CN107058470B - Diagnostic kit for predicting acute mountain sickness onset risk by combining miR-136 and miR-4791 - Google Patents
Diagnostic kit for predicting acute mountain sickness onset risk by combining miR-136 and miR-4791 Download PDFInfo
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Abstract
The invention relates to a microRNA marker for detecting a person susceptible to acute mountain sickness and application of the microRNA marker in preparation of a kit for predicting the onset risk of the acute mountain sickness. microRNA markers consist of: microRNA-136-3p and microRNA-4791. The invention mainly adopts methods such as fluorescence quantitative PCR and the like to detect the 2microRNA molecules in the human protoplasm and predicts the risk of acute mountain sickness by the expression level. The two microRNA markers are both suitable for screening large-scale acute mountain sickness susceptible persons on plain, and the sensitivity and specificity of combined application are obviously superior to those of single use.
Description
Technical Field
The invention relates to a detection kit, in particular to a method for predicting the risk of acute mountain sickness by the expression levels of plain plasma circulating microRNA-136-3p and microRNA-4791, so as to evaluate the susceptibility of the acute mountain sickness of a human body.
Background
Acute Mountain Sickness (AMS), also known as acute mild altitude sickness, occurs in people who live in low altitude areas for a long time and rapidly enter into plateaus of over 2500m without adaptation to new environments for 1-3 days, and includes a series of symptoms such as insomnia, headache, dizziness, anorexia, emotional restlessness, vomiting, and the like, wherein severe headache is a typical symptom of AMS. AMS has a disease rate of 50-85% according to the difference of ascending speed and specific altitude (Bartsch P and Swenson E R (2013), Clinical practice: Acute high-altitudins, N Engl J Med (368 (24), 2294-. More seriously, if AMS is not effectively controlled and treated, it is likely to develop into High Altitude Cerebral Edema (HACE) with High lethality rate (Boos C J et al (2016), High Altitude Albuted and Acute Motor Package and Change in circulating Endothelin-1, Interleukin-6, and Interleukin-17a, High Altitude Albuted Medicine & Biology, 17(1), 25-31).
AMS has obvious genetic tendency and individual susceptibility, and both environmental factors and genetic factors of high altitude hypoxia can influence the occurrence of AMS. For many years, AMS genetic predisposition and individual susceptibility have been the focus of academic interest both at home and abroad, and although it has been proposed to use the SNP sites of the hypoxia-sensitive genes EGLN 1and HIF-1AN to predict AMS-susceptible populations, it is presently seen that these markers are not satisfactory in terms of accuracy and specificity (Zhang E, Zhang J, Jin J, Qin J, Li H, Huang L: Variants of the low oxygen sensors EGLN 1and HIF-1AN associated with the access molecule sites, International patent of molecular sciences 2014, 15 (12): 21777-21787.). In recent years, the average altitude of the Qinghai-Tibet plateau is more than 4000 meters, along with the vigorous development of the tourism industry of the plateaus and the economic construction of the plateaus at home and abroad, more and more plateaus of the plateaus and the occurrence of AMS (advanced personal Access control) causes serious influence on the life and work of people, so an effective method for predicting the disease susceptibility of AMS in the plateaus is urgently needed to be found.
MicroRNA is a kind of endogenous small molecular non-coding RNA widely existing in eukaryote, and the length of the MicroRNA is 18-24 nucleotides. MicroRNA inhibits the expression of target genes horizontally after transcription, regulates and controls the vital activities of cell differentiation, proliferation, apoptosis and the like, and plays an important role in various physiological and pathological processes such as embryonic development, body metabolism, disease occurrence and development and the like. In recent years, researchers have proposed the concept of circulating microRNA by detecting microRNA in various body fluids such as blood, saliva, and urine. In addition, the expression level of the microRNA is highly related to the difference of the genetic genes of the microRNA, and a large number of researches show that the circulating microRNA has good specificity and sensitivity on the advanced diagnosis and disease prediction of tumors, hypertension, stroke and a series of diseases in recent years. In addition, body fluid samples such as blood and the like are easy to obtain, strong in clinical operability and small in wound, and circulating microRNA is good in stability and convenient to detect, so that the circulating microRNA has the potential of serving as an AMS noninvasive biomarker and is suitable for AMS susceptibility population screening (Ghai V and Wang K (2016), Recent progress aware of circulating microRNAs as clinical biomarkers, Arch toxin).
However, no report has been made on the correlation between circulating microRNA and AMS susceptibility.
No report for detecting the expression level of microRNA-136-3p and microRNA-4791 in blood to predict the risk of AMS is found. The method for predicting the AMS onset risk by using the combination of the microRNA-136-3p and the microRNA-4791 is not reported.
Through screening of chip spectrums of plain plasma circulating microRNA of the plain life residents and combining with the AMS morbidity of the plain life residents after high altitude hypoxia exposure, the differences of the plain plasma circulating microRNA-136-3p and the microRNA-4791 between AMS susceptible persons and AMS tolerant persons are found. And detecting the expression levels of the plain plasma circulating microRNA-136-3p and the microRNA-4791 by a SYBR (SYBR Green dye, abbreviated as SYBR) real-time fluorescent quantitative PCR (polymerase chain reaction) method, and confirming that the correlation exists between the expression levels of the plain plasma circulating microRNA-136-3p and the microRNA-4791 and the AMS susceptibility.
Disclosure of Invention
The invention aims to search novel biological markers of the plain plasma related to AMS, and provides application of the plain plasma microRNA-136-3p and microRNA-4791 in preparation of a kit for predicting AMS onset risk by the plain plasma. The kit can be used for screening AMS susceptible persons before plateau entrance of plateau persons, guiding AMS prevention and reducing AMS threat.
After the plasma microRNA expression profiles of 13 AMS patients and 9 healthy controls are compared and analyzed, the expression levels of plasma microRNA-136-3p and microRNA-4791 of 41 AMS patients and 46 healthy controls are compared, the correlation between the microRNA-136-3p and the microRNA-4791 and AMS is studied, and sensitive and credible AMS susceptibility biological genetic markers are searched. Collecting 22 peripheral blood 2ml of population which is expected to rapidly enter a plateau from a plain by using an EDTA-Na anticoagulation tube, separating at 3000 Xg and 25 ℃ for 10 minutes, extracting upper plasma and storing at-80 ℃ for later use, detecting the microRNA expression level in the plasma by using a microRNA expression profile chip (mircurytM LNA Array (v.18.0)), distinguishing AMS from healthy population according to an AMS international universal diagnostic standard Louis lake scoring diagnostic system after the population enters the plateau, comparing the AMS with the healthy population microRNA expression profile, screening AMS susceptibility related microRNA, and finding that the expression of the microRNA-136-3p and the microRNA-4791 in AMS susceptible people and healthy population has obvious difference.
The expression profiles of microRNA-136-3p and microRNA-4791 in AMS susceptible (41 cases) and healthy control (46 cases) were examined in another independent population using the qPCR technique. In the whole process, Plasma RNA is extracted by adopting a Plasma microRNA column extraction Kit (miRNeasy Serum/Plasma Kit, the product number is 217184) of Germany Qiagen technology Limited company, and then the microRNA-136-3p, the microRNA-4791 and the external reference cel-miR-39 are amplified by adopting a real-time fluorescent quantitative PCR (Hairpin-itTMmiRNAs RT-PCR quantitative Kit, the product number is E01008); respectively calculating the normalized expression levels of the microRNA-136-3P and the microRNA-4791 of each sample relative to cel-miR-39, and detecting the results through SPSS 19.0, wherein the expression levels of the plasma microRNA-136-3P and the microRNA-4791 of AMS susceptible group samples (41 cases) and normal groups (46 cases) are found to have significant difference by taking P < 0.05 as a significance detection standard (Table 1)
The invention aims to solve the technical problem that an AMS susceptible person and an AMS tolerant person can be screened by finding a plain plasma microRNA marker. By detecting the content of microRNA-136-3p and microRNA-4791 in human plain plasma, AMS susceptible persons and AMS tolerant persons are distinguished by high and low expression levels, and the risk of AMS onset after the AMS onset into plateau is predicted.
The technical scheme for solving the problems is as follows: and detecting the content of microRNA-136-3p and microRNA-4791 in the plasma of the plain to distinguish AMS susceptible persons from AMS tolerant persons, wherein the specific information of the microRNA-136-3p and the microRNA-4791 is shown in a table 2.
The benefits of the invention are: the screened microRNA has good prediction efficiency on AMS, can predict the morbidity risk of AMS after the AMS reaches the plateau in the plain, guides the prevention and treatment of the AMS, and lightens the threat of the AMS.
Besides the technical scheme, the invention also makes the following improvements.
The invention also comprises the function of the plasma microRNA (microRNA-136-3p and microRNA-4791) in preparing a kit for predicting the AMS morbidity risk.
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FIG. 1. MicroRNA-136-3p expression levels (i.e., normalized levels of microRNA-136-3p compared to cel-miR-39) in plasma of AMS susceptible and tolerant subjects.
FIG. 2. microRNA-4791 expression levels (i.e., normalized levels of microRNA-4791 compared to cel-miR-39) in plasma of AMS susceptible and tolerant subjects.
Wherein AMS is the patient with AMS and non-AMS is the healthy control. *: p < 0.05, i.e. there was a significant statistical difference, x: p < 0.01, i.e. there were very significant statistical differences, x: p is less than 0.001, namely, the statistical difference is very significant.
FIG. 3 is a working characteristic curve (ROC curve for short) of AMS susceptive plasma microRNA-136-3p and microRNA-4791 alone or in combination, which well shows the ROC curve, area under the curve (AUC), sensitivity (sensitivity), and specificity (specificity) of AMS susceptive, wherein AUC reflects the predicted efficiency (AUC ═ 0.5, no predicted efficiency; AUC < 0.5, very small predicted value; AUC < 0.7 < 0.9, rather accurate predicted value; AUC < 0.9, very accurate predicted value).
Detailed Description
The present invention will now be described with reference to the accompanying drawings, which illustrate examples only for the purpose of illustrating the present invention and do not limit the scope of the present invention.
Example 1 correlation study of expression of MicroRNA-136-3p and MicroRNA-4791 in plasma samples with AMS onset Risk
Description of Material and specimen Collection
AMS susceptible plasma specimens were collected from AMS patients in the population of rapidly advancing plateaus, and the total number was 41. The plasma specimens of the normal population are collected from the normal healthy population in the fast-advancing plateau population before entering the plateau, and the total number is 46. Diagnosis of AMS was confirmed by the International Universal diagnostic Standard-Louis lake score. All people did not take any preventive medication before blood was drawn. Each sample was pooled into 2ml of blood using an EDTA-Na anticoagulation tube.
Second, sample treatment and RNA extraction
After centrifugation at 3000 Xg for 10 minutes at 25 ℃ within 10min after venous blood collection, the supernatant plasma was taken with RNAse-free and bacteria-free tips and stored at-80 ℃ in RNAse-free and bacteria-free EP tubes for later use. RNA in Plasma was extracted and purified by a Plasma microRNA column extraction Kit (miRNeasy Serum/Plasma Kit, cat # 217184) from Qiagen technologies, Germany, according to the procedure described in the specification.
Three, real-time fluorescent quantitative PCR (SYBR dye method)
Amplifying microRNA-136-3p, microRNA-4791 and exogenous cel-miR-39 by using a microRNA real-time fluorescent quantitative PCR Kit (Hairpin-itTMmiRNAs RT-PCR quantification Kit, the cat number is E01008) of Shanghai Jima pharmaceutical technology Co., Ltd; ct values (cycle threshold) were obtained, respectively, by the formula: expression quantity 2Ct(cel-miR-39)-Ct(microRNA-136-3p)The expression level is 2Ct(cel-miR-39)-Ct(microRNA-4791)The specific operation process is shown in the specification when the expression levels of the microRNA-136-3p and the microRNA-4791 of each sample are respectively calculated. Three replicates per sample were performed. The sequences of the primers of the microRNA-136-3p, the microRNA-4791 and the cel-miR-39 are shown in a table 3.
And fourthly, a statistical analysis method.
Statistics were performed using statistical software SPSS 19.0. The positive Test adopts a Shapiro-Wilk method, and the significant difference is evaluated by using a Mann-Whitney Test (Mann-Whitney Test), a working characteristic curve (ROC curve for short) and an area under the line (AUC) to evaluate the single prediction efficiency of the microRNA-136-3p and the microRNA-4791. Statistical differences were considered when p < 0.05.
And establishing a correlation equation of the microRNA-136-3P and the microRNA-4791 by using binary logistic regression to obtain a prediction probability P, performing ROC curve analysis by using the prediction probability P as a test variable, and then evaluating the prediction efficiency of the combined application of the microRNA-136-3P and the microRNA-4791. Statistical differences were considered when p < 0.05.
Sixthly, result analysis
Compared with the expression level of plasma microRNA-136-3p of an AMS susceptible person and an AMS tolerant person, p is less than 0.001, and the statistical difference is very significant.
Compared with the expression level of plasma microRNA-4791 of AMS susceptible persons and AMS tolerant persons, p is less than 0.001, and the statistical difference is very significant.
3. Prediction of efficacy of plasma microRNA-136-3p on AMS susceptible versus AMS tolerant As can be seen from the ROC curve, the prediction of efficacy of microRNA-136-3p on AMS susceptible versus AMS tolerant is very good, and AUC is 0.724 (95% CI, 0.617-0.830).
4. Prediction potency of plasma microRNA-4791 on AMS susceptible versus AMS tolerant subjects it was shown by the ROC curve that microRNA-4791 was very good in prediction potency on AMS susceptible versus AMS tolerant subjects, with an AUC of 0.748 (95% CI, 0.644-0.852).
5. The prediction efficacy of the combined application of the plasma microRNA-136-3p and the microRNA-4791 on AMS susceptible persons and AMS tolerant persons can be known through an ROC curve, the prediction efficacy of the combined application of the plasma microRNA-136-3p and the microRNA-4791 on the AMS susceptible persons and the AMS tolerant persons is good and superior to that of the combined application of the plasma microRNA-136-3p and the microRNA-4791 on the AMS susceptible persons and the AMS tolerant persons, and the AUC is 0.814 (95% CI, 0.720-0.908).
Seven, conclusion
The microRNA-136-3p and the microRNA-4791 in blood have good prediction efficacy on AMS susceptible persons and AMS tolerant persons, can predict the onset risk of AMS, and the prediction efficacy of the combined application of the two is better than that of the two which are respectively used independently.
TABLE 1 expression levels of plasma microRNAs for AMS-susceptible and AMS-tolerant groups
AMS susceptible group vs. AMS tolerant group: p < 0.001, data expressed as median (25% -75% quantile).
TABLE 2 basic MicroRNA information
TABLE 3 primer information of microRNA-136-3p, microRNA-4791, cel-miR-39
Claims (1)
1. The application of the primers for detecting the expression levels of the microRNA-136-3p and the microRNA-4791 in preparing the pre-test kit for the acute mountain sickness susceptible is characterized in that the sequence of the microRNA-136-3p is SEQ ID NO. 1, and the sequence of the microRNA-4791 is SEQ ID NO. 2.
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| WO2006137941A2 (en) * | 2004-11-12 | 2006-12-28 | Ambion, Inc. | Methods and compositions involving mirna and mirna inhibitor molecules |
| CN104955950A (en) * | 2012-09-26 | 2015-09-30 | 米尔克斯治疗学公司 | Oligomers with improved off-target profile |
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| WO2006137941A2 (en) * | 2004-11-12 | 2006-12-28 | Ambion, Inc. | Methods and compositions involving mirna and mirna inhibitor molecules |
| CN104955950A (en) * | 2012-09-26 | 2015-09-30 | 米尔克斯治疗学公司 | Oligomers with improved off-target profile |
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| TPA: Homo sapiens microRNA hsa-mir-136 precursor;Accession No: LM608515;《Genbank》;20150503;全文 * |
| TPA: Homo sapiens microRNA hsa-miR-4791;Accession No: LM382593;《Genbank》;20150503;全文 * |
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