Open Access

Associations of genetic polymorphisms of SAA1 with cerebral infarction

  • Li-Jun Zhang1,
  • Bin Yuan1,
  • He-Hua Li1,
  • Sheng-Bo Tao1,
  • Hai-Qing Yan1,
  • Li Chang1 and
  • Jian-Hua Zhao1Email author
Lipids in Health and Disease201312:130

https://doi.org/10.1186/1476-511X-12-130

Received: 26 July 2013

Accepted: 14 August 2013

Published: 29 August 2013

Abstract

Background

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).

Conclusion

Genetic polymorphism of SAA1 may be a genetic maker of cerebral infarction in Chinese.

Keywords

Genetic polymorphisms Serum amyloid A Cerebral infarction

Introduction

Stroke is the second leading cause of death throughout the world, causing more serious chronic disabilities than any other diseases [1]. Many studies demonstrated that ischemic stroke including cerebral infarction is a multifactor disorder resulting from the interaction between environmental factor and genetics background [25].

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 [6]. Recently, several studies reported the association of SAA1 genetic polymorphism with carotid atherosclerosis [7], lipids levels [8], Uric acid level [9], and peripheral arterial disease [10]. 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.

Genotyping

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 [9]. Four tagging SNPs (rs12218, rs4638289, rs7131332 and rs11603089) for Chinese Han were genotyped by TaqMan method as described previously [11].

Biochemical analysis

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.

Statistical analyses

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.

Results

Characteristics of study participants

The clinical and metabolic characteristics of the study population are shown in Table 1.
Table 1

Characteristics of the participants

Groups

N

Age (years)

BMI Kg/m2

SBP (mmol/L)

DBP (mmol/L)

Uric acid (mmol/L)

GLU (mmol/L)

TG (mmol/L)

TC (mmol/L)

HDL-C (mmol/L)

LDL-C (mmol/L)

Case group

287

61.1 ± 10.4

23.2 ± 3.6

144.6 ± 22.1

89.2 ± 12.4

302.4 ± 130.3

7.1 ± 3.7

3.14 ± 2.11

5.3 ± 2.5

1.9 ± 1.3

2.82 ± 1.42

Control group

376

62.2 ± 10.5

23.9 ± 3.1

126.1 ± 18.4

78.1 ± 11.9

278.3 ± 81.2

5.3 ± 1.6

1.44 ± 1.21

4.7 ± 1.5

1.7 ± 0.9

2.38 ± 1.11

P

 

0.14

0.33

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

0.19

0.07

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.
Table 2

Distributions of SAA1 genotypes

SNPs

Allels (1/2)

Groups

n

Genotypes (n,%)

P value

MAF

P value

1/1

1/2

2/2

rs11603089

A/G

Control

376

271 (72.07)

98(26.06)

7(1.86)

0.610

0.15

0.364

  

Case

287

199(69.34)

80(27.87)

8(2.79)

 

0.17

 

rs4638289

A/T

Control

376

150(39.89)

189(50.27)

45(11.97)

0.102

0.37

0.372

  

Case

287

112(39.02)

155(54.01)

20(6.97)

 

0.34

 

rs12218

C/T

Control

376

218(57.98)

146(38.83)

12 (3.19)

0.001

0.23

0.004

  

Case

287

145(50.52)

114 (39.72)

28(9.76)

 

0.30

 

rs7131332

A/G

Control

376

91(24.20)

224(59.57)

61(16.22)

0.017

0.46

0.252

  

Case

287

94 (32.75)

140 (48.78)

53(18.47)

 

0.43

 

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).

Discussion

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 [9]. 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 [8], HDL-C [9], Ankle-brachial index (ABI) [10], and plasma Uric acid levels [11] 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.

Abbreviations

SAA: 

Serum amyloid A

CI: 

Cerebral infarction

HDL-C: 

High-density lipoprotein

LDL-C: 

Low-density lipoprotein.

Declarations

Acknowledgements

This study was funded by the Xinxiang Medical college Science and Technology Projects (grant number 2007YJAO2).

Authors’ Affiliations

(1)
Department of Neurology, First Affiliated Hospital of Xinxiang Medical College, Henan

References

  1. 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.0067738PubMed CentralView ArticlePubMedGoogle Scholar
  2. 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.Google Scholar
  3. 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.0066374PubMed CentralView ArticlePubMedGoogle Scholar
  4. 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.0065863PubMed CentralView ArticlePubMedGoogle Scholar
  5. 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.2013.05.034View ArticlePubMedGoogle Scholar
  6. 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.108.178681PubMed CentralView ArticlePubMedGoogle Scholar
  7. 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.0013997PubMed CentralView ArticlePubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.0040263PubMed CentralView ArticlePubMedGoogle Scholar
  10. 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. 10.3109/08037051.2011.566244View ArticlePubMedGoogle Scholar
  11. 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. 10.1177/1076029608329581View ArticleGoogle Scholar
  12. 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.xView ArticlePubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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/s11745-008-3169-2View ArticlePubMedGoogle Scholar

Copyright

© Zhang et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement