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Associations of genetic polymorphisms of SAA1 with cerebral infarction
Lipids in Health and Disease volume 12, Article number: 130 (2013)
Serum amyloid A protein (SAA) is both an inflammatory factor and an apolipoprotein. However, the relation between genetic polymorphisms of SAA and cerebral infarction (CI) remains unclear.
Methods and results
The previously reported 4 Single Nucleotide Polymorphisms (rs12218, rs4638289, rs7131332, and rs11603089) of SAA1 gene were genotyped by TaqMan method in a case–control study including 287 cerebral infarction patients and 376 control subjects. We found rs12218 CC genotype and rs7131332 AA genotype were more frequent among CI patients than among controls (9.76% versus 3.19%, P = 0.001; 32.75% versus 24.20%; p = 0.017; respectively). After adjustment of confounding factors such as sex, age, smoking, drinking, hypertension, diabetes, and lipids profile, the difference remained significant in rs12218 (P < 0.01, OR = 2.106, 95% CI: 1.811–7.121).
Genetic polymorphism of SAA1 may be a genetic maker of cerebral infarction in Chinese.
Stroke is the second leading cause of death throughout the world, causing more serious chronic disabilities than any other diseases . Many studies demonstrated that ischemic stroke including cerebral infarction is a multifactor disorder resulting from the interaction between environmental factor and genetics background [2–5].
Serum amyloid A (SAA) is a sensitive acute phase proteins in plasma, also SAA is an apolipoprotein that can replace apolipoprotein A1 (apoA1) as the major apolipoprotein of high-density lipoprotein (HDL), particularly during the acute phase response . Recently, several studies reported the association of SAA1 genetic polymorphism with carotid atherosclerosis , lipids levels , Uric acid level , and peripheral arterial disease . However, the relationship between genetic polymorphisms of SAA and cerebral infarction remains unknown.
In this exploratory study, we investigated the association between genetic polymorphisms of SAA1 and cerebral infarction in a Chinese population.
Subjects and methods
The present study was approved by the Ethics Committee of the First Affiliated Hospital of Xinxiang Medical College and was conducted according to the standards of the Declaration of Helsinki. Written informed consent was obtained from the participants.
The present study included 287 unrelated adult Chinese patients with acute hemispheric ischemic stroke and 376 symptom free Chinese controls. Cases were selected among patients suffering from atherothrombotic ischemic stroke admitted to the neurology services, within 24 h after onset. Recruitment of the patients was performed consecutively. Stroke was defined as clinical designation for a rapidly developing loss of brain functions that lasted at least 24 h and had no apparent cause other than that of vascular origin. The cerebral infarction was initially diagnosed on the basis of neurological examination and brain computer tomography (CT) scan and then transthoracic echocardiographic examination, Holter study and Transcranial Doppler emboli detection procedure to rule out emboli source. In order to be considered eligible, the patients should meet following criteria: having anterior circulation stroke, no other major illnesses, including autoimmune diseases, neoplasms, coagulopathies, hepatic or renal failure, no known embolic source (aortic arch, cardiac or carotid), no family history of hematological, autoimmune or chronic inflammatory diseases, and no history of myocardial infarction within 3 weeks.
Control subjects were selected randomly from the neurology outpatient clinics who did not have stroke or transient ischemic attack at any time. All exclusion criteria were applied to the controls exactly plus not having ischemic heart disease, carotid stenosis (lumen narrowing) or ulcerated carotid plaque.
Blood samples were collected from all participants, and genomic DNA was extracted from the peripheral blood leukocytes by DNA extraction Kit (Beijing Bioteke Co. Ltd. China). We selected the tagging single-nucleotide polymorphisms (SNPs) according to the previous studie . Four tagging SNPs (rs12218, rs4638289, rs7131332 and rs11603089) for Chinese Han were genotyped by TaqMan method as described previously .
Serum and plasma collected for measurement was immediately frozen at - 80°C until analysis. We measured the plasma concentration of total cholesterol and HDL cholesterol and the serum concentration of creatinine and uric acid for all the subjects.
Analyses were carried out using SPSS version 17.0 (SPSS, Chicago, IL, USA). The Hardy–Weinberg equilibrium was assessed by chi-square analyses. The differences in the distribution of genotypes between cerebral infarction patients and control subjects were analyzed using the chi-square test. Logistic regression analyses were used to assess the contribution of the major risk factors. Two-tailed p -values, 0.05, were considered significant.
Characteristics of study participants
The clinical and metabolic characteristics of the study population are shown in Table 1.
SAA1 genotype and allele frequencies
All genotyped SNPs were in Hardy-Weinberg equilibrium in the control group (P > 0.05, data not shown). Table 2 shows detailed information for each SNP as well as the allele frequencies.
Association of SAA1 gene polymorphisms and CAD
We found rs12218 CC genotype and C allele were more frequent among cerebral infarction patients than among controls subjects (9.76% versus 3.19%, P = 0.001; 0.30 versus 0.23, P = 0.004; respectively). For rs7131332, we found AA genotype was associated with cerebral infarction (32.75% versus 24.20%, P = 0.017). After adjustment of confounding factors such as sex, age, smoking, alcohol consumption, hypertension, diabetes, and lipids levels, the difference remained significant between the cerebral infarction patients and the control subjects in rs12218 ((P < 0.01, OR = 2.106, 95% CI: 1.811–7.121).
In the present study, we found that rs12218 variation in the SAA1 gene was associated with cerebral infarction in a Chinese population. To the best of our knowledge, this is the first study to investigate the common allelic variants in SAA1 gene and its association with cerebral infarction in Chinese population.
SAA1 encodes one important inflammation factor, SAA, which is also a kind of apolipoprotein . In plasma, SAA is associated with HDL [7, 12, 13] and, during severe inflammation, can contribute about 80% of its apo-protein composition [14, 15]. Therefore, SAA1 is candidates for atherosclerosis and cerebral infarction. Recently, Xie et al. reported that rs12218 polymorphism in SAA1 gene was associated with IMT , HDL-C , Ankle-brachial index (ABI) , and plasma Uric acid levels  which was related to cardiovascular and cerebrovascular disease.
In the present study, we performed a case–control study to observe the relationship between SAA1 genetic polymorphism and cerebral infarction. We found rs12218 CC genotype was very common in the cerebral infarction patients than that in the control subjects. After adjustment some confounders, the association remains significant, which indicated that rs12218 CC genotype was an independent risk factor for cerebral infarction.
The mechanisms which may link SAA1 genetic polymorphism to cerebral infarction are largely unknown. According to the previous studies, plasma HDL-C and SAA levels is demonstrated to be associated with SAA polymorphism, which may be a possible mechanism linking SAA1 genetic polymorphism to cerebral infarction which merits further investigation. In addition, the present study was limited by the relatively small sample size. This may have led to weak statistical significance and wide CIs when estimating OR.
In conclusion, the SAA1 genetic polymorphisms were associated with cerebral infarction in a Chinese population.
Serum amyloid A
Peng L, Li P, Chen J, Yan K, Huo F, Han L, Li C, Tan S, Jiang X: Association between transforming growth factor-beta 1 T869C polymorphism and ischemic stroke: a meta-analysis. PLoS One. 2013, 8: e67738 10.1371/journal.pone.0067738
Yao YS, Chang WW, Jin YL, He LP: An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with ischemic stroke. Gene. 2013, 10.1016/j.gene.2013.06.047.
Liu X, Zhu R, Li L, Deng S, Li Q, He Z: Genetic polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis. PLoS One. 2013, 8: e66374- 10.1371/journal.pone.0066374
Guo L, Zhang LL, Zheng B, Liu Y, Cao XJ, Pi Y, Li BH, Li JC: The C825T polymorphism of the G-protein β3 subunit gene and its association with hypertension and stroke: an updated meta-analysis. PLoS One. 2013, 8: e65863- 10.1371/journal.pone.0065863
Liang B, Qin L, Wei H, Yan Y, Su L, Wu G, Tan J, Gu L: AGT M235T polymorphisms and ischemic stroke risk: a meta-analysis. J Neurol Sci. 2013, 331: 118-25. 10.1016/j.jns.2013.05.034
Jahangiri A, de Beer MC, Noffsinger V, Tannock LR, Ramaiah C, Webb NR: HDL remodeling during the acute phase response. Arterioscler Thromb Vasc Biol. 2009, 29: 261-267. 10.1161/ATVBAHA.108.178681
Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Huang D: Polymorphisms in the SAA1/2 gene are associated with carotid intima media thickness in healthy Han Chinese subjects: the cardiovascular risk survey. PLoS One. 2010, 5: e13997- 10.1371/journal.pone.0013997
Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Ma X: Association of genetic polymorphisms of serum amyloid protein A1 with plasma high density lipoproteins cholesterol. Zhonghua Yi Xue Za Zhi. 2010, 90: 1824-6.
Xie X, Ma YT, Yang YN, Li XM, Fu ZY, Zheng YY: Serum uric acid levels are associated with polymorphism in the SAA1 gene in Chinese subjects. PLoS One. 2012, 7: e40263- 10.1371/journal.pone.0040263
Xie X, Ma YT, Yang YN, Fu ZY, Li XM, Zheng YY: Polymorphisms in the SAA1 gene are associated with ankle-to-brachial index in Han Chinese healthy subjects. Blood Press. 2011, 20: 232-8. 10.3109/08037051.2011.566244
Xie X, Ma YT, Fu ZY, Yang YN, Ma X, FU ZY: Haplotype analysis of the CYP8A1 gene associated with myocardial infarction. Clin Appl Thromb Hemost. 2009, 15: 574-580. 10.1177/1076029608329581
Benditt EP, Hoffman JS, Eriksen N, Parmelee DC, Walsh KA: SAA, an apoprotein of HDL: its structure and function. Ann N Y Acad Sci. 1982, 389: 183-189. 10.1111/j.1749-6632.1982.tb22136.x
Clifton PM, Mackinnon AM, Barter PJ: Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction. J Lipid Res. 1985, 26: 1389-1398.
Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS: Serum amyloid A-containing human high density lipoprotein 3: density, size, and apolipoprotein composition. J Biol Chem. 1986, 261: 9644-9651.
Graversen JH, Castro G, Kandussi A, Nielsen H, Christensen EI: A pivital role of the human kidney in catabolism of HDL. Protein components apolipoprotein A-I and A-IV but not of A-II. Lipids. 2008, 43: 467-470. 10.1007/s11745-008-3169-2
This study was funded by the Xinxiang Medical college Science and Technology Projects (grant number 2007YJAO2).
The authors declare that they have no competing interests.
LJZ and BW carried out the molecular genetic studies and drafted the manuscript. HHL and SBT carried out the genotyping. HQY, LC participated in the design of the study and performed the statistical analysis. JHZ and LJZ conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
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Cite this article
Zhang, L., Yuan, B., Li, H. et al. Associations of genetic polymorphisms of SAA1 with cerebral infarction. Lipids Health Dis 12, 130 (2013). https://doi.org/10.1186/1476-511X-12-130
- Genetic polymorphisms
- Serum amyloid A
- Cerebral infarction