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Original Article Two DOCK7 Polymorphisms and Their Haplotypes Are Associated with the Risk of Coronary Artery Disease and Ischemic Stroke

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Original Article Two DOCK7 Polymorphisms and Their Haplotypes Are Associated with the Risk of Coronary Artery Disease and Ischemic Stroke Int J Clin Exp Pathol 2016;9(2):2169-2180 www.ijcep.com /ISSN:1936-2625/IJCEP0020107 Original Article Two DOCK7 polymorphisms and their haplotypes are associated with the risk of coronary artery disease and ischemic stroke Rong-Jun Nie1, Rui-Xing Yin1, Feng Huang1, Xiao-Li Cao2, Jin-Zhen Wu1, Wu-Xian Chen1, Zhi-Min Li3 1Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital, Guangxi Medical Uni- versity, Nanning, Guangxi, China; Departments of 2Neurology, 3Radiotherapy, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China Received November 19, 2015; Accepted January 24, 2016; Epub February 1, 2016; Published February 15, 2016 Abstract: The association between the dedicator of cytokinesis 7 (DOCK7) rs10889353 and rs10889335 polymor- phisms and the risk of coronary artery disease (CAD) and ischemic stroke (IS) has not been reported previously. The present study was undertaken to examine the association between the DOCK7 rs10889353 and rs10889335 polymorphisms and their haplotypes and the risk of CAD and IS in the Han Chinese population. Genotypes of the two polymorphisms were determined by the Snapshot technology platform in 1,139 unrelated patients (CAD, 584 and IS, 555) and 627 healthy controls. The frequency of the rs10889353 alleles and genotypes was different be- tween controls and CAD (P < 0.01) or IS (P < 0.05). The frequency of the 10889335 alleles and genotypes was also different between controls and CAD (P < 0.01). The rs10889353C allele and CC genotype were associated with an increased risk of CAD and IS, and the rs10889335G allele, GG genotype and rs10889353C-rs10889335G (21.0%) haplotype were also associated with an increased risk of CAD. Both rs10889353CC and rs10889335GG genotypes were associated with the angiographic severity of CAD. The rs10889353C and rs10889335G allele carriers in the healthy controls had higher serum total cholesterol (TC) and triglyceride (TG) levels than the rs10889353C and rs10889335G allele non-carriers. Stratified analyses showed that the two polymorphisms may interact with gender, age, body mass index, smoking, drinking, hypertension and hyperlipidemia to influence the risk of CAD and IS. This study shows that the DOCK7 rs10889353 and rs10889335 polymorphisms and their haplotypes in the Han Chi- nese population are associated with the risk of CAD and IS, and with serum TC and TG levels in the healthy controls. Keywords: Dedicator of cytokinesis 7 gene, single nucleotide polymorphism, coronary artery disease, ischemic stroke, lipids Introduction predisposition to CAD [6] or to IS [7] in Caucasian populations. Furthermore, certain Cardiovascular disease is the leading cause of genetic variants originally shown to influence morbidity and mortality in most industrialized the risk of CAD were also subsequently found to nations and is of growing concern in developing be associated with IS [8, 9], suggestive of a countries [1]. Both coronary artery disease shared genetic architecture for these condi- (CAD) and ischemic stroke (IS) are atheroscle- tions. Although CAD and IS may share genetic rotic diseases that may share many common factors in Caucasian populations, the genes aspects of their underlying pathogenesis, as that confer susceptibility to the two diseases in well as risk factors, including dyslipidemia, the Chinese individuals are very few [10-14]. hypertension, diabetes, chronic kidney disease and cigarette smoking [1, 2]. Previous twin and The dedicator of cytokinesis 7 protein (DOCK7) family studies have shown that CAD [3] and IS belongs to the DOCK family, which consists of [4] are highly heritable, with evidence of a eleven guanine nucleotide exchange factors shared heritability for the two conditions [5]. (GEFs) [15]. Although the molecular structures Previous genomewide association studies of DOCK proteins are similar, the small guanine (GWASs) and meta-analyses of such studies nucleotide triphosphatases (GTPases), includ- have identified various genes and loci in the ing Rac and Cdc42, are regulated by specific DOCK7 SNPs and their haplotypes with CAD and IS stroke DOCK proteins [15]. DOCK1 (OR DOCK180), as well as increases in the serum markers DOCK2 and DOCK3 are Rac-specific GEFs. including creatinine kinase-MB and troponin T. DOCK4 and DOCK5 are structurally deduced Coronary angiography was performed in GEFs for Rac. DOCK6, DOCK7 and DOCK8 are patients with CAD. The selected CAD patients GEFs for Rac and Cdc42. DOCK9, DOCK10 and were subject to significant coronary stenosis (≥ DOCK11 are Cdc42-specific GEFs. It is also 50%) in at least either one of the three main known that each DOCK protein is differentially coronary arteries or their major branches expressed in different cell types [15, 16]. (branch diameter ≥ 2 mm). Additionally, angio- DOCK7 is composed of two DOCK homology graphic severity of disease was defined as sin- region (DHR) domains: the N-terminal (DHR-1) gle or multi-vessel disease based on the num- domain mediates a specific interaction with ber of involved artery (luminal narrowing ≥ 50%) PIP2 and PIP3, and the C-terminal (DHR-2) in the three major coronary arteries [31, 32]. domain is involved in binding to, and revealing The classification of IS was made according to GEF activity towards, Rac1, Rac3, and/or the TOAST (Trial of Org 10172 in Acute Stroke Cdc42 [17, 18]. DOCK7 is expressed mainly in Treatment) criteria [33]. The selected IS neuronal cells [19]. Cellular functions of DOCK7 patients in the study included individuals who remain poorly defined; it is postulated it might were eligible for one of the two subtypes of be involved in neurogenesis [20, 21]. Perisic et TOAST criteria: Large-artery atherosclerosis al. [22] have demonstrated that the DOCK7 and small-vessel occlusion. Subjects with a his- was upregulated in symptomatic carotid tory of hematologic, neoplastic, renal, liver, thy- plaques, suggesting that the DOCK7 may be roid, autoimmune diseases and type 1 diabe- associated with the development of carotid tes were excluded. The selected IS patients atherosclerosis. DOCK7 gene (DOCK7; gene ID: who had a past history of CAD were excluded, 85440, MedGen: CN189147, OMIM: 615859) while the selected CAD patients who had a past is located on chromosome 1p31.3 (Exon count: history of IS were excluded from the study. 53). Several transcript variants encoding differ- ent isoforms have been found for this gene A total of 627 control subjects matched by age, [23]. Recent GWASs in different populations gender, and ethnic group were consecutively have showed that several DOCK7 single nucle- recruited from Physical Examination Center of otide polymorphisms (SNPs; rs1168013, the First Affiliated Hospital, Guangxi Medical rs10889353, rs10889335, rs1167998 and University during the same period when IS and rs11207995) were associated with total cho- CAD patients were recruited. The controls were lesterol (TC) [24-27], triglyceride (TG) [26-29] free of IS and CAD by questionnaires, history and low-density lipoprotein cholesterol (LDL-C) taking and clinical examination. All enrolled [30] levels. However, it is still unclear whether individuals were Han Chinese from Guangxi, these loci identified in the general population the People’s Republic of China. A standard and/or healthy subjects also exert the same questionnaire was used to ascertain the gen- effect on lipid metabolism in the patients with eral information and medical history for all par- cardiovascular disease. Therefore, the purpose ticipants. The study protocol was approved by of the present study was to detect the associa- the Ethics Committee of the First Affiliated tion of the DOCK7 rs10889353 and Hospital, Guangxi Medical University. Informed rs10889335 SNPs and serum lipid traits and consent was obtained from all subjects after the risk of CAD and IS in the Han Chinese they received a full explanation of the study. population. Biochemical measurements Materials and methods Venous blood specimens were obtained from Study population all subjects after at least 12 hours of fasting. The levels of serum TC, TG, high-density lipo- A total of 1,139 unrelated patients with CAD (n protein cholesterol (HDL-C), and LDL-C in sam- = 584) and IS (n = 555) were recruited from ples were determined by enzymatic methods hospitalized patients in the First Affiliated with commercially available kits. Serum apoli- Hospital, Guangxi Medical University. The diag- poprotein (Apo) A1 and ApoB levels were nosis of CAD was based on typical clinical detected by the immunoturbidimetric immuno- symptoms and electrocardiographic changes, assay. The normal values of serum TC, TG, HDL- 2170 Int J Clin Exp Pathol 2016;9(2):2169-2180 DOCK7 SNPs and their haplotypes with CAD and IS stroke C, LDL-C, ApoA1, ApoB levels, and the ratio of GGTTTAGGCAAGAGGA-3’, rs10889335F: 5’-CT- ApoA1 to ApoB in our Clinical Science GTGCAGCTTCAGCATGATTG-3’, rs10889335R: Experiment Center were 3.10-5.17, 0.56-1.70, 5’-CTCCCAGCTTGGGAAGCACATA-3’. 0.91-1.81, 2.70-3.20 mmol/L, 1.00-1.78, 0.63- 1.14 g/L, and 1.00-2.50; respectively [12, 13]. Statistical analyses Type 2 diabetes was diagnosed according to the WHO diagnostic criteria for diabetes: (1) The statistical analyses were carried out using fasting glucose (FPG) ≥ 7.0 mmol/L; (2) 2 h the statistical software package SPSS 21.0 postprandial glucose ≥ 11.1 mmol/L; or (3) (SPSS Inc., Chicago, Illinois). Quantitative vari- self-reported diagnosis of diabetes or use of ables were expressed as mean ± standard anti-diabetic medications [34]. The individuals deviation (serum TG levels were presented as with TC > 5.17 mmol/L, and/or TG > 1.70 medians and interquartile ranges). Qualitative mmol/L were defined as hyperlipidemic [35]. variables were expressed as percentages. Hypertension was defined according to the cri- Allele frequency was determined via direct teria outlined by the 1999 World Health counting, and the standard goodness-of-fit test Organization-International Society of Hyper- was used to test the Handy-Weinberg equilibri- tension Guidelines for the management of um.
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