CN103630678A - Biological marker of male infertility and application thereof - Google Patents
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Abstract
The invention discloses a method for diagnosing male infertility, and discloses a biological marker indicating male infertility, a method for indentifying and detecting the biological marker indicating male infertility, and a kit for diagnosing or detecting male infertility. The method combined with seminal fluid routine inspection helps to realize the accurate diagnosis on male infertility.
Description
Technical field
The present invention relates to biomarker, the biomarker that particularly relates to male sterility, comprise the method for the identification of screening male sterility associated biomolecule mark, comprise the method for detection of male sterility biomarker, also comprise for diagnosing or detect the kit of male sterility.
Background technology
Male sterility has become worldwide great public health problem.Traditional seminal fluid conventional analysis conventional semen analysiss such as () sperm quantity, viability, activity ratio and forms is the conventional means that judges at present male fertility, but it is very inaccurate only to rely on seminal fluid conventional analysis to predict that male fertility situation is still.Still unclear to most male sterility patients' real sterile reason clinically, especially clinically nearly nearly 30% male sterility patient's conventional semen analysis result is all normal and approaching normal, therefore there is very large difficulty in the clinical diagnosis to male sterility for a long time, main cause is sperm quantity, viability, the conventional semen analysis index such as activity ratio and form can only reflect the most basic semen quality, and can not reflect all sperm functions, therefore need to find new biomarker auxiliary traditional seminal fluid conventional analysis, the Accurate Diagnosis of realization to male sterility.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of method of diagnosing male sterility, relate generally to the analytical test of humoral sample.In certain aspects, comprised the biomarker that is used to indicate male sterility, comprised for the identification of the method with detecting indication male sterility biomarker, also comprised for diagnosing or detect the kit of male sterility.The present invention, as a kind of aided diagnosis method, can realize the Accurate Diagnosis to male sterility.
In one aspect of the invention, provide a kind of method of diagnosing male sterility herein, having comprised:
(a) provide male subject humoral sample, humoral sample is selected from experimenter's urine, serum, blood plasma, blood, seminal fluid, sperm, refining, saliva, especially urine;
(b) humoral sample, through necessary pre-treatment, comprises and makes it keep liquid condition, dilution, and precipitation is removed in centrifugal or filtration;
(c) by enzyme immunoassay (EIA) or LC-MS-MS method, measure the level of the indication male sterility biomarker of the one or two or more combination in any of acetylcarnitine, aspartic acid, carnitine C3:1, ketone carnitine, leucyl proline, carnitine C8, methyl xanthine, carnitine C10:2, carnitine C10:1, adenine in experimenter's body fluid, and compare with corresponding reference levels, the level of wherein said at least one indication male sterility biomarker and the difference of reference levels indicate this experimenter to suffer from male sterility.
In one embodiment, reference levels refer to the level of described at least one indication male sterility biomarker corresponding in described body fluid corresponding in experimenter's control population of not suffering from male sterility.
In one embodiment, described male subject is not limited to the mankind, also comprises all mammals.
In one embodiment, described enzyme immunoassay (EIA) refers to solid-phase enzyme immunoassay (ELISA).
In another aspect of this invention, provide a kind of for the identification of the method with detecting indication male sterility biomarker herein, the method comprises:
(a) by LC-MS-MS, measure all levels that can detection of biological mark in the humoral sample of suffering from male sterility population of subjects and not suffering from male sterility population of subjects;
(b) by record suffer from male sterility population of subjects and do not suffer from the humoral sample of male sterility population of subjects all can detection of biological mark level one by one correspondence compare, the biomarker of significant difference is accredited as the biomarker of indication male sterility.
In one embodiment, described body fluid is selected from experimenter's urine, serum, blood plasma, blood, seminal fluid, sperm, refining, saliva, especially urine.
In one embodiment, described liquid phase chromatogram-mass spectrometry combination method is not limited to identifies indication male sterility biomarker, also comprises the mensuration that is independently used to indicate male sterility biomarker.
In another aspect of this invention, provide a kind of for diagnosing the kit that detects male sterility herein, it comprises:
(a) standard items of described acetylcarnitine, aspartic acid, carnitine C3:1, ketone carnitine, leucyl proline, carnitine C8, methyl xanthine, carnitine C10:2, carnitine C10:1, adenine indication male sterility biomarker;
(b) for detection of the medium of the existence of described indication male sterility biomarker;
(c) for detection of reagent and/or the instructions of the described medium of described indication male sterility biomarker.
In one embodiment, the described medium for detection of the existence of described indication male sterility biomarker is antibody, antibody fragment or antibody derivatives.
In one embodiment, wherein said antibody, antibody fragment or antibody derivatives can be incorporated into described indication male sterility biomarker or its modified ligand specifically.
In one embodiment, wherein said kit is for measuring the level from least one indication male sterility biomarker of acetylcarnitine described in experimenter's humoral sample, aspartic acid, carnitine C3:1, ketone carnitine, leucyl proline, carnitine C8, methyl xanthine, carnitine C10:2, carnitine C10:1, adenine, and compare with corresponding reference levels, the level of wherein said at least one indication male sterility biomarker and the difference of reference levels indicate this experimenter to suffer from male sterility.
In one embodiment, described reference levels can be by determining with experimenter's control population of not suffering from male sterility, and for human experimenter, a kind of more common mensuration is the statistical combination from the result of a plurality of normal individuals.
In one embodiment, described mensuration is undertaken by solid-phase enzyme immunoassay (ELISA).
Compared with prior art, the invention has the beneficial effects as follows: (1) detects required sample is body fluid, obtain conveniently, avoided the process of harmful complexity such as body injury, radial imaging; (2) as a kind of aided diagnosis method, in conjunction with conventional semen efamination, can realize sterility, especially conventional semen efamination is normally considered to the Accurate Diagnosis of the sterility of unknown cause.
Accompanying drawing explanation
Fig. 1 is: the ROC of carnitine C8 analyzes.Solid line is that the ROC of carnitine C8 risks and assumptions analyzes (AUC=0.65, P=4.06E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 2 is: the ROC of carnitine C10:1 analyzes.Solid line is that the ROC of carnitine C10:1 risks and assumptions analyzes (AUC=0.62, P=1.71E-03); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 3 is: the ROC of carnitine C10:2 analyzes.Solid line is that the ROC of carnitine C10:2 risks and assumptions analyzes (AUC=0.64, P=2.30E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 4 is: the ROC of ketone carnitine analyzes.Solid line is that the ROC of ketone carnitine risks and assumptions analyzes (AUC=0.66, P=1.67E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 5 is: the ROC of acetylcarnitine analyzes.Solid line is that the ROC of acetylcarnitine risks and assumptions analyzes (AUC=0.69, P=2.11E-03); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 6 is: the ROC of methyl xanthine analyzes.Solid line is that the ROC of methyl xanthine risks and assumptions analyzes (AUC=0.65, P=8.77E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 7 is: the ROC of leucyl proline analyzes.Solid line is that the ROC of leucyl proline risks and assumptions analyzes (AUC=0.66, P=2.64E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 8 is: the ROC of carnitine C3:1 analyzes.Solid line is that the ROC of carnitine C3:1 risks and assumptions analyzes (AUC=0.68, P=2.19E-06); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Fig. 9 is: the ROC of adenine analyzes.Solid line is that the ROC of adenine risks and assumptions analyzes (AUC=0.61, P=9.63E-04); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Figure 10 is: the ROC of aspartic acid analyzes.Solid line is that the ROC of aspartic acid risks and assumptions analyzes (AUC=0.68, P=5.22E-05); Dotted line is reference line and represents that 0.5 AUC(is indifference).
Embodiment
By being described in more detail the present invention by following examples.Following examples are only illustrative, and the present invention is not subject to the restriction of these embodiment.
Embodiment
Sample collection
Urine sample is from 135 sterility male patients and 158 normal health male sex contrasts.Male sterility patient is not for to take the normal sexuality of contraceptives still sterile with its spouse above through 1 year herein, but that its spouse is assessed as reproductive function through clinical examination is normal.Normal control be with its spouse 1 year in the male sex of normal fertility.Male sterility patient's mean age is 29.45+4.47, and the range of age is 24-34 year; The normal control male sex mean age is 29.11+5.07, and the range of age is 24-34 year.All affiliated hospital of urine sample Jun Nanjing Medical University collects, and all experimenters all sign written Informed Consent Form.
Urine preparation
Before analysis, at room temperature dissolve urine sample.300 μ L deionized waters are added in 300 μ L urines, under 4 ° of C, centrifugal 10 minutes of 12000 * g.Before carrying out liquid chromatography-mass spectrography (LC/MS) analysis, with injection filter, make the centrifugal rear supernatant of sample by the membrane filtration of aperture 0.22 μ m.
LC/QTOF-MS condition
Urine metabolism collection of illustrative plates obtains by Ultimate-3000 liquid chromatograph (U.S. Dai An company) and MicrOTOF-Q II-level Four bar flight time mass spectrum (Bruker Daltonics, USA) combined system.What reverse phase separation was used is that filler aperture is the C18 chromatographic column (Phenomenex, USA) of 2.1 * 150 mm 2.6 μ m, and column temperature maintains 30 ° of C, and sampling volume is 5 μ L.Mobile phase is the aqueous formic acid of (A) 0.1% and (B) mixed liquor of 0.1% formic acid acetonitrile solution, gradient is as follows: in 1.5 minutes, Mobile phase B volume fraction rises to 20% by 5%, in the time of 8.5 minutes, Mobile phase B rises to 60%, after 0.1 minute, Mobile phase B rises to 95% and keep 1.9 minutes, in 0.1 minute, drop to 5% again, final Mobile phase B volume fraction maintains 3 minutes 5%.Flow rate of mobile phase is 200 μ L/min.Mass spectrometer, at positive ion, moves under ESI scan pattern, and sweep limit is 50 to 1000m/z.Data are collected under centroid pattern.Capillary voltage and end plate drift potential be set to respectively 4500V and-500V.Spray pressure is set to 0.6bar, and dry gas flow is 6 L/min, and temperature is 200 ° of C.Utilize further potential biomarker of second order ms experiment.Collision gas is argon gas, and for each biomarker, impact energy scope is adjusted into 10eV to 35eV.
Data analysis
All chromatograms that collect are carried out to peak alignment, background noise removal and the right extraction of retention time-molecular mass ion, after normalization and pareto medelling, import SIMCA-P v12 software and carry out multivariate data analysis.Utilize the inclined to one side minimum variance discriminatory analysis of quadrature (OPLS-DA) to distinguish and screen biomarker to infertile patients and the check sample that can educate.In training set, based on the various metabolins of remarkable contribution that change are accredited as to potential biomarker.Variable importance projection (VIP) figure based on building from OPLS-DA model and S figure, filter out potential biomarker, and further confirm by Wilcoxon-Mann-Whitney non-parametric test method.P value is less than 0.005 and thinks to have the significance of difference statistically.
Biomarker is identified
The all samples of mixed in equal amounts are prepared the urine specimen of a mixing, analyze this mixing sample to obtain accurate molecular weight information and the isotopic pattern of target organism mark.Use assistant software DataAnalysis 4.0 (Bruker Daltonics, the possible molecular formula of the metabolin that USA) digital simulation screens, the structural information of the urinary biomarkers thing filtering out is submitted to for database retrieval, the database using is Human Urine Metabolome Database (HMDB, http://www.urinemetabolome.ca/) and Metabolite and Tandem MS Database (METLIN, http://metlin.scripps.edu/), and candidate markers is carried out to second order ms analysis, finally by comparing with commercial standard items, the special metabolin that identification goes out.
Statistical study
Use SPSS Statistics 18 softwares (SPSS Inc.) to carry out statistical study.Adopt Mann-Whitney nonparametric U method of inspection to compare the biomarker level between case group and control group, p value is less than the 0.05 indication significance of difference.Adopt SPSS Statistics 18 softwares (SPSS Inc.) to carry out experimenter's operating characteristics (Receiver Operating Characteristic Curve, ROC) tracing analysis, distinguishes sterile individuality and can educate the individual predictive ability of contrast to assess these biomarkers.By ROC curve calculation area under curve (AUC).To what distinguish that sterile individuality has the strongest predictive power, be each biomarker or the mark combination with maximum ROC area under curve.By retrieving those, there is maximum sensitivity and specific biomarker simultaneously, determine the best section of each biomarker.
The urine metabolism group research of case
Employing have the OPLS-DA of supervision to maximize sterile patient and the contrast individuality that can educate between metabolic map spectral difference different.Selection is contributed the diagnosis for sterility as potential biomarker of maximum variable to the classification between two groups.First, adopt the VIP score of variable as a key factor of the superset of screening potential source biomolecule mark.It is selected in this step that VIP score is greater than 3.0 variable.Secondly, from short-list, remove the variable that jack-knifing fiducial interval is less than 0.Then, adopt the S-plot setting up from OPLS-DA model further to get rid of inappropriate variable.Select absolute p value in S-plot and be greater than 0.04 variable that is greater than 0.02 with relative p (corr) value.Due to faint to category of model contribution, be positioned near the variable in matrix dot center and be removed.Adopt Wilcoxon-Mann-Whitney non-parametric test as final program, get rid of the variable that p value is greater than 0.005.Finally, in conjunction with the result of VIP and S-plot and significance test, 17 in 56 initial variablees are chosen to be biomarker and carry out further Structural Identification.
10 identified tables 1 that are out listed in 17 potential source biomolecule marks, comprise six kinds of fatty acyl carnitines, adenine, aspartic acid, leucyl proline and methyl xanthine.
The urine difference metabolin that table 1 obtains from infertile patients and normal healthy controls individuality
| Metabolin | VIP a | p[1] | p(corr)[1] | P b | Trend | Change multiple c |
| Carnitine C8 | 16.71 | 0.30 | 0.31 | 4.06E-04 | ↓ | 0.73 |
| Carnitine C10:1 | 6.89 | 0.14 | 0.27 | 1.71E-03 | ↓ | 0.76 |
| Carnitine C10:2 | 5.75 | 0.10 | 0.27 | 2.30E-04 | ↓ | 0.78 |
| Ketone carnitine | 5.38 | 0.09 | 0.31 | 1.67E-04 | ↓ | 0.81 |
| Acetylcarnitine | 4.26 | 0.07 | 0.37 | 2.11E-03 | ↓ | 0.73 |
| Methyl xanthine | 3.49 | -0.07 | -0.30 | 8.77E-04 | ↑ | 1.36 |
| Leucyl proline | 3.23 | 0.06 | 0.32 | 2.64E-04 | ↓ | 0.78 |
| Carnitine C3:1 | 3.17 | 0.04 | 0.25 | 2.19E-06 | ↓ | 0.64 |
| Adenine | 3.09 | -0.06 | -0.21 | 9.63E-04 | ↑ | 1.15 |
| Aspartic acid | 3.07 | 0.05 | 0.33 | 5.22E-05 | ↓ | 0.65 |
avIP comes from OPLS-DA model, and threshold value is 3.0;
bp value and variation multiple calculate by Wilcoxon-Mann-Whitney non-parametric test;
cit is higher that variation multiple is greater than the relative concentration of this mark of 1 indication in infertile patients, and it is individual lower than normal healthy controls to be less than this mark relative concentration of 1 indication.
The ROC of biomarker analyzes
ROC analyzes and is widely used in clinical chemistry.The evaluation of biomarker analyzes to assess the accuracy of diagnosis through ROC.Sample in training set is used to ROC and analyzes.AUC evaluates biomarker overall sensitivity and specific module.Susceptibility (Sensitivity) is corresponding to real positive rate, and 1-specificity (1-Specificity) is corresponding to false positive rate.AUC be 0.5 explanation model prediction to be contingency; AUC is greater than 0.5, and representative has the recognition capability to disease.ROC curve is the closer to the upper left corner, and the accuracy of test is just higher.The ROC curve of 10 biomarkers identifying in an embodiment: carnitine C8(AUC=0.65, P=4.06E-04) (Fig. 1); Carnitine C10:1(AUC=0.62, P=1.71E-03) (Fig. 2); Carnitine C10:2(AUC=0.64, P=2.30E-04) (Fig. 3); Ketone carnitine (AUC=0.66, P=1.67E-04) (Fig. 4); Acetylcarnitine (AUC=0.69, P=2.11E-03) (Fig. 5); Methyl xanthine (AUC=0.65, P=8.77E-04) (Fig. 6); Leucyl proline (AUC=0.66, P=2.64E-04) (Fig. 7); Carnitine C3:1(AUC=0.68, P=2.19E-06) (Fig. 8); Adenine (AUC=0.61, P=9.63E-04) (Fig. 9); Aspartic acid (AUC=0.68, P=5.22E-05) (Figure 10).In table 2, the various combinations of first three kind biomarker are used to investigate male sterility, and the AUC value of any two kinds of biomarker combinations patterns has been brought up to more than 0.7 (table 2).And by adopting first three to plant biomarker---acetylcarnitine, the integrated mode of carnitine C3:1 and aspartic acid, has obtained the highest AUC value (0.73), susceptibility and 1-specificity have also promoted respectively 65% and 71%.
Therefore, in embodiment, these 10 kinds of biomarkers are useful especially for the diagnosis of male sterility.
Table 2 ROC analysis result
| Biomarker | AUC area | 95% asymptotic confidence interval lower limit | The 95% asymptotic confidence interval upper limit | Susceptibility a | Specificity a |
| Acetylcarnitine (A) | 0.69 | 0.62 | 0.76 | 57% | 72% |
| Aspartic acid (B) | 0.68 | 0.61 | 0.75 | 48% | 81% |
| Carnitine C3:1 (C) | 0.68 | 0.61 | 0.75 | 66% | 67% |
| Ketone carnitine | 0.66 | 0.59 | 0.73 | 63% | 63% |
| Leucyl proline | 0.66 | 0.59 | 0.73 | 84% | 40% |
| Carnitine C8 | 0.65 | 0.58 | 0.72 | 70% | 53% |
| Methyl xanthine | 0.65 | 0.58 | 0.72 | 85% | 45% |
| Carnitine C10:2 | 0.64 | 0.57 | 0.72 | 64% | 63% |
| Carnitine C10:1 | 0.62 | 0.54 | 0.69 | 78% | 41% |
| Adenine | 0.61 | 0.54 | 0.69 | 72% | 48% |
| A+B | 0.71 | 0.65 | 0.78 | 70% | 64% |
| A+C | 0.72 | 0.65 | 0.78 | 45% | 90% |
| B+C | 0.71 | 0.64 | 0.77 | 58% | 78% |
| A+B+C | 0.73 | 0.66 | 0.79 | 65% | 71% |
asusceptibility and specificity are calculated at their best section place.
Claims (14)
1. for diagnosing a method for male sterility, it is characterized in that:
(a) detect the level of at least one indication male sterility biomarker in experimenter's body fluid, wherein at least one indication male sterility biomarker is selected from acetylcarnitine, aspartic acid, carnitine C3:1, ketone carnitine, leucyl proline, carnitine C8, methyl xanthine, carnitine C10:2, carnitine C10:1, adenine;
(b) level and the reference levels of at least one indication male sterility biomarker in described experimenter's body fluid are compared, the level of wherein said at least one indication male sterility biomarker and the difference of reference levels indicate this experimenter to suffer from male sterility.
2. method according to claim 1, wherein, described reference levels are levels of not suffering from described at least one indication male sterility biomarker corresponding in described body fluid corresponding in experimenter's control population of male sterility.
3. according to method described in claim 1-2 any one, wherein, described body fluid is selected from experimenter's urine, serum, blood plasma, blood, seminal fluid, sperm, refining, saliva, especially urine.
4. according to method described in claim 1-3 any one, wherein, described experimenter is the male sex, but is not limited to the mankind, comprises other all mammals.
5. according to method described in claim 1-4 any one, wherein, described mensuration is measured and is carried out by enzyme immunoassay (EIA) or liquid phase chromatogram-mass spectrometry combination method.
6. for the identification of the method with detecting indication male sterility biomarker, it is characterized in that:
(a) measure and to suffer from male sterility population of subjects and not suffer from all levels that can detection of biological mark in the humoral sample of male sterility population of subjects;
(b) by record suffer from male sterility population of subjects and do not suffer from level that all in the humoral sample of male sterility population of subjects can detection of biological mark one by one correspondence compare, show that the biomarker of difference is accredited as the biomarker of indication male sterility.
7. method according to claim 6, wherein, described body fluid is selected from experimenter's urine, serum, blood plasma, blood, seminal fluid, sperm, refining, saliva, especially urine.
8. method according to claim 6, wherein, described mensuration is undertaken by liquid phase chromatogram-mass spectrometry combination method.
9. according to method described in claim 6 and claim 8, wherein, described liquid phase chromatogram-mass spectrometry combination method is not limited to the evaluation of indication male sterility biomarker, comprises the mensuration that is independently used to indicate male sterility biomarker.
10. for diagnosing a kit that detects male sterility, comprise the medium for detection of the existence of the indication male sterility biomarker described in claim 1.
11. kits according to claim 10 wherein, are antibody, antibody fragment or antibody derivatives for detection of the described medium of the existence of described biomarker.
12. antibody according to claim 11, antibody fragment or antibody derivatives can be incorporated into indication male sterility biomarker claimed in claim 1 or its modified ligand specifically.
13. kits according to claim 10 wherein, are solid-phase enzyme immunoassay (ELISA) for detection of the method for indication male sterility biomarker claimed in claim 1.
14. kits according to claim 10, also comprise for using reagent and/or the instructions of the described medium of detection of biological mark in the method described in claim 10-14 any one.
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| CN106556655A (en) * | 2016-10-10 | 2017-04-05 | 南京医科大学 | Medium-chain fatty acid mark related to idiopathic male infertility in serum and its detection method and application |
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| CN106442770A (en) * | 2016-09-05 | 2017-02-22 | 南京医科大学 | Idiopathic male infertility-related seminal plasma metabolic small molecular marker as well as detection method and application thereof |
| CN106442770B (en) * | 2016-09-05 | 2019-01-18 | 南京医科大学 | Refining metabolism small molecule marker relevant to idiopathic male infertility and its detection method and application |
| CN106483212A (en) * | 2016-09-22 | 2017-03-08 | 南京医科大学 | The urine estrogen metabolism thing mark related to idiopathic male infertility and its detection method and application |
| CN106483212B (en) * | 2016-09-22 | 2019-03-01 | 南京医科大学 | Urine estrogen metabolism object marker relevant to idiopathic male infertility and its detection method and application |
| CN106198815A (en) * | 2016-09-23 | 2016-12-07 | 南京医科大学 | Metabolic markers relevant to idiopathic male infertility in urine and detection method thereof and application |
| CN106556655A (en) * | 2016-10-10 | 2017-04-05 | 南京医科大学 | Medium-chain fatty acid mark related to idiopathic male infertility in serum and its detection method and application |
| CN107917980A (en) * | 2017-11-14 | 2018-04-17 | 河南科技大学 | Identify biomarker, acquisition methods and its application of the elm age of tree |
| CN107998397A (en) * | 2017-12-07 | 2018-05-08 | 复旦大学附属华山医院 | Application of the EMC10 albumen as biomarker in male sterility is diagnosed |
| CN107998397B (en) * | 2017-12-07 | 2020-09-04 | 复旦大学附属华山医院 | Application of EMC10 protein as biomarker in diagnosis of male infertility |
| CN112129876A (en) * | 2020-09-24 | 2020-12-25 | 南京医科大学 | Seminal plasma organic acid marker related to idiopathic male sterility and detection method and application thereof |
| CN112129876B (en) * | 2020-09-24 | 2021-07-20 | 南京医科大学 | Seminal plasma organic acid marker related to idiopathic male sterility and detection method and application thereof |
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