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Original Article Association of LRRFIP1 Gene Polymorphisms with Susceptibility to Ischemic Stroke in a Chinese Population

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Original Article Association of LRRFIP1 Gene Polymorphisms with Susceptibility to Ischemic Stroke in a Chinese Population Int J Clin Exp Pathol 2017;10(2):2187-2192 www.ijcep.com /ISSN:1936-2625/IJCEP0044436 Original Article Association of LRRFIP1 gene polymorphisms with susceptibility to ischemic stroke in a Chinese population Hong-Jun Guan1, Yu-Peng Guo1, Jun-Hua Lu2, Li-Li Meng1, Sheng-Zhong Rong1, Jing Dong1, Yong Yang1, Ying-Ying Niu1, Li-Yan Yao1, Xiao-Xia Li1 1College of Public Health, Mudanjiang Medical University, Mudanjiang, Heilongjiang, P. R. China; 2Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, P. R. China Received November 16, 2016; Accepted November 26, 2016; Epub February 1, 2017; Published February 15, 2017 Abstract: Previous studies showed that leucine-rich repeat (in FLII) interacting protein 1 (LRRFIP1) was proposed as one regulator of the toll-like receptor (TLR) pathway signaling. The activation of LRRFIP1 protein may regulate TLR pathway signaling culminating in the production of a range of inflammatory markers, and its gene expression was influenced by a functional polymorphism in the exon region. The genetic basis of the ischemic stroke has now been largely determined, so the aim of the study was to examine the role of LRRFIP1 genetic variants in the ischemic stroke (IS) risks in a Chinese population. We conducted a case-control study with 239 IS patients and 240 controls. SNP rs3769053 of LRRFIP1 gene was analyzed for association with risk of IS in Han population. The distributions of genotypes in LRRFIP1 gene were slightly different between IS groups and health controls. And then we evaluated the association between LRRFIP1 gene (rs3769053) polymorphisms and IS with multivariate logistic regression. We found that neither TC (OR=1.353, 95% CI: 0.457-4.008, P=0. 585) nor TT (OR=1.309, 95% CI: 0.850-2.016, P=0.221) genotype was significantly associated with the risk of IS. In summary, our study reveals that the LRRFIP1 gene polymorphism (C→T) may not be a risk factor for the development of IS in Chinese Han population. Keywords: Case-control study, ischemic stroke, leucine-rich repeat (in FLII) interacting protein 1, polymorphism Introduction like receptor (TLR) signaling pathway via inter- actions with flightless I homolog (FliiH), which Stroke is the third cause of mortality and the interacts with MyD88 [22, 23]. The Toll-like first cause of serious disability in developed receptor (TLR) gene is recently proposed as countries [1]. There are 2.5 million new stroke one potential molecular link between obesity, cases each year and 7.5 million stroke survi- inflammation, and insulin resistance [24]. TLRs vors in China [2]. Ischemic stroke (IS) account- also play a role in ischemic brain injury [25]. ed for 85-90% of strokes [3]. The occurrence Hence, since IS is a complex disease that is and development of IS results mostly from commonly associated with an inflammatory genetic and environmental influences plus state [26]. LRRFIP1 gene is identified one interaction effects between genes and behav- regulator of the TLR pathway signaling [27]. ior. The role and importance of gene polymor- Moreover, it is recently reported that activation phisms have been confirmed by a large number of the LRRFIP1 protein may lead to a cascade of studies [4-9]. In recent years, the associa- of signaling events culminating in the produc- tion of multitudinous gene polymorphisms with IS population were found in Chinese population tion of tumor necrosis factor-a and other mark- [10-14]. LRRFIP1 (leucine-rich repeat (in FLII) er of inflammation related to extracellular treats interacting protein 1) is a poorly characte- [28]. However IS results from a reduction in rized protein that has been described as both cerebral blood flow triggering a cascade of cel- a transcriptional repressor and as a MyD88 lular and molecular events [29]. In addition, (myeloid differentiation primary response gene variations in the LRRFIP1 gene are associated (88))-interacting protein [15-21]. Recently, sev- with adiposity and inflammation [30], breast eral studies have identified its role in the toll- and colorectal cancers [31]. LRRFIP1 gene polymorphisms with susceptibility to ischemic stroke With the achievement of the Human Genome lowing vascular risk factors and environmental Project (HGP) and International HapMap Project factors were recorded: history of cigarette (HapMap), genetic susceptibility has been a smoking, tea-drinking, alcohol-drinking. All very hot subject in current research in function- participants were measured for their current al genomics. Identification of disease suscepti- height and weight. bility gene is of great significance for the early warning, prevention and individualized treat- Biochemical variables and genotyping ment. The overexpression of LRRFIP1 in cere- bral ischemia has been described earlier [1] A 5 ml venous blood sample was drawn into and LRRFIP1 gene is involved in stroke damage tubes containing 5% EDTA after at least 12 to and recovery [32, 33]. Whether there is an 14 h of fasting. Plasma total trigly-ceride, cho- association of polymorphism of LRRFIP1 gene lesterol, low-density lipoprotein cholesterol with susceptibility to IS remains unknown. (LDL), and high-density lipopro-tein cholesterol Therefore, we first investigate the relationship (HDL) were measured using enzymatic meth- between LRRFIP1 gene polymorphism and the ods. Plasma glucose was measured by a glu- IS in a Chinese population. cose oxidase procedure. In case of acute or other emergencies, blood samples were col- Subjects and methods lected 6 days later. Genomic DNA was purified from whole blood samples using a DNA blood Subjects kit (QIAGEN, Hilden, Germany) according to the manufacturer’s instructions. DNA samples This study protocol was reviewed and approved were stored at -80°C before use. According to by the Department of Science and Technology the information in the NCBI SNP database, of Mudanjiang City and the local Ethics SNPs which had a minor allele frequency of Committees of all the participating hospitals. more than 5% or those established in the lite- Cases and controls were Han Chinese recruited rature were chosen. TaqMan SNP genotyping consecutively from the same geographic re- assay was used to determine the polymorphism gion from September 2009 to June 2013 in (rs3769053) of LRRFIP1 gene. The primers Mudanjiang city and consented to provide bio- were forward, 5’-GACCTTGAGGCTGCATTTCT- logical samples for genetic analysis. A case- AAA-3’ and reverse, 5’-CCACTCTCACTTCTCA- control study design was adopted. Cases were ATGAACAAC-3’. The Taqman minor groove bind- patients with new-onset IS registered in No.1, ing (MGB) probes for detection of C/T polymor- No.2 People’s Hospital and Hongqi Hospital phism were FAM-AAATTACTtGAAAGCTGC-MGB Affiliated to Mudanjiang Medical University in and HEX-AAATTACTcGAAAGCTG-MGB. The pri- Mudanjiang city. We consecutively recruited mers and probes were commercially supplied 239 patients (147 males, 92 females; mean by Shanghai GeneCore Biotechnologies. Ther- age, 55.45 years) with IS diagnosed by neuro- mal cycling was performed on ABI 7500 sys- logical examination and CT, or MRI, or both tems from Applied Biosystems (Applied according to International Classification of Biosystems, Foster City, CA, USA). Allele fre- Diseases (9th edition). Patients with hemor- quencies were also determined by ABI 7500 rhagic stroke, cancer, autoimmune disease, or systems. chronic inflammation were excluded in this Statistical analysis study. The control group consisted of 240 sub- jects (147 males and 93 females), who were Epidata 3.0 was used to establish the data- unrelated healthy individuals without a history base. Allele and genotype frequencies in pa- of stroke. 240 subjects were recruited from the tients and controls were compared by χ2 test or same geographic region as controls. The con- Fisher exact test. A goodness-of-fit χ2 test was trols had no clinical evidence of related neuro- used to observe the deviation of genotype dis- logical diseases according to the same exclu- tribution from Hardy-Weinberg equilibrium. Con- sion criteria adopted for the case group and tinuous variables were expressed as mean ± no a history of stroke. The cases and con- SE and categorical variables were assessed by trols were interviewed by investigators using χ2 test or Fisher’s exact test. First, risk factors the same structured questionnaire. Besides were screened by Student’s t test or χ2 test, history of hyper-tension, history of Diabetes, and then logistic regression models were used and history of coronary artery disease, the fol- to evaluate the effects of risk factors. Odds 2188 Int J Clin Exp Pathol 2017;10(2):2187-2192 LRRFIP1 gene polymorphisms with susceptibility to ischemic stroke Table 1. Demographic characteristics and distribution of tradi- tween the patients and con- tional risk factors trols. But the prevalence of Case Control Wald conventional risk factors for Variable P (n=239) (n=240) or F vascular disease was higher in Age (year) 55.45±10.17 52.18±8.99 3.709 <0.001 patients, and these risk factors included history of hyperten- Gender(M/F) 147/92 147/93 0.003 0.954 sion, history of diabetes, smok- BMI ing, LDL-C and GLU (all P<0.05). ≥25 (kg/ m2) 146 143 0.113 0.736 <25 (kg/ m2) 93 97 Distribution of LRRFIP1 gene History of hypertension 110 78 5.471 0.019 polymorphism in two groups History of diabetes 33 14 8.605 0.003 History of heart diseases 33 26 0.981 0.322 Genotypes were obtained for all subjects for rs3769053 Smoking 95 72 5.012 0.025 polymorphism as shown in Alcohol drinking 87 87 0.001 0.972 Table 2. The genotypes of Tea drinking 50 105 28.514 <0.001 rs3769053 in LRRFIP1 gene Triglyceride (mmol/l) 2.11±2.03 1.94±0.97 1.182 0.238 were in accordance with Hardy- Cholesterol (mmol/l) 5.06±1.87 5.15±0.81 0.710 0.478 Weinberg equilibrium in con- HDL-C (mmol/l) 1.42±0.80 1.43±0.37 0.274 0.785 trols (HWP=0.338).
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