CN109001443A - It is a kind of for detecting the early sign object of gouty attack,acute - Google Patents
It is a kind of for detecting the early sign object of gouty attack,acute Download PDFInfo
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- CN109001443A CN109001443A CN201810626714.1A CN201810626714A CN109001443A CN 109001443 A CN109001443 A CN 109001443A CN 201810626714 A CN201810626714 A CN 201810626714A CN 109001443 A CN109001443 A CN 109001443A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The present invention relates to acute gout early detection fields, and in particular to a kind of for detecting the early sign object of gouty attack,acute；It is a kind of for detecting the early sign object of gouty attack,acute the technical problem to be solved is that providing；The technical solution used for including l-Isoleucine etc. in interior amino acid as early sign object.
Description
Technical field
The present invention relates to acute gout early detection fields, and in particular to a kind of for detecting the early stage of gouty attack,acute
Marker.
Background technique
Gout is the inflammatory arthritic for depositing initiation in joint, tendon and peripheral tissues by monosodium urate (MSU) crystallization
It is scorching.MSU deposition can cause the quick row of periphery joint simple joint synovitis at causing often caused by chronic hyperuricemia
Patient has an intense pain (Kuo et al. 2015 in gouty attack,acute；Richette & Bardin 2010; Richette
et al. 2014).Hyperuricemia clinical definition is that male's serum uric acid concentration is higher than 7.0 mg/dL, and women serum uric acid is dense
Degree is higher than 6.0 mg/dL, and the cause of disease as gout is well known (Aung et al. 2017; Mok et al.
2012).It is estimated that 21% general population and 25% inpatient suffer from asymptomatic hyperuricemia (AHU) (George &
Minter 2018).And the disease incidence of gout has geographic difference, in the ratio in general population about between 0.5% ~ 3.8%
(Chen et al. 2017; Rai et al. 2017).Hyperuricemia and gout and cardiovascular disease (Bang et al.
2016; Borghi et al. 2018; Feig et al. 2008;Hannawi et al. 2017), metabolic syndrome
(Chen et al. 2018;King et al. 2018) and chronic kidney disease (Conijn et al. 2016; Fouad
et al. 2016; Hsieh et al. 2017;Mok et al. 2012) there is close relation.Moreover, hyperuricemia and
The illness rate and disease incidence of gout persistently increase (Rai et al. 2015).Although asymptomatic hyperuricemia and acute
Gout (AG) is difficult to distinguish AG and AHU with serum Uric Acid Concentration all caused by blood uric acid height, because of their serum Uric Acid Concentrations
Quite.The deposition of confirmation MSU is often gone in the diagnosis of AG by means of other means such as ultrasound and dual energy CTs.
In addition, causing the raised factor of serum Uric Acid Concentration very much, for example: BMI body-height exponent is drunk and glycerol in serum
Concentration of three esters etc. is all independent hazard factor (the Miao et al. 2008 of hyperuricemia; Villegas et al.
2010).In China, the disease incidence of hyperuricemia and gout in city is higher than rural area (Liu et al. 2014), such
Difference is perhaps with life style, age composition, economic development (Li et al. 2015 related to eating habit; Miao et
al. 2008; Qiu et al. 2013; Villegas et al. 2010; Zhang et al. 2012).Amino acid
(AAs) it is not only the nutrient in body energy source, and participates in many biochemical route of synthesis, the synthesis including purine, and
Purine formally synthesizes the precursor of uric acid.A large amount of evidence shows AAs and metabolic syndrome, insulin resistance, hyperlipidemia and 2 types
Diabetes correlation (Guasch-Ferre et al. 2016; Mook-Kanamori et al. 2014; Wurtz et al.
2013).Also studies have found that serum Uric Acid Concentration increases the absorption (Mook-Kanamori that placenta system can be inhibited to absorb to AA
et al. 2014).However, the relationship of AA and AHU and AG in adult not yet illustrates completely so far.
Summary of the invention
Overcome the deficiencies in the prior art of the present invention, it is a kind of for detecting acute gout the technical problem to be solved is that providing
The early sign object of breaking-out.
The technical scheme adopted by the invention is as follows: it is a kind of for detecting the early sign object of gouty attack,acute, the mark
Will object includes l-Isoleucine.
Preferably, the marker further includes L-lysine and l-Alanine.
Preferably, the marker concentration is as the index diagnosed and prediction gout is broken out.
Preferably, the index also uric acid concentration carries out comprehensive descision.
Preferably, the marker is made into product to early diagnose acute gout in the form of kit.
Have the beneficial effect that marker dosage of the present invention is few, while not increasing original inspection sample size, can quickly and
It is sensitively detected, accuracy is high, the inexpensive testing product that acute gout diagnosis is used in other.
Table 1: beneficial effect abridged table of the present invention compared with conventional method
| Item compared | Feature of the present invention | Used other congenic methods |
| Sample dosage | 10 microlitres of blood plasma | 100 microlitres or more |
| The sample pretreatment time | 30 minutes | 2-3 hours |
| Sample pretreating method | It is not required to derivatization treatment | Need derivatization treatment |
| Detect speed | 20 kinds of amino acid are detected simultaneously within 20 minutes | The 10 kinds of amino acid of detection in 10 minutes |
| Leucine and isoleucine resolution capability | It can differentiate | It can not differentiate |
| Sensitivity and accuracy | 90~110% | 85~115% |
| Price | 90 yuan | 350 yuan |
Detailed description of the invention
Fig. 1 is that Plasma Amine Acid is differentiated acute gout (AG) group and asymptomatic hyperuricemia group (AHU) group and is good for
Health compares (CON) group.
Fig. 2 be Ile, Lys, Orn, and Ala plasma concentration differentiate AG group and AHU group and CON group.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.
The present invention uses abbreviation meaning as follows: AA for amino acid (odd number), AAs is amino acid (plural number), ACN is second
Nitrile, AG are acute gout, AHU is asymptomatic hyperuricemia, CON group is control group, CUDA solution is inner mark solution, ESI
For electrospray ionisation, MeOH be methanol, PCA is principal component analysis, OPLS-DA is orthogonal partial least squares discriminant analysis, MSU is
Monosodium urate salt, UA are uric acid, LOD is minimum detectability, LOQ be minimum quantitative limit, DP be go cluster voltage, CE be impact energy,
CXP be collision cell outlet current potential, SUS be shared and unique texture, VIP be variable different degree in projection, ROC is subject's work
Make feature.
Reagent employed in technical solution of the present invention are as follows: 21 AAs standard items and their corresponding internal standards (are detailed in table
2)；MSU (CAS:1198-77-2) and uric acid-1,3-15N2(CAS:62948-75-8) it is purchased from Sigma-
Agent of the Aldrich (St. Louis, MO) in Shanghai；2ml sample injection bottle (Catalogue:C5000-2W) and mating
Lid, LC-MS grades of solvent include acetonitrile (ACN, Catalogue:A955), methanol (MeOH, Catalogue:
A456) and water (Catalogue:W6) and formic acid (Catalogue:A117) are purchased from Thermo Fishier
Branch of the Scientific (Shanghai, China) in China；The interpolation pipe of the inactivation of 150 μ l springs is purchased from Waters
Branch of the Corporation (MA, USA) in Shanghai；Ultrafree centrifugal filtration tube (UFC30VV00) is purchased from Merck
Millipore Ltd (Darmstadt, Germany)；2.1 × 150 3.0 μm of chromatographies of mm Venusil ASB-C18
Column and corresponding guard column are purchased from Beaune Ai Jieer company (Tianjin, China).
2 AG group of table, AHU group and CON group clinical elementary information and concentration of blood amino acids
Data are expressed as variable different degree (VIP) value in mean value ± variance (minimum value ~ maximum value) projection by SIMCA 14.1
Software measures under OPLS-DA model, and the significant difference of gender is measured by Chi-square statistic, conspicuousness between the group of other parameters
Difference is analyzed by ANOVA and carries out multiple comparative test between group through Tukey ' s or Games-Howell method.
The blood collection of volunteer of the present invention with separate: experimental program of the invention is through Shanghai Tenth People's Hospital's ethics
Committee's audit passes through (SHSY-IEC-KY-4.0/17-60/01).CON group meets following inclusion criteria: 18 ~ 80 years old age it
Between, without tumour, cardiovascular system, kidney, nerve, digestion and mental disease；AHU and AG group meets following inclusion criteria: age
18-80 years old and through clinical diagnosis be AHU or AG.All participants voluntarily participate in research after being informed the risk of research, and sign
Order informed consent form.
Peripheric venous blood is acquired from EDTA anticoagulant tube, is centrifuged 10 minutes under 4 DEG C, 1500 g revolving speeds immediately, and blood plasma turns
It moves in 1.5 mL EP pipes and is saved backup in -80 DEG C.
The configuration of working solution: 21 AAs standard items and their corresponding internal standards are configured to 1mg/mL's with water respectively
Solution.
Inner mark solution is to mix and be diluted to 10 μ g/mL with ACN corresponding interior target working solution.
The standard solution (concentration range: 10,20,100,200,1000,2000 and 10000 ng/Ml) of 7 gradients is by each
A working solution mixes and uses the mixed liquor of blood plasma, water and ACN to dilute constant volume.Standard solution be stored in -20 DEG C it is spare.
LOD and LOQ with the minimum standard solution of ACN gradient dilution through being measured.
Analyze the preparation of sample: the blood plasma (25 μ L) for shifting defrosting contains 50 CUDA solution (100 ng/mL to 1.5 ml
In ACN) EP pipe in, add 25 μ L ACN, 1400 rpm revolving speeds shake 5 minutes mixing after, at 4 °C in 10000
10 min are centrifuged under rpm revolving speed.Take 70 Μ L supernatants through Ultrafree centrifugal filtration tube under 4 DEG C, 10000 rpm revolving speeds
Centrifugation 5 minutes, 50ML filtrate is transferred to the sample injection bottle equipped with interpolation pipe, be stored in -20 °C it is spare.
The instrumental conditions of AAS sample: AAs concentration is detected with LC-MS/MS method in blood sample, and this method is tested
Demonstrate,prove accuracy with higher (being higher than 90%) and precision (RSD is lower than 10%).Sample separation is being furnished with 2.1 × 150 mm
Venusil ASB-C18It is completed on the 1260 Infinity liquid phase instrument of Agilent of 3.0 μm of chromatographic columns, column temperature is 45 °C of degree, stream
Dynamic is mutually the aqueous solution (solvent A) containing 0.3% formic acid and the methanol/water (v/v containing formic acid 0.3%;95/5) solution
(solvent B).The change of gradient of mobility such as table 3.Sample volume is 5 μ L, and automatic sampling instrument is controlled at 4 DEG C.AAs is by AB
Sciex QTrap6500 mass spectrograph uses MRM mode detection under positive ionization electrospray.The parent ion of MRM mode, daughter ion with
And cluster voltage (DP), impact energy (CE) and collision cell exit potential (CXP) are removed accordingly see Table 4 for details.
Several key amino acids of table 3 and uric acid The ROC area under the curve (AUC)
* PValue is measured under nonparametric hypothesis by ROC curve.
Saturated concentration (35 °C) of 4 MSU of table in several amino acid normal saline solutions
*The concentration of amino acid concentration simulation gouty attack,acute patient and asymptomatic hyperuricemia patients Amino Acid.†Number
According to expression means standard deviation (n=3)‡The saturated concentration of monosodium urate salt in various concentration amino acid normal saline solution
Between difference by double tail T- examine measure.
Data processing method of the invention is as follows: the data obtained to experiment first pre-process: if (1) for AAs
30% sample is lower than LOQ, then all data of the amino acid exclude, and are not further analyzed；(2) for sample, appoint
The data of one AA are except four times of mean value of standard deviation range, then the total data of the sample is excluded, and are not further analyzed.
Blood AAs data after pretreatment import SIMCA-P software (version 14.1, Umetrics AB,
Umea, Sweden) carry out multi-variate statistical analysis.PCA and OPLS-DA analysis data are utilized respectively, check whether to pass through
Blood AAs distinguishes AG group and AHU group or CON group.AG group and other groups of key amino acid can be distinguished through SUS- figure and VIP
Value determines.Value > 1.1 VIP are considered as crucial amino acid.Crucial AAs to AG group and other two groups of separating capacities by
ROC curve assessment.
The measurement of MSU saturation degree in various concentration AAS solution: by MSU (2 mg) be suspended in 1 mL physiological saline or
In the AA normal saline solution of various concentration.See Table 4 for details for the type and concentration of amino acid, concentration of analog this item of surveyed amino acid
The actually measured concentration of blood amino acids of mesh.The suspension of sealing is placed in shaking bath, with 50 min at 35 DEG C-1Frequency is persistently mixed
It closes overnight.Second day, suspension are centrifuged 10 min at 35 DEG C with 18000 rpm, take supernatant (5 μ L) to be placed in and include 10 uL
uric acid-1,3-15N22 mM ammonia spirits (10 μ g/mL) and 985 uL ACN mix.MSU concentration is with having been established
LC-MS/MS method measure (Liu et al. 2017).
Statistical analysis technique: data generally indicate with means standard deviation, except separately having a mark.Using SPSS 17.0
(SPSS, Chicago, IL, USA) software is examined with double tail T-, and ROC curve and single factor test ANOVA are respectively to corresponding data
It is analyzed.
Plasma Amine Acid distinguishes AG group and AHU group: analyzing AG group and AHU group, first three principal component packet first with PCA
67.8% variable is contained, 2 dimension visualization figures such as Figure 1A can be clearly seen that AG and AHU are divided into two groups.Then it utilizes
OPLS-DA analyzes data, containing 1 2D model such as Figure 1B for predicting component and 2 orthogonal components (R2X=0.686,
R2Y=0.938, Q2=0.908) shown in, it can clearly illustrate that two groups are separated.As referring to figure 1E, at M3.p (corr)
[1]-axial expression different aminoacids contribution separated to AG group and AHU group.It can be seen that l-Alanine (Ala,
HMDB0000161), Valine (Val, HMDB0000883), l-Isoleucine (Ile, HMDB0000172), L- bird ammonia
Sour (Orn, HMDB0000214), L-lysine (Lys, HMDB0000182) and glycine (Gly, HMDB0000123) are
Distinguish the significant contributor of AG group and AHU group.It is greater than 1.10 in conjunction with VIP value (table 2) Ile, Orn, Ala, Asn and Lys, is
Distinguish this two groups of most important amino acid.
Plasma Amine Acid distinguishes AG group and CON group: AG group and CON group analyzed using same analysis method,
First three principal component contains 71.4% variable.Its 2 dimension visualization figure such as Fig. 1 C, can be clearly seen that AG and CON are divided
It is two groups.Then data are analyzed using OPLS-DA, the 2D model containing 1 prediction component and 2 orthogonal components is such as
Shown in Fig. 1 D (R2X=0.650, R2Y=0.932, Q2=0.895), clearly illustrate that two groups are separated.Such as Fig. 1 E institute
Show, axially indicates the different aminoacids contribution separated to AG group and CON group in M5. p (corr) [1]-.It can be seen that Ala,
Val, Ile, Orn, Lys and Gly are to discriminate between the significant contributor of AG group and CON group.In conjunction with VIP value (table 1) Ile, Orn,
Ala, Gly and Lys are greater than 1.10, are to discriminate between this two groups of most important amino acid.In conjunction with VIP value as a result, Ile, Orn,
Lys, and Ala may be to discriminate between the key amino acid of AG group and AHU group and CON group.
The plasma concentration of three kinds of amino acid can distinguish AG group and AHU group or CON group: as shown in Fig. 2, Ile, Lys, Orn and
The ROC curve of Ala show this four AAs can differentiate well AG group and AHU (Fig. 2 E ~ 2H) or CON group (Fig. 2 I ~
2L).Their AUCs and corresponding significance,statistical are shown in Table 3, and wherein the AUC value of Ile, Lys and Ala are both greater than 0.9,
It is the primary amino acid that AG group is different from AHU group and CON group.
MSU is in the saturated concentration in different AA solution: saturation of the MSU in various concentration amino acid normal saline solution
The amino acid solution of concentration see Table 4 for details generally high concentration can dissolve more MSU.
Fig. 1 Plasma Amine Acid differentiates acute gout (AG) group and asymptomatic hyperuricemia group (AHU) group and health
Compare (CON) group.(A) PCA scatter plot visually differentiates AG group (dot) and AHU group (triangle). R2X =
0.678, Q2=0.385. (B) OPLS-DA scatter plot visually differentiates AG group (dot) and AHU group (triangle
Shape).R2X=0.686, R2Y=0.938, Q2=0.908. (C) scatter plot visually differentiate AG group (dot) and
CON group (soft dot).R2X=0.714, Q2=0.497. (D) OPLS-DA scatter plot visually differentiates AG
Group (dot) and CON group (soft dot).R2X=0.650, R2Y=0.932, Q2=0.895. (E) SUS- chart is bright
It is that AG group distinguishes over AHU group and CON group ground key amino acid that Ile, Lys, Orn, and Gly blood plasma, which significantly increase,.Volcano figure
Show AG group with being different from AHU group (F) and CON group (G) key amino acid.
Fig. 2 Ile, Lys, Orn, and Ala plasma concentration differentiate AG group and AHU group and CON group.In blood plasma
Ala (A), Orn (B), Lys (C), and Ile (D) concentration.Data indicate means standard deviation ns, and no conspicuousness is poor
It is different; *,P < 0.05; ***, P < 0.001; and ****, P< 0.0001 is analyzed with ANOVA and through Tukey '
S or Games-Howell method carries out multiple comparative test between group.ROC curve assessment Ala (E), and Orn (F),
Lys (G) and Ile (H) distinguishes the ability of AG group and AHU group.ROC curve Ala (I), and Orn (J), Lys
(K) and Ile (L) distinguish AG group and CON group ability.See Table 3 for details for corresponding area under the curve (AUC), is greater than 0.9 explanation
There is extraordinary resolution capability.
Claims (5)
1. a kind of for detecting the early sign object of gouty attack,acute, which is characterized in that the marker includes the different bright ammonia of L-
Acid.
2. according to claim 1 a kind of for detecting the early sign object of gouty attack,acute, which is characterized in that described
Marker further includes L-lysine and l-Alanine.
3. according to claim 1 or 2 is any described a kind of for detecting the early sign object of gouty attack,acute, feature exists
In the marker concentration is as the index diagnosed and prediction gout is broken out.
4. a kind of for detecting the early sign object of gouty attack,acute according to claim 3, which is characterized in that the finger
Mark also needs that serum Uric Acid Concentration is combined to carry out comprehensive descision.
5. a kind of for detecting the early sign object of gouty attack,acute according to claim 1, which is characterized in that the mark
Will object is made into product to early diagnose acute gout in the form of kit.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111175398A (en) * | 2019-11-25 | 2020-05-19 | 广州丹晨医疗科技有限公司 | Kit for diagnosing gout and application thereof |
| CN116539880A (en) * | 2022-12-05 | 2023-08-04 | 四川大学华西医院 | Application of reagent for detecting metabolites and/or tissue proteins in preparation of gouty arthritis screening kit |
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| CN1854730A (en) * | 2005-04-18 | 2006-11-01 | 清华大学 | Method for diagnosing gout and hyperuicemia by serum analysis |
| CN104076100A (en) * | 2007-06-29 | 2014-10-01 | 奎斯特诊断投资公司 | Analysis of amino acids in body fluid by liquid chromatography-mass spectrometry |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1854730A (en) * | 2005-04-18 | 2006-11-01 | 清华大学 | Method for diagnosing gout and hyperuicemia by serum analysis |
| CN104076100A (en) * | 2007-06-29 | 2014-10-01 | 奎斯特诊断投资公司 | Analysis of amino acids in body fluid by liquid chromatography-mass spectrometry |
Non-Patent Citations (3)
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| MH MAHBUB 等: "Alteration in plasma free amino acid levels and its association with gout", 《ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE》 * |
| MH MAHBUB 等: "Association of plasma free amino acids with hyperuricemia in relation to diabetes mellitus, dyslipidemia,hypertension and metabolic syndrome", 《SCIENTIFIC REPORTS》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111175398A (en) * | 2019-11-25 | 2020-05-19 | 广州丹晨医疗科技有限公司 | Kit for diagnosing gout and application thereof |
| CN116539880A (en) * | 2022-12-05 | 2023-08-04 | 四川大学华西医院 | Application of reagent for detecting metabolites and/or tissue proteins in preparation of gouty arthritis screening kit |
| CN116539880B (en) * | 2022-12-05 | 2023-12-08 | 四川大学华西医院 | Application of reagent for detecting metabolites and/or tissue proteins in preparation of gouty arthritis screening kit |
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Application publication date: 20181214 |