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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Neurology 1/2017

CDKN2BAS gene polymorphisms and the risk of intracranial aneurysm in the Chinese population

Zeitschrift:
BMC Neurology > Ausgabe 1/2017
Autoren:
Yunchang Chen, Gancheng Li, Haiyan Fan, Shenquan Guo, Ran Li, Jian Yin, Xin Zhang, Xifeng Li, Xuying He, Chuanzhi Duan
Abbreviations
ACA
Anterior cerebral artery
ACoA
Anterior communicating artery
CI
Confidence intervals
CTA
Computed tomography angiography
DSA
Digital subtraction angiography
GWAS
Genome-wide association study
IA
Intracranial aneurysm
ICA
Internal carotid artery
LDR
Ligase detection reaction
lncRNA
long noncoding RNA
MAF
Minor allele frequency
MCA
Middle cerebral artery
MRA
Magnetic resonance angiography
MRI
Magnetic resonance imaging
OR
Odds ratio
PCA
Posterior cerebral artery
PCoA
Posterior communicating artery
PCR
Polymerase chain reaction
SNP
Single nucleotide polymorphism

Background

IA is a complex disease affecting human health, it is the primary cause of subarachnoid hemorrhage. According to statistics, in the event of rupture of IA, patients’ mortality and morbidity is 30 and 25%, respectively. It is generally accepted that IA influenced both by genetic and environmental risk factors. Environmental factors including smoking, drinking, hypertension, diabetes and so on. Genetic factors, there are a number of human genes associated with the occurrence and development of IA [1, 2, 22]. Genome-wide association study(GWAS) as a kind of method research on diseases, which applied to study of IA has found associated with these chromosomes:4q(EDNRA),5q31.3,6q24.2,8q12.1(SOX17), 9p21.3(CDKN2A/CDKN2B/CDKN2BAS),10q24.32(CNNM2),12q22,13q13.1(KL/STARD13), 18q11.2(RBBP8), 20p2.1 [3, 7, 9, 10, 17, 20, 21].
CDKN2BAS located in chromosome 9p21, a 3.8 kb long non-coding RNA(lncRNA) expressed in the opposite direction from INK4A-ARF-INK4B gene cluster, it is associated with a variety of human diseases, such as prostate cancer, stomach cancer, pancreatic cancer, leukemia, glioma, colorectal cancer, lung cancer, diabetes and aneurysm [4, 5, 14, 16]. There has been a lot of scholar studies supported CDKN2BAS gene multiple SNPs loci associated with IA. Hashikata confirmed rs1333040 associated with familial and sporadic IA in Japanese [8]. Foroud and his colleagues study United States population also confirmed CDKN2BAS SNP loci could lead to susceptibility of IA on the basis of predecessors’ research results, and believe rs6475606 have significant effect on IA [6]; another research on Japanese found that rs10757272 is a new susceptibility locus of IA, and confirmed rs10757278 associated with IA [13]; other chromosome gene polymorphism loci showed association with intracranial aneurysm, such as rs6841581(4q), rs12411886(10q), rs6538595(12q), rs9315204(13q), but the CDKN2BAS SNP loci were replicated successfully the most time in later studies [12, 21]. Due to the limitation of the study sample size, these studies credibility is not so high, the relationship between CDKN2BAS SNP loci and IA needs more study.
Whether CDKN2BAS SNP loci associated with China IAs patients has not been reported. Taking into account the same gene mutation rates is differ greatly in different populations and the genetic heterogeneity between races of people, so we use the database to find the minor allele frequency(MAF ≥ 0.05) of CDKN2BAS SNP loci at an r2 > 0.8 threshold in Chinese population, including rs3217992, rs974336, rs3217986, rs1063192, explore CDKN2BAS SNP effect on IAs, hope to provide new strategies for prevention and treatment of IAs.

Methods

The research object

This study was supported by Zhujiang Hospital of Southern Medical University ethics com- mittee, all the participants reported themselves to be of Han residents, have signed informed consent. Zhujiang Hospital is located in developed areas of China—Guangzhou, where the people from other provinces of China accounts for a large part of city population, and popul- ation flow is also very frequent, so the subjects of this study are representative. All particip- ants exclude genetic history, family history and history of malignancy, controlling the age between 18 and 80 years.
Within 14 months, this study recruited 200 patients with sporadic IAs, the median age was 52.69 ± 11.50 years. Patients with IAs diagnosed by computed tomography angiography(CTA), magnetic resonance angiography(MRA) or digital subtraction angiography(DSA) has at least one aneurysm. For the diagnosis of hemorrhage caused by aneurysms, especially ruptured IAs, not only combined with clinical symptoms, but also confirmed by the DSA results eventually. All cases with confirmed IAs based on DSA were retrospectively reviewed by 2 independent doctors, a neuroradiologist and a neurosurgeon, they are all experienced in the diagnosis of aneurysms. All patients in the study underwent either craniotomy or interventional therapy to confirm the correct diagnosis of IAs again.
During the same period, 200 blood donors form a control group for the study, with a median age of 49.99 ± 13.00. Considering the prevalence of IAs vary between 0.2 and 9% of the population, this study does not recruit volunteers from the outside, control participants were patients(such as cerebral hemorrhage, cerebral trauma, epilepsy) from the Department of Neurosurgery of Zhujiang Hospital, as most of them have imaging data(computed tomography(CT), magnetic resonance imaging(MRI), MRA) and clinical information excluded the presence of aneurysms. Controls were eliminate diseases not only including polycystic kidney disease, Malaysia’s syndrome, systemic lupus erythematosus (SLE), etc., but also severity of neurological diseases.
The subjects fully considered the balance and comparable of the baseline data during collection process, genomic DNA was extracted from Peripheral whole blood use kit, using agarose gel electrophoresis to detect the DNA integrity, ensure the follow-up test smoothly.

Genotyping and SNP selection of CDKN2BAS

Through foreign research literatures found the highest positive sites correlation with IAs, they are rs1333040, rs6475606, rs10757272; and using genetic database Hapmap (http://​hapmap.​org), Haploview (http://​www.​broad.​mit.​edu/​mpg/​haploview) found the tagSNP loci of CDKN2BAS in Chinese population, including rs3217992, rs974336, rs3217986, rs1063192; so the seven sites as this research objects, SNP genotyping by PCR-LDR in Shanghai Biowing Applied Biotechnology Co., Ltd. The seven SNPs primer sequences and PCR length are given in Table 1; these SNPs probe sequences and LDR length are read in Table 2. PCR and LDR manipulated as previous describe [18], Firstly, PCR amplification of SNP sites in 20ul master mix, containing 2ul 1 × buffer, 0.6ul Mg++, 2ul dNTPs, 0.2ul Taq polymerase, 4ul 1 × Q-solution, 0.4ul primer mix and 9.8ul ddH2O, after thoroughly incorporated, take 19ul partial shipments in PCR reaction tube and add 1ul genomic DNA of samples, set the following program on Gene Amp PCR system (model 9600, Perkin Elmer): denaturing at 95 °C for 15 min; then denaturing at 94 °C for 30 s, annealing at 56 °C for 1 min, extension at 72 °C for 1 min, repeat 35 cycles; also need to extend 7 min under 72 °C temperature. Secondly, LDR performed to further amplification in 10ul volume of Multiplex LDR mixture, before operation LDR add the same as volume ddH2O to PCR amplification product, the LDR mixture containing resultant PCR product of 1ul, 1ul probe mix, 0.05ul Taq DNA ligase, and 6.95ul ddH2O, after thoroughly incorporated, take 9ul partial shipments in PCR reaction tube and add 1ul PCR amplification product, set LDR conditions: initial denaturing at 95 °C for 2 min, followed by 35 cycles of denaturing at 94 °C for 30 s, and annealing at 50 °C for 2 min, mix 1ul of LDR product with 0.6ul ROX(ABI.GS-500), after denaturing at 95 °C for 2 min, in the ice cold snap, following capillary electrophoresis, meanwhile applying Genemapper(ABI, Inc.) for data analysis and genotyping.
Table 1
Primer sequences and PCR length
Primer name
sequence(5-3) up
low
PCR length
rs1333040
TAATGGGATGGAGTGCAGGG
AACCTCCATGAGAACTGGCT
193
rs3217986
CTCCACCAGATAGCAGAGGG
CCACCACCTCATCCTGTGTA
176
rs10757272
CCTGAGGAGAAGAGAAGGGC
TGGGGCACATGATTCCAAAA
180
rs6475606
AAAGGAAGAACATGGCACCC
TTGTAGAACACAACAACCCC
87
rs1063192
GTGTAATATAGTACTGTGGG
CTTGTGGAATCTTTCCTAAT
85
rs974336
CAGACATCAGAGACCTGAAC
GCAGGTGGAGCCATTTAAAG
78
rs3217992
GGAATTAATTTTTACATGGC
TGGGTATCAATTACCACCTG
67
Table 2
Probe sequences and LDR length
Probename
sequence(5-3)
LDR length
rs1333040_modify
P-CATTCTTACCTCTGACCCTCTTTTTTTTTTTTTTTTTT-FAM
 
rs1333040_C
TTTTTTTTTTTTTTTTCTTCCTCTCTGTCCCAGCGGTAG
77
rs1333040_T
TTTTTTTTTTTTTTTTTTCTTCCTCTCTGTCCCAGCGGTAA
79
rs3217986_modify
P-CCTCTCTTACCCCTCTGCTATTTTTTTTTTTTTTTTTTTTT-FAM
 
rs3217986_A
TTTTTTTTTTTTTTTTTTAGCATCTGTCGTCGCTTGCACAT
82
rs3217986_C
TTTTTTTTTTTTTTTTTTTTAGCATCTGTCGTCGCTTGCACAG
84
rs10757272_modify
P-CTTCTTACGACCTTTCATAATTTTTTTTTTTTTTTTTTTTTTTT-FAM
 
rs10757272_C
TTTTTTTTTTTTTTTTTTTTATAATAAAACATTGCAACATTCG
87
rs10757272_T
TTTTTTTTTTTTTTTTTTTTTTATAATAAAACATTGCAACATTCA
89
rs6475606_modify
P-CTTTCACTGAGTGTCCATTATTTTTTTTTTTTTTTTTTTTTTTTTTT-FAM
 
rs6475606_C
TTTTTTTTTTTTTTTTTTTTTTCCAAAAATGATGATGATAGCCAG
92
rs6475606_T
TTTTTTTTTTTTTTTTTTTTTTTTCCAAAAATGATGATGATAGCCAA
94
rs1063192_modify
P-GTTGTCATTAGGAAAGATTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-FAM
 
rs1063192_C
TTTTTTTTTTTTTTTTTTTTTTTTTCTTTAGTTTCCCTTAATATCAG
97
rs1063192_T
TTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTAGTTTCCCTTAATATCAA
99
rs974336_modify
P-AAAGTTTTCACCCAGTGCAGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-FAM
 
rs974336_A
TTTTTTTTTTTTTTTTTTTTTTTTTTCATTTAAAGAAACACCTAATTGT
102
rs974336_G
TTTTTTTTTTTTTTTTTTTTTTTTTTTTCATTTAAAGAAACACCTAATTGC
104
rs3217992_modify
P-AATACAACCAGGTGGTAATTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-FAM
 
rs3217992_A
TTTTTTTTTTTTTTTTTTTTTTTTTTTTTGGCATTGATAAGTTACTATTTT
107
rs3217992_G
TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGGCATTGATAAGTTACTATTTC
109

Statistical analysis

Hardy-Weinberg equilibrium tested by chi-square in control, allelic and genotype frequencies are evaluated by chi-square test or Fisher’s exact tests, all data analysis using SPSS 20.0, considering statistical differences when P value is less than 0.05.

Results

Clinical background of patients

The clinical information of the study participants was summarized in Table 3. Female patients with IAs accounted for 61.5%, is 1.60 times of male patients, and consistent with other related reports [18, 23]. The baseline data balanced between the experimental group and the control group, including gender, smoking, drinking, hypertension and diabetes. Patients with IAs also make specific statistic about aneurysm number and position. There were 90 patients with IAs located in the posterior communicating artery and internal carotid artery, 41 patients in the anterior cerebral artery and 32 patients in posterior cerebral artery. The numbers of patients with one aneurysm, two aneurysms, three aneurysms, more than 3 aneurysms are 130, 35, 21, 14 respectively.
Table 3
Characteristics of patients with IAs vs. controls
 
Aneurysms group
Controls group
X2 value
P value
Number
200
200
  
Male
77(38.5)
78(39.0)
  
Female
123(61.5)
122(61.0)
0.011
0.918
Age
52.69 ± 11.50
49.99 ± 13.00
1.639
0.201
Smoking
43(21.5)
40(20.0)
  
Non-smoking
157(78.5)
160(80.0)
0.137
0.711
Drinking
44(22.0)
42(21.0)
  
Non-drinker
156(78.0)
158(79.0)
0.059
0.808
Hypertension
59(29.5)
54(27.0)
  
Non-hypertension
141(70.5)
146(73.0)
0.308
0.579
Diabetes
24(12.0)
22(11.0)
  
Non-diabetes
176(88.0)
178(89.0)
0.098
0.754
Site of aneurysm(%)
 ACA
41(20.5)
   
 PCA
32(16.0)
   
 ACoA
16(8.0)
   
 ICA,PCoA
90(45.0)
   
 MCA
10(5.0)
   
 other
11(5.5)
   
Number of aneurysm(319)
 One
130(65.0)
   
 Two
35(17.5)
   
 Three
21(10.5)
   
  > three
14(7.0)
   
ACA anterior cerebral artery, ACoA anterior communicating artery, ICA internal carotid artery, MCA middle cerebral artery, PCA posterior cerebral artery, PCoA posterior communicating artery

Allelic association study with SNPs of CDKN2BAS

We randomly selected two loci of the Genemapper as shown in Fig. 1. The genotype and allele frequency of cases and controls was presented in Table 4. The control group completely accorded with Hardy-Weinberg equilibrium and objects included in the study could represent the crowd finely. The difference in seven sites of genotype and allele frequency was compared with chi-square or Fisher’s exact tests. The genotype frequency of rs6475606 show significant difference between cases and controls(X2 = 10.961, P = 0.004), There also existed difference among groups when compared frequency of TT with CC and CT genotypes combined (X2 = 9.008, OR 1.831 [95% confidence interval 1.232—2.723], P = 0.003), the C allele showed reduction the risk of IAs(X2 = 4.784, OR 0.710 [95% confidence interval 0.522—0.966], P = 0.029). The distribution of the variants rs1333040 was significantly different in genotype frequency among cases and controls(X2 = 8.545, P = 0.014), and compared frequency of TT with CC and CT genotypes combined, the results were significant(X2 = 7.295, OR 1.722 [95% confidence interval 1.159—2.558], P = 0.007).
Table 4
genotype and allele frequencies of patients with IAs vs. controls
 
Aneurysms
Controls
X2 value
P value
OR(95%CI)
rs1333040
CC
19(9.5)
18(9)
8.545
0.014
 
CT
65(32.5)
92(46)
   
TT
116(58)
90(45)
   
CC + CT
84(42)
111(55.5)
7.295
0.007
1.722(1.159—2.558)
C allele
103/297(25.75)
128/272(32)
3.804
0.051
0.737(0.542—1.002)
rs3217986
AA
166(83)
157(78.5)
1.597
0.445
 
AC
32(16)
39(19.5)
   
CC
2(1)
4(2)
   
AC + CC
34(17)
43(21.5)
1.303
0.254
0.748(0.454—1.233)
rs10757272
CC
21(10.5)
22(11)
0.497
0.780
 
CT
97(48.5)
90(45)
   
TT
82(41)
88(44)
   
CC + CT
112(56)
111(55.5)
0.368
0.544
1.131(0.760—1.681)
rs6475606
CC
19(9.5)
17(8.5)
10.961
0.004
 
CT
63(31.5)
95(47.5)
   
TT
118(59)
88(44)
   
CC + CT
82(41)
112(56)
9.008
0.003
1.831(1.232—2.723)
C allele
101/299(25.25)
129/271(32.25)
4.784
0.029
0.710(0.522—0.966)
rs1063192
CC
6(3)
5(2.5)
0.783
0.676
 
CT
56(28)
49(24.5)
   
TT
138(69)
146(73)
   
CC + CT
62(31)
54(27)
0.777
0.378
1.215(0.788—1.872)
rs974336
AA
9(4.5)
3(1.5)
3.983
0.137
 
AG
63(31.5)
74(37)
   
GG
128(64)
123(61.5)
   
AA + AG
72(36)
77(38.5)
0.267
0.605
0.899(0.599—1.348)
rs3217992
AA
61(30.5)
60(30)
1.021
0.600
 
AG
101(50.5)
94(47)
   
GG
38(19)
46(23)
   
AG + GG
139(69.5)
140(70)
0.012
0.913
0.977(0.637—1.496)
OR odds ratio, CI confidence intervals, P value was considered significant at a level of <0.05

Genotype is related to clinical manifestation

The study aimed to assess the correlation between CDKN2BAS SNP genotypes and clinical presentation(such as hemorrhage, epilepsy, aneurysm location and size) of aneurysms(Table 5). Statistical analysis indicated that both of rs1333040 and rs6475606 were associated with hemorrhage. The C allele of rs1333040 reduced the incidence of hemorrhage. The C allele of rs6475606 was overrepresented in controls which controversial with it was the risk of hemorrhage(X2 = 9.626, OR 2.002 [95% confidence interval 1.286—3.119], P = 0.002); and rs13330 40 also related to aneurysm size(P < 0.000), the C allele was the risk factor of IAs with size < 3 cm(X2 = 7.358, OR 2.020 [95% confidence interval 1.207—3.380], P = 0.007). The study did not find that CDKN2BAS SNP genotypes was associated with epilepsy and aneurysm location.
Table 5
Analysis of genotype and clinical presentation
  
Hemorrhage
(136 patients)
No Hemorrhage
(64 patients)
X2 value
P value
OR(95%CI)
rs1333040
CC
14(10.29)
5(7.80)
   
CT
31(22.79)
34(53.13)
18.421
0.000*
 
TT
91(66.92)
25(39.07)
   
C allele
59/272(21.69)
44/128(34.38)
4.182
0.041
0.631(0.405—0.983)
rs6475606
CC
13(9.56)
6(9.38)
   
CT
26(19.12)
37(57.81)
31.628
0.000*
 
TT
97 (71.32)
21(32.81)
   
C allele
52/272(22.43)
49/128(31.25)
9.626
0.002
2.002(1.286—3.119)
 
Size(≥3 cm)
(72 patients)
Size(<3 cm)
(128 patients)
X2 value
P value
 
rs1333040
CC
8(11.11)
11(8.59)
   
CT
6 (8.33)
57(44.53)
28.355
0.000*
 
TT
58(80.56)
60(46.88)
   
C allele
22/144(15.28)
79/256(30.86)
7.358
0.007
2.020(1.207—3.380)
rs6475606
CC
7(9.72)
12(9.37)
   
CT
23(31.94)
40(31.25)
0.021
0.989
 
TT
42(58.33)
76(59.38)
   
*P < 0.000

Discussion

In this study, we aim to explore CDKN2BAS genetic relationship with Chinese han nationality of IAs. We provided evidence that the variants rs1333040 and rs6475606 were associated with IAs, in agreement with the results of Hashikata et al. and Foroud et al., respectively. Hashikata et al. based on previous results of Genome-wide association studies(GWAS) confirmed rs1333040 association with familial and sporadic IAs in Japanese patients, their study included 419 sporadic IA cases and 408 control subjects; Foroud et al. utilized the similar approach to investigate the role of rs6475606 in 1095 IA cases and 1286 controls, as the size of the sample, our results with theirs differ markedly.
Rs3217992, rs974336, rs3217986, rs1063192 are the highest mutation rate locus of CDKN2BAS gene in Chinese population. We can learn from the Table 4 that the four sites genotype frequency and allele frequency were close in the experimental group and the control group. Statistical results show that these loci loss correlation with sporadic IAs of China(all P values > 0.05), rs6475606, rs1333040 and rs10757272 are the highest positive sites correlation with IAs in overseas study,reflect the Japan and the United States population, rs1333040 and rs6475606 were also replicated, but no association of the variant rs10757272 with sporadic IAs was found in our study, the conflicting results mainly root in genetic heterogeneity in different ethnic populations, additionally, the presence of genetic heterogeneity may be relevant in a bias caused by variation in the prevalence of a positive family history between populations, because familial IAs have a higher risk than sporadic IAs, negative results for this SNP do not exclude CDKN2BAS SNP plays an important role in aneurysms. The other four loci selected in this study which is the highest mutation rates in Chinese population were unrelated to aneurysms, among previous studies, a research thinks disease-causing mutations may be located in MAF < 0.05, and influence the formation of IAs. We also detected statistically significant correlations between CDKN2BAS SNPs and hemorrhage and aneurysm size, rs1333040_C did not work in aneurysm formation, but it could reduce the occurrence of hemorrhage and it was the risk factor of IAs with size < 3 cm; the rs6475606_C could reduce the occurrence of IAs, but the impact of it on hemorrhage and size was not clear, the reason may be related to the research errors.
The sequence of CDKN2BAS gene is so long that it will be very difficult to find the exact loci associated with IA. Rs6475604, rs1333040, rs10757272 associated with IA come from GWAS mostly, these loci are not for more research, and lack of functional studies. IA is a complex genetic disease, the interaction between genes and genes as racial differences will affect the results of our study. CDKN2BAS belongs to long noncoding RNA(lncRNA) and affects the surrounding gene expression indirectly play a role in the disease, Bai Y research results show that CDKN2BAS can regulate the expression of CARD8 level, which affects the progress of atherosclerosis, compare the RNA in aneurysm tissue and normal cerebrovascular, hundreds of lncRNA exists differences, we can’t help but question: would CDKN2BAS cause IA formation? Or CDKN2BAS associated with IA could be caused by other lncRNA [2, 15, 19].
The current generally accepted IA is the result of the dual role of genetic and environmental factors, screening finds a large number of genes associated with IA, but these genes effect on IA is too low, thus known that the influence of environmental factors on the disease may be greater, CDKN2BAS gene polymorphism correlated with IA in other population, but has nothing to do with the Chinese people, there is a hypothesis: the environment makes IA more susceptible to CDKN2BAS in other population, although rs3217992, rs974336, rs3217986 and rs1063192 are the highest mutation rate loci of CDKN2BAS gene in Chinese population, influenced by environmental factors, they without associated with IA [11].
In addition to the above mentioned several assumptions, our study associated with the degree and distribution of linkage disequilibrium [1]. Research work in susceptibility genes of IA did not make substantive progress, scholars have been staying at the screening level, but many of genes repeatability is poor, the author considers not all IA are related to gene mutation, genetic, environmental and perhaps many other factors involved in the IA progress, it needs us to further research.

Conclusions

Our study showed that CDKN2BAS polymorphism might be associated with intracranial aneurysms in Chinese population. Additional studies are needed to confirm our finding.

Acknowledgments

We thank the DNA donors and the supporting medical staff for making this study possible.

Funding

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. This study was supported by the National Natural Science Foundation of China (Grants No.81271315), National Key Research Development Program (Grants No.2016YFC1300804,2016YFC1300800), Specialized Research Fund for the Doctoral Program of Higher Education (Grants No.20124433110014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

individual data is stored by the corresponding author. The raw data generated and/or analyzed during the current study are not publicly available due to the fact that consent was obtained to provide only cumulative anonymized data but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Ethical Committees of Zhujiang Hospital of Southern Medical University. All participants volunteered to be part of the activity after informed the purpose and significance of the study and signed the informed consent form, the blood samples obtained from this study were from volunteers who signed informed consent.

Consent for publication

Consent for data sharing and publication was obtained as part of the informed consent form.

Competing interests

The authors declare that they have no competing interests.

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