CN103013989A - Single-nucleotide polymorphisms of cyclin dependent kinase 5 related to senile dementia incidence - Google Patents
Single-nucleotide polymorphisms of cyclin dependent kinase 5 related to senile dementia incidence Download PDFInfo
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Abstract
The invention discloses single-nucleotide polymorphisms of a cyclin dependent kinase 5 related to senile dementia incidence. The single-nucleotide polymorphisms are rs2069452 and rs2069459 of a cyclin dependent kinase 5 of the Han people. Through a polymerase chain reaction method, gene polymorphisms of cyclin dependent kinases 5 of 47 patients and 51 normal control groups having matched ages are detected and the correlation of gene frequency, allele frequency distribution and senile dementia incidence is comprehensively analyzed. Compared with the normal control groups, a result of rs2069452 and rs2069459 allele frequency and haploid analysis shows that rs2069452 and rs2069459 are related to senile dementia incidence.
Description
Technical field
The present invention relates to gene engineering technology field, be specifically related to the mononucleotide polymorphism site of the cell cycle dependant kinase 5 relevant with the senile dementia morbidity.
Background technology
Nerve retrograde affection comprises the various diseases such as senile dementia, Parkinson's disease, is the modal cause of disease of elderly population generation dementia symptom.This type of disease causes the degeneration of neuronal cell and cynapse, and cerebral tissue atrophy and being losing one's memory has had a strong impact on patient's social activity, self-care ability, causes quality of life significantly to descend.Typical senile dementia pathological change comprises: the formation of mat-ups (neurofibrillary tangles, NFTs) and senile plaque (senile plaques, SPs) in the neurocyte.At present, still there is not effective treatment means for senile dementia.
(cyclin dependent kinases 5, CDK5) gene is positioned at karyomit(e) No. 7 to cell cycle protein dependent kinase 5, contains 12 exons, the mRNA of 987 base length of coding.The CDK5 molecular weight of albumen is 33KD, has kinase activity and can regulate cell cycle progression and the neurocyte differentiation after its incitant is combined.At present a large amount of evidences demonstrations, the CDK5 gene is grown in cynapse, all plays an important role during synaptic plasticity forms.The unusual rising of CDK5 activity can cause nerve cell death, illustrates that the regulation and control of CDK5 activity have great importance to Neuronal Survival.Studies show that, Tau albumen is the important substrate of CDK5, in patients of senile dementia brain tissue by Hyperphosphorylationof, and loss of function
[7], and then aggregate into NFTs.In containing the neuronal cell of a large amount of NFTs, the activity of CDK5 reduces greatly, has illustrated that CDK5 plays a significant role in the formation of NFTs
[8]On the other hand, 668 sites that CDK5 can Direct Phosphorylation amyloid protein precursor (amyloid precursor protein, APP) also are important factors to the formation of SPs.These results of study show, CDK5 not only can surpass phosphorylation Tau albumen, and can also be by the formation of senile plaque, thus the mediation neuronal death.
Although a large amount of research has been illustrated the effect of CDK5 AD occurs from the molecular mechanism angle, the cognation research of the genetic polymorphism of CDK5 gene and AD particularly in Chinese Han Population, also rarely has report.
Summary of the invention
The object of the invention is to by to CDK5 full length gene order-checking, and compare with Normal group, we have therefrom chosen 5 mononucleotide polymorphism sites, find that the CDK5 gene polynorphisms may be the Hazard Factor in AD spot.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
The present invention detects the gene pleiomorphism of cell cycle dependant kinase 5 in 47 routine patients and the 51 routine age-matched Normal groups by methods such as polymerase chain reactions, analysis-by-synthesis gene frequency, the correlation analysis that gene frequency distributes and senile dementia occurs, the result shows, compare with Normal group, the gene frequency of rs2069452 and rs2069459 and Haplotype analysis result show, itself and senile dementia have a dependency.
Description of drawings
Fig. 1 ~ 4 are 5 selected SNPs and the collection of illustrative plates that checks order thereof.
Embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of restriction to the present invention.
Embodiment
Case is collected
Selection is Han nationality from primary senile dementia patients 47 examples of year December in July, 2008-2009 at the attached Huashan of Fudan University in Shanghai hospital admission.The AD Case definition is with reference to American National sacred disease and (the National Institute of Neurological Disorders and Stroke of apoplexy institute, NINDS)/Case definition of Alzheimer's disease and relative disease association (Alzheimer's Disease and Related Disorders Association, ADRDA) carries out.Each sufferer is carried out respectively disease history inquire and family line investigation by independent two neurosurgeons, comprising: detailed questionnaire, basal level test and peripheral blood collection.The Normal group of 51 routine age-matched from the BeiJing University ShenZhen Hospital, is got rid of the healthy human peripheral blood of various organic diseases.All patients the intention and meaning of collecting sample are known the inside story and signature is agreed, all sampling processes all meet the academic morality standard that Peking University formulates.
Polymerase chain reaction (polymerase chain reaction, PCR)
Extracting vein blood 2 ml, anticoagulant heparin prepares genomic dna by the total DNA extraction agent of peripheral blood box (Shenzhen Yi Nuojin biotech firm) method, and DNA is 10 mg/L with aseptic double-distilled water dilution gene group, and-20 ℃ are frozen.Conventional polymerase chain reaction (polymerase chain reaction, PCR).The PCR reaction system is: 50 ml, comprising 2 ml genomic dnas, 5 ml, 10 * Taq PCR buffer, 3 ml, 1.5 mmol/L MgCl2,1 ml, 10 mmol/L dNTP, the above reagent of 0.5 ml, 1.5 U Taq polymerase(all purchase the precious biotech firm in Dalian).Each 2 ml of 5 mmol/L upstream and downstream primers (worker biotech firm is given birth in Shanghai).The upstream and downstream primer sequence of rs2069442 and rs2069443 is shown in SEQ ID NO:1 ~ 2; The upstream and downstream primer sequence of described rs1549759 and rs2069452 is shown in SEQ ID NO:3 ~ 4; The upstream and downstream primer sequence of described rs2069459 is shown in SEQ ID NO:5 ~ 6.Amplified reaction is finished at thermal cycler (BIO-RAD), and loop parameter is: 95 ℃ of denaturation 5 min, and 95 ℃ of sex change 1 min, 58 ℃ of annealing 30 s, 72 ℃ are extended 30 s, totally 30 circulations, last 72 ℃ are extended 8 min, 4 ℃ of preservations.The order-checking of tall and handsome wound Tianjin, Guangzhou company limited will be sent behind the PCR product purification.
Gene frequency and genotype frequency are calculated
Gene frequency (allele frequency) and genotype frequency (genotypic frequency) adopt direct-counting method to obtain.Genotype frequency refers to that the individuality of certain specific gene type in the colony accounts for the ratio of the individual sum of this colony, and it reflects the relative populations of a certain genotype individuality in colony. gene frequency refers to the relative populations of a certain gene in colony.Specifically, it refers to that a certain allelotrope accounts for the ratio of whole allelotrope sums that may occur on this locus.Full gene frequency summation must equal 1 on any locus.
The equilibrium law check
Carry out the check of Hardy-Weinberg equilibrium law with chi square test.Hardy-Weinberg equilibrium law content is: the gene frequency of colony is handed down from age to age under the condition that is fit to, remain unchanged, no matter colony's initial gene type frequency how, after generation random mating, the genotype frequency of colony will reach balance, as long as equilibrium conditions is constant, genotype frequency also remains unchanged from generation to generation.
Polymorphic site linkage disequilibrium and haplotyping
Estimate the haplotype frequency of two sites and multidigit point with maximum expected value method HaploView software, reference literature calculates pairing linkage disequilibrium coefficient D ',
p＜10
-4For having the linkage disequilibrium of statistical significance, take D '〉0.8 be strong linkage disequilibrium.
Statistical analysis
Difference with each polymorphic site genotype between chi square test analysis patient AD of Han nationality and gene frequency distribution.Check each polymorphic site genotype or the distributional difference of gene frequency between case group and normal population with the definite stochastic method of Fisher.Odds ratio (odd ratio, OR) and 95% credibility interval (confidence interval, CI) are used for the Estimation Study factor to the risk level size of AD.Use the definite stochastic method of Fihser's and analyze the related of each genotype and AD morbidity.
The result
The sample that all are selected comprises patient AD and Normal group, and its basic document sees Table 1.
On the basis of our existing sample size, analyze the full gene sequencing result of CDK5, compare with Normal group, we have finally selected 5 SNPs, wherein distribution frequency surpasses 50%(Fig. 1 ~ 5 AD patient).Five SNP (seeing Fig. 1 for details) that (rs2069442, rs2069443, rs1549759, rs2069452 and rs2069459) is chosen are known SNP site.DbSNPs(http wherein: //www.ncbi.nlm.nih.gov/SNP) listed essential characteristic and the distribution of these 5 selected SNP.The generality of selected these 5 SNP is described and is seen Table 2.Wherein two SNP are positioned at the upstream of 1 exon, and remaining distributes all at No. 5 introns and No. 9 introns.And in this experiment, do not observe SNPs and be positioned at the coding region.
Table 1
*P>0.05, *
*P>0.05
Table 2
*Position according to sequence NT007914.14 from NCBI (www.ncbi.nlm.nih.gov/SNP/);
**Position according to Gene bank accession number AC010973.6
TSS: Transcription Start Site
These 5 SNPs genotype distribute all meet the Hardy-Weinberg balance (
P=0.334-0.655).The selected distribution frequency of 5 SNPs in patient AD and normal control sees Table 3.Compare with Normal group, the genotype frequency of rs2069459 (
P=0.002), the gene frequency of rs2069452 (
P=0.016, OR=0.499 [95CI% 0.274-0.907]) and the gene frequency of rs2069459 (
P=0.005, OR=0.421 [95CI% 0.225-0.790]) has significant difference.And in AD patient, the haplotype distribution frequency of G and T is compared with Normal group among allelotrope rs2069452 and the rs2069459, has obvious significant difference, and prompting may be relevant with the danger of AD morbidity.And remaining SNPs, for example rs2069442(
P=0.472), rs2069443(
P=0.472) and rs1549759(
P=0.543) its distribution frequency is compared with Normal group, without obvious significant difference.
Because the function of single SNP itself is limited, the quantity of information that provides is also less, utilizes the effect of snp analysis evaluation candidate gene of Single locus comprehensive not.The research discovery is not isolated between the SNP on the same karyomit(e), and adjacent allelotrope SNP often tends to occur simultaneously.If when the frequency that adjacent allelotrope occurs has simultaneously surpassed the probability of random generation, be called linkage disequilibrium.Being in SNP loci linkage disequilibrium, adjacent also tends to entail the offspring with the form integral body of haplotype.D ' and r
2Be two kinds of most important balancing methods, their value all is to 1 (complete linkage is uneven) from 0 (without linkage disequilibrium).In this experiment, find rs2069442/rs2069443 (D'=1; r
2=1) and rs2069452/rs2069459
Table 3
*OR was calculated for allele frequence between AD petients and controls.
(D'=0.82; r
2=0.57) there is strong linkage disequilibrium (table 4).And all there are not linkage disequilibrium in rs1549759 and other 4 SNPs.Next, utilize online HaploView software that two groups of linkage disequilibriums are carried out haplotyping, find that in rs2069452/rs2069459, the monomer whose type mainly contains 4 kinds of distributions, and the distribution frequency of Hap A in patient AD apparently higher than Normal group (
P=0.001), the morbidity that is distributed in AD of prompting Hap A is to a certain degree relevant (table 5).And among the rs2069442/rs2069443, the monomer whose type distributes does not have difference (
P=0.115), this illustrates that also the genotype frequency of patient AD and Normal group rs2069442 and rs2069443 and gene frequency distribution do not have difference.
Table 4
D’and r
2 values were calculated using Haploview software.
Table 5
*Haplotype estimated using the haplotype software; **p-value (patients
vs controls) estimated using Unphased software package
8 brief summaries and discussion
Different from other CDK family member is, the activation of CDK5 need to two special adjusting albumen p35, p39 combines.Because regulate albumen and only in central nervous system (CNS) great expression is arranged for these two, therefore, the activity of CDK5 almost can only detect in CNS.There are some researches show, CDK5 plays an important role in nerve degenerative diseases, comprises senile dementia, and amyotrophic lateral sclerosis (amyotrophic lateral sclerosis, ALS) and C type-Niemann Pick is sick.Simultaneously, the activity of CDK5 has vital effect for the normal development of central nervous system, lacks the expression of CDK5, can cause neurocyte and aixs cylinder migration obstacle.Opposite, if CDK5 is excessive and ectopic expression, the function of the unit that can affect the nerves too, in fact, in AD, the gathering of A β is all relevant with the nerve cell death of CDK5 gene mediated with neurofibrillary tangles.Therefore, relatively the correlation research of the generation of the SNP of CDK5 gene and AD has more important suggesting effect to further understanding clinically the AD disease.
In this research, by the order-checking comparison to CDK5 gene among the normal control crowd of 47 routine AD sufferers and 51 routine age-matched, we pick out 5 SNP site (rs2069442 that express above 50% in patient AD, rs2069443, rs1549759, rs2069452 and rs2069459), as our candidate SNP s site.Compare with Normal group, we find, the genotype frequency of rs2069459 (
P=0.002), the gene frequency of rs2069452 (
P=0.016, OR=0.499 [95CI% 0.274-0.907]) and the gene frequency of rs2069459 (
P=0.005, OR=0.421 [95CI% 0.225-0.790]) has significant difference.And in AD patient, the haplotype distribution frequency of G and T is compared with Normal group among allelotrope rs2069452 and the rs2069459, has obvious significant difference, and prompting may be relevant with the danger of AD morbidity.Simultaneously, we also find the genotype distribution frequency of rs2069442 in Chinese Han Population and Rademakers etc. in the crowd of Northern Europe the distribution frequency of reporting more consistent, the SNP of prompting in this site distributes may Chinese Han Population and Northern Europe crowd's indifference.Haplotype analysis shows, apparently higher than Normal group (23.4%), may there be to a certain degree relevant in the morbidity of prompting AD with the CDK5 gene polynorphisms to the distribution frequency of Hap A (GT) in AD sufferer (49.3%).Equally, Arias-V á squez etc. also finds to carry among the allelic Denmark crowd of apolipoprotein Eε4 (APOE ε 4) non-, and there be showing relevant in rs2069459 with the generation of AD.Although in the crowd of Northern Europe, different study group all report, be positioned at the dependency that exists of SNP site rs2069454 on No. 5 intron of CDK5 gene and AD, but in this research, do not find, the result of study that (comprises 408 routine patients AD and 444 normal controls) with V á zquez-Higuera etc. in the Spain crowd is consistent, analyzing its reason, may be because the genetic heterogeneity of different crowd causes this difference.
Present studies show that, the gene pleiomorphism of Cdk5 may be the Hazard Factor that AD occurs.The increase of the gene frequency of single nucleotide polymorphism rs2069452 and rs2069459, thus pointed out the change of its some structure that may cause the CDK5 gene or function to cause that the susceptibility to AD increases.Simultaneously, we also need to collect more patient AD and normal control crowd's dna sample, further verify our the above results.
SEQUENCE LISTING
＜110〉Shenzhen Hong Kong University of Science and Thchnology of Peking University medical center
＜120〉mononucleotide polymorphism site of the cell cycle dependant kinase 5 relevant with the senile dementia morbidity
<130>
<160> 6
<170> PatentIn version 3.2
<210> 1
<211> 25
<212> DNA
＜213〉upstream primer of rs2069442 and rs2069443
<400> 1
gtcaagaggc cgttgggaac acaat 25
<210> 2
<211> 25
<212> DNA
＜213〉downstream primer of rs2069442 and rs2069443
<400> 2
gaggagctct tgcaggaaca tctcg 25
<210> 3
<211> 25
<212> DNA
＜213〉upstream primer of rs1549759 and rs2069452
<400> 3
tggtgacctc gatcctgaga ttgta 25
<210> 4
<211> 21
<212> DNA
＜213〉downstream primer of rs1549759 and rs2069452
<400> 4
tccccacctt cctggaccat a 21
<210> 5
<211> 23
<212> DNA
＜213〉upstream primer of rs2069459
<400> 5
caatgctggg cggcctcttt ttc 23
<210> 6
<211> 25
<212> DNA
＜213〉downstream primer of rs2069459
<400> 6
gcccacttct caccctccct ttacc 25
Claims (2)
1. the mononucleotide polymorphism site of the cell cycle dependant kinase 5 relevant with the senile dementia morbidity is characterized in that described site is rs2069452 and rs2069459.
2. a method that detects the mononucleotide polymorphism site dependency of senile dementia and cell cycle dependant kinase 5 is characterized in that comprising the steps:
(1) determines the Normal group of senile dementia patients group and age-matched, choose mononucleotide polymorphism site rs2069442, rs2069443, rs1549759, rs2069452 and the rs2069459 of 5 known cell cycle dependant kinases 5;
(2) extracting vein blood, the preparation genomic dna carries out PCR; The upstream and downstream primer sequence of described rs2069442 and rs2069443 is shown in SEQ ID NO:1 ~ 2; The upstream and downstream primer sequence of described rs1549759 and rs2069452 is shown in SEQ ID NO:3 ~ 4; The upstream and downstream primer sequence of described rs2069459 is shown in SEQ ID NO:5 ~ 6;
(3) calculate gene frequency and genotype frequency;
(4) Hardy-Weinberg equilibrium law check;
(5) polymorphic site linkage disequilibrium and haplotyping;
(6) statistical analysis;
(7) result shows, there are dependency in the mononucleotide polymorphism site rs2069452 of cell cycle dependant kinase 5 and rs2069459 and senile dementia morbidity.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106650318A (en) * | 2016-11-17 | 2017-05-10 | 北京大学深圳医院 | Method for judging correlation between Chinese population rs125055 single nucleotide polymorphism and child IBD |
| CN114540478A (en) * | 2021-11-29 | 2022-05-27 | 武汉儿童医院 | Rare neurodegenerative disease genetic screening kit, application and screening system |
| CN114568028A (en) * | 2019-08-29 | 2022-05-31 | 香港科技大学 | Genetic variants for diagnosing alzheimer's disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113568A2 (en) * | 2003-06-20 | 2004-12-29 | Aventis Pharma S.A. | Methods for the diagnosis and prognosis of alzheimer's disease |
| CN101525665A (en) * | 2009-04-13 | 2009-09-09 | 卫生部北京医院 | SNP G10320A molecular marker of mitochondrion ND3 gene of senescence-associated degenerative disease, detecting method and kit thereof |
-
2011
- 2011-09-23 CN CN2011102857877A patent/CN103013989A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113568A2 (en) * | 2003-06-20 | 2004-12-29 | Aventis Pharma S.A. | Methods for the diagnosis and prognosis of alzheimer's disease |
| CN101525665A (en) * | 2009-04-13 | 2009-09-09 | 卫生部北京医院 | SNP G10320A molecular marker of mitochondrion ND3 gene of senescence-associated degenerative disease, detecting method and kit thereof |
Non-Patent Citations (2)
| Title |
|---|
| A. ARIAS-VASQUEZ ET AL.: "Cyclin-dependent kinase 5 is associated with risk for Alzheimer’s disease in a Dutch population-based study", 《JOURNAL OF NEUROLOGY》, vol. 255, no. 5, 31 May 2008 (2008-05-31) * |
| WANG L ET AL.: "No association of polymorphisms in the CDK5, NDEL1, and LIS1 with autism in Chinese Han population", 《PSYCHIATRY RES. 》, vol. 190, no. 23, 3 September 2011 (2011-09-03) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106650318A (en) * | 2016-11-17 | 2017-05-10 | 北京大学深圳医院 | Method for judging correlation between Chinese population rs125055 single nucleotide polymorphism and child IBD |
| CN114568028A (en) * | 2019-08-29 | 2022-05-31 | 香港科技大学 | Genetic variants for diagnosing alzheimer's disease |
| CN114540478A (en) * | 2021-11-29 | 2022-05-27 | 武汉儿童医院 | Rare neurodegenerative disease genetic screening kit, application and screening system |
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Application publication date: 20130403 |