CN105586426B - IL-6 gene rs2069852 site marker relevant to chronic HBV infection and its application - Google Patents
IL-6 gene rs2069852 site marker relevant to chronic HBV infection and its application Download PDFInfo
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- CN105586426B CN105586426B CN201610116382.3A CN201610116382A CN105586426B CN 105586426 B CN105586426 B CN 105586426B CN 201610116382 A CN201610116382 A CN 201610116382A CN 105586426 B CN105586426 B CN 105586426B
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Abstract
The present invention relates to the private medical services of chronic HBV (Hepatitis B virus, HBV) the infected's disease progression.In particular it relates to application of the site the rs2069852 marker of tumor susceptibility gene IL-6 relevant to HBV chronic infection's disease progression in the early warning and genetic counselling of HBV chronic infection's Prognosis.The present invention provides one kind to lapse to chronic hepatitis b disease feelings, and relevant IL-6 gene rs2069852 site marker and its detection reagent and detection method are especially lapsed to hepatitis b cirrhosis.The site gene rs2069852 IL-6 and its application in chronic HBV infection crowd's early warning.To with AG genotype Hepatitis B carriers, then can to progress science intervention, such as suggest that it carries out the measures such as therapeutic prevention as early as possible, can pointedly reduce the risk that hbv-liver cirrhosis occurs for these Susceptible population in this way.
Description
Technical field
The present invention relates to the individuals of chronic HBV (Hepatitis B virus, HBV) the infected's disease progression
Neurological susceptibility.In particular it relates to the rs2069852 of tumor susceptibility gene IL-6 relevant to HBV chronic infection's disease progression
Application of the site marker in the early warning and genetic counselling of HBV chronic infection's Prognosis.
Background technique
WHO in 2015 update data show, global about 200,000,000 4,000 ten thousand people of chronic HBV (HBV) the infected.
The various complication that the whole world more has the people per year over 780000 to die of hepatitis B, including cirrhosis and liver cancer.China is disease
Virus hepatitis district occurred frequently, about 93,000,000 people of existing Patients with Chronic HBV Infection, wherein chronic hepatitis B (CHB) patient about 2000
Ten thousand people.General chronic hepatitis B is that progressive development causes complication, but some patients do not undergo apparent chronic
Just there are the sings and symptoms of cirrhosis suddenly in the process of type hepatitis, some patients have even arrived the decompensation stage and have just been found.
Then, to chronic hepatitis B cirrhosis scientifically early warning and alert and early diagnosis early intervention for control progression of the disease and drop
Low case fatality rate is most important.
The classical cell factor that IL-6 is made of 184 amino acid, its gene are located on No. 7 chromosomes.IL-6
There are 2 receptors: IL-6 receptor (IL-6R) and gp130.IL-6R has 2 kinds of forms, membranous type IL-6R and solubility IL-6R (sIL-
6R).What IL-6 was mediated by membranous type IL-6R is classical signal path, and what is mediated by sIL-6R is upside down signal access.It is right
For Healthy People, the IL-6 of blood plasma level is not almost detected.But in chronic inflammation disease, such as chronic type b liver
Inflammation can detecte the Association of Plasma IL-6 Level of abnormal secretion.There is studies have shown that IL-6 level in chronic hepatitis B (CHB) disease
It is significantly increased in people than in Healthy People, and compares patient CHB, late hepatopathy (cirrhosis or liver cancer) is sick for IL-6 level
That expresses in people is more significant.And the gene polynorphisms may change its expression or combine activity, thus influence hepatic injury and
Disease severity.Therefore, the judgement and early warning that IL-6 Polymorphism Analysis lapses to CHB conditions of patients have important valence
Value, the early warning for progressing to cirrhosis especially for chronic hepatitis B more have irreplaceable meaning.
Summary of the invention
In order to solve problem above, the present invention provides one kind to lapse to chronic hepatitis b disease feelings, especially with it is B-mode
Hepatitis cirrhosis lapses to relevant IL-6 gene rs2069852 site marker and its detection reagent and detection method.
The relevant site IL-6 gene rs2069852 marker is lapsed to chronic hepatitis b disease feelings, IL-6 gene
The site rs2069852 shows as AG genotype.
To hepatitis B to the relevant site the IL-6 gene rs2069852 marker of cirrhosis transfer, IL-6 gene
The site rs2069852 shows as AG genotype.
The site IL-6 gene rs2069852 relevant to hepatitis b cirrhosis marker, the rs2069852 of IL-6 gene
Site shows as AG genotype.
A kind of reagent, the reagent of the site the rs2069852 marker for detecting IL-6 gene.
In addition, the present invention also provides a kind of Taqman probes for detecting IL-6 gene SNP site rs2069852 marker
Method includes the following steps:
1) primer and Taqman probe for detecting the site IL-6 gene rs2069852 are bought in ABI company, and to sample
This genomic DNA carries out specific PCR amplification in II PCR instrument of Roche LC480, and the Taqman probe is contaminated by two kinds of fluorescence
Expect Vic, Fam double labelling, which is the different genotype for double equipotential SNP, the probe ability only exactly matched respectively
Amplify corresponding genotype；
2) it is reacted by following condition: originating 95 DEG C of preheating 10min, then 95 DEG C of denaturation 10s, 60 DEG C of annealing and extension
30s is recycled 45 times；Product scans on II type fluorescence quantitative PCR instrument of Roche LC480 reads data, and analysis obtains research pair
The genotype of elephant.
The reagent that the site rs2069852 for detecting IL-6 gene shows as AG genotype is chronic for HBV in preparation
Application in the diagnostic kit of the infected's Prognosis.
The reagent that the site rs2069852 for detecting IL-6 gene shows as AG genotype is used for hepatitis B in preparation
Application of the infection population disease into cirrhosis progress diagnostic kit.
The reagent that the site rs2069852 for detecting IL-6 gene shows as AG genotype is used for hepatitis B in preparation
Application in the diagnostic kit of cirrhosis.
Inventor first screens IL-6 gene SNP site.First pass through inquiry relative literature or record, sieve
Selecting may there are associated SNP sites between disease；Then in second generation HapMap database, with MAF > 5% be into
Standard is selected, the site rs2069852 has been screened.Therefore the present invention, which is identified, lapses to relevant IL-6 base to chronic hepatitis b disease feelings
The SNP site of cause.
The present invention also provides a kind of detections to lapse to relevant IL-6 gene SNP site to chronic hepatitis b disease feelings
The Taqman sonde method of rs2069852.
Relevant IL-6 gene SNP is lapsed to chronic hepatitis b disease feelings as described above, present invention employs a kind of detections
The method in site, this method is Taqman sonde method, specifically, including following steps:
1. being directed to the site IL-6 gene rs2069852, primer and probe is bought in ABI company, and to sample genomic dna
Specific PCR amplification is carried out in II PCR instrument of Roche LC480.Taqman probe was carried out double labelling, was needle respectively
To the different genotype of double equipotential SNP, the probe only exactly matched can just amplify corresponding genotype；And both
Probe is respectively by two kinds of fluorescent dye Vic, Fam labels.
2. being reacted by following condition: originating 95 DEG C of preheating 10min, then 95 DEG C of denaturation 10s, 60 DEG C of annealing and extension
30s is recycled 45 times.Product scans on II type fluorescence quantitative PCR instrument of Roche LC480 reads data, and analysis obtains research pair
The genotype of elephant.
On the other hand, the present invention also provides the SNP sites that relevant IL-6 gene is lapsed to hepatitis b cirrhosis, i.e.,
The site gene rs2069852 IL-6 and its application in chronic HBV infection crowd's early warning.For example, due to present invention demonstrates
IL-6 gene rs2069852 site AG genotype exists with the disease progression of hepatitis B to be associated with, therefore, in HBV chronic infection crowd
Early warning in, it is necessary to IL-6 gene rs2069852 locus gene type analysis is carried out to the object seeked advice from, to judge the object
Whether susceptible AG genotype is carried.In general population, compared with AA, GG genotype Hepatitis B carriers, the site rs2069852 AG
Genotype Hepatitis B carriers disease progression is more rapid, is finally easier to that cirrhosis occurs.To with AG genotype Hepatitis B carriers,
Then can to progress science intervention, such as suggest its carry out as early as possible it is therapeutic prevention etc. measures, can pointedly reduce in this way
The risk of these Susceptible population generation hbv-liver cirrhosis.
Specific embodiment
The present invention is described in detail With reference to embodiment.
Embodiment 1
The embodiment uses a kind of side detected and lapse to relevant IL-6 gene SNP site to chronic hepatitis b disease feelings
Method.
One, the extraction of genomic DNA
Using Qiagen company, U.S. QIAamp DNA Blood Mini kit, and by specification method extracts whole blood
DNA。
Prepare before experiment: blood sample being transferred to 4 DEG C of refrigerators on the day before mentioning, blood is allowed to melt.It opens metal bath and adjusts
To 56 DEG C, it gets out centrifuge tube, mask, napkin paper, paper for kitchen, alcohol watering can, wastepaper basket, waste liquid cylinder etc..(referring to qiagen
Kit)
1. 20ul protease is added into 1.5ml centrifuge tube；If you need to remove RNA, then 4ulRNA enzyme is added into pipe.
2. 200ul sample is added in 1.5ml centrifuge tube；Asking when draw blood not touch tube wall, in order to avoid pollution liquid relief
Device.
3. 200ul buffer solution A L is added, sufficiently it is mixed by inversion, vibrates 15s.
4. 56 DEG C of warm bath 1h or so.
5. 200ul dehydrated alcohol is added, 15s (can not acutely vibrate) is mixed well, at this time it is possible that flocculent deposit,
Brief centrifugation is to remove the droplet of cap wall.
6. previous step acquired solution and flocculent deposit are all added in an adsorption column (adsorption column is put into collecting pipe),
8000rpm is centrifuged 1min, outwells waste liquid, adsorption column is put into new collecting pipe.
7. 500ul buffer solution A W1 is added into adsorption column, 8000rpm is centrifuged 1min, outwells waste liquid, adsorption column is put into
In new collecting pipe.
8. 500ul buffer solution A W2 is added into adsorption column, 8000rpm is centrifuged 1min, outwells waste liquid, adsorption column is put into
In new collecting pipe.
9. adsorption column is put into new collecting pipe, 13000rpm is centrifuged 3min, outwells waste liquid.Adsorption column is placed in room temperature
It places several minutes, thoroughly to dry rinsing liquid remaining in adsorption column material.
10. adsorption column is transferred in a clean centrifuge tube, 50ul is vacantly added dropwise to the intermediate position of adsorbed film
Buffer AE.Incubation at room temperature 5min.8000 turns of centrifugation 1min.
11: repeating step 10.- 80 DEG C of preservations are put after quality inspection.
Two, PCR amplification
PCR reaction system is configured by following component, process for preparation carries out on ice.
It is reacted by following condition:
95 DEG C of preheating 10min are originated, then 95 DEG C of denaturation 10s, 60 DEG C of annealing and extension 30s are recycled 45 times.
Embodiment 2
The method of embodiment embodiment 1 suffers from 191 chronic hepatitis B patients, 177 hepatitis b cirrhosis
In person, 48 hepatitis B hepatic failure patients, 93 HBsAg and HBeAg all negative carrier and 112 international health physical examinations
The genotype and allele in the site IL-6 gene rs2069852 of the physical examination of healthy population of the heart are analyzed.
One, subjects
This research, to during in November, 2015, had collected and goes to a doctor in Medical College of Zhejiang Univ. attached first in November, 2013
The HBsAg and HBeAg of hospital or the outpatient clinic all carrier 93 of feminine gender, chronic hepatitis B patient 191, second
The physical examination of healthy population 112 of type Patients with Hepatitis Hepatocirrhosis 177, hepatitis B hepatic failure patients 48 and international health medical center
Example, totally 621.
Patient selection's standard
Case diagnosis is carried out according to case judgment criteria specified in 2015 version " the guideline ":
1. carrier: serum HBsAg is positive, shows Serum ALT and AST in normal model continuous follow-up 2 times or more in 1 year
It encloses, liver histological inspection is slight without lesion or lesion.
2. chronic hepatitis B: previously have hepatitis B medical history or the HBsAg positive more than 6 months, existing HBsAg and (or)
HBV DNA is still positive, and ALT continues or exception or liver histological inspection have hepatitis lesion repeatedly.
3. hepatitis b cirrhosis: 1. there are the evidences of cirrhosis for histology or clinical prompt；2. the specific HBV of teiology
Infect evidence.By medical history or it is corresponding check defined or excluded other the common cause of disease for causing cirrhosis such as HCV infections,
Alcohol and drug etc..
Case diagnosis is carried out according to case judgment criteria specified in 2012 version " hepatic failure diagnosis and treatment guide ":
4. hepatitis B hepatic failure: 1. jaundice is deepened rapidly, and serum T BIL is greater than 10 times of Upper Limit of Normal Value or daily rising
≥17.1μmol/L；2. hemorrhagic tendency, PTA≤40/o (or INR >=1.5), and the person that excludes other reasons.
Patient's exclusion criteria
1) patient for merging other hepatopathys, such as other types of hepatitis virus infections, drug-induced liver disease, autoimmune are excluded
Hepatopathy, alcoholic liver disease etc.；
2) patient that recent other factors cause hepatic lesion, such as poisoning, bacterium infection are excluded；
3) exclude have long-term alcohol history, generally more than 5 years；
4) patient with organic diseases such as serious heart, kidney, brain, lungs is excluded；
5) it excludes with primary or metastatic biliary tract neoplasm and patients with gastrointestinal carcinoma.
Normal healthy controls inclusion criteria
1) the marker negatives person such as HBsAg, HBeAg, HBV-DNA；
2) the normal person of liver function.
Normal healthy controls exclusion criteria
HBsAg or HBeAg or HBV-DNA positive markers, and exclude other virus hepatitis, autoimmune liver disease,
The physical examination healthy person of the diseases such as alcoholic liver disease and kidney, heart, brain.
Two, Hardy-Weinberg genetic equilibrium is examined
The site gene rs2069852 IL-6 meets Hardy- after the inspection of the Hardy-Weinberg law of genetic equilibrium
Weinberg genetic equilibrium has populational representation (table 1).
1 IL-6 gene rs2069852 loci gene type genetic equilibrium of table is examined
Three, IL-6 gene pleiomorphism and chronic hepatitis b disease feelings lapse between relationship analysis
In the site IL-6 gene rs2069852, the genotype frequency ratio of hepatitis b cirrhosis group and Hepatitis B carriers group
There is significant (χ compared with difference2=6.43, P=0.04) (table 2).Remaining each comparison among groups is all not statistically significant.
The distribution of 2 IL-6 gene rs2069852 loci gene type of table and allele in two groups
Therefore, the site gene rs2069852 IL-6 has been parsed with method of the invention and the hepatitis b cirrhosis state of an illness turns
Relationship between returning.
It should be understood that those skilled in the art can make the present invention various after having read above content of the invention
Change or modification, but the equivalent form changed or modified is also fallen within the application letter of authorization limited range.
Claims (2)
1. the reagent that the site rs2069852 for detecting IL-6 gene shows as AG genotype is used for hepatitis B sense in preparation
Contaminate application of the human diseases into cirrhosis progress diagnostic kit.
2. the reagent that the site rs2069852 for detecting IL-6 gene shows as AG genotype is used for hepatitis B liver in preparation
Application in cirrhosis-diagnostic kit.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102175868A (en) * | 2011-01-07 | 2011-09-07 | 中国医学科学院肿瘤研究所 | Application of combined quantitative detection of IL-1[beta], IL-6, IL-10, IL-17, IL-23 and TNF-[alpha] in serum in early-stage prediction of liver cancer |
| CN102292106A (en) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Antibodies to IL-6 and use thereof |
| CN102740888A (en) * | 2009-11-24 | 2012-10-17 | 奥尔德生物制药公司 | Antibodies to IL-6 and use there |
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2016
- 2016-03-01 CN CN201610116382.3A patent/CN105586426B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102292106A (en) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Antibodies to IL-6 and use thereof |
| CN102740888A (en) * | 2009-11-24 | 2012-10-17 | 奥尔德生物制药公司 | Antibodies to IL-6 and use there |
| CN102175868A (en) * | 2011-01-07 | 2011-09-07 | 中国医学科学院肿瘤研究所 | Application of combined quantitative detection of IL-1[beta], IL-6, IL-10, IL-17, IL-23 and TNF-[alpha] in serum in early-stage prediction of liver cancer |
Non-Patent Citations (2)
| Title |
|---|
| IL-6基因多态性与慢性HBV感染的相关性研究;赵小苗;《安徽医科大学 硕士学位论文》;20141130;摘要、第10-18页、35-36页 |
| Relationship between interleukin-6 polymorphism and susceptibility to chronic hepatitis B virus infection;Xiao-Miao Zhao et AL;《World J Gastroenterol》;20131031;第19卷(第40期);摘要 |
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