. Our results rosclerosis and further ischemic stroke, which indicated that no CC genotype was observed deserved further investigation in multiracial in rs9420907, and no significant difference and larger sample studies. was found in allele or genotype or any genetic model. Telomerase prolongs telomere sequence dur- ing DNA replication by adding the short telo- The results from our study should be inter- mere repeats (TTAGGG) to maintain chromo- preted with caution in light of several limita- somal integrity and stability. TERT is a rate- tions. Firstly, the statistic difference existed in limiting catalytic component of this enzyme. age between cases and controls. The present Therefore, mutations in the TERT gene may study had a disproportionate number of sub- change the telomerase enzyme activity, short- jects under the age of 40 (20.1% in controls en telomere length and further induce the and only 2% in cases). Secondly, there were sig- development of some disease [27, 28]. The nificantly higher blood lipid levels in controls variants rs10069690 and rs2242652 were compared to the case group. This might be found to increase the risk of lung cancer, but due to the use of lipid-lowering drugs or more not in rs2853676 [27]. And rs2736100 was attention was given on physical activity and associated with coronary artery disease in healthy life style in the case group. European population [4]. We performed the study on the association between rs2853676, We concluded that variants within the TERT rs2853677, rs10069690 and rs2242652 and and OBFC1 probably played no major risk of AIS. However, our results demonstrated role in the determination of AIS. SNP (rs7708- that no statistical difference was found bet- 392) within the TNIP1 gene was associated ween them after adjustment for confounders with an increased risk of AIS, which maybe in any model. unlikely to be caused by telomere shortening, hypertension, diabetes and serum lipid. Haplo- Oligonucleotide/oligosaccharide binding fold type analysis showed no significant difference containing 1 (OBFC1) codes for oligosaccha- between the case and the control within TNIP1 ride-binding fold-containing protein 1. Some and OBFC1. study suggested that OBFC1 could bind to telo- Acknowledgements meric single-stranded DNA in vitro, and overex- pression of OBFC1 mutant resulted in elon-gat- This work was supported by the Key Scientific ed telomeres [29]. GWAS meta-analysis sho- and Technological Project of Hainan Province wed that many SNPs including rs9325507, (No. ZDXM20130066). rs3814220, rs12765878 and rs9420907 were associated with leukocyte telomere length Disclosure of conflict of interest and further confirmed in replication [30]. Some previous study manifested that mutations in None. OBFC1 were associated with an increased risk in ischemic heart disease [20]. For ischemic Address correspondence to: Dr. Dan Yu, Depart- stroke, five polymorphisms including rs932- ment of Neurology, Haikou Municipal Hospital, 5507, rs3814220, rs12765878, rs11191865 Affiliated Haikou Hospital of Xiangya Medical College and rs9420907 were selected to test the of Central South University, Haikou 570208, Hainan,

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