CN115505638A - Application of biomarker combination in risk prediction of highly myopic male susceptible population - Google Patents
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Abstract
The invention discloses application of a biomarker combination in risk prediction of a highly myopic male susceptible population, wherein the biomarker relates to 20 SNP loci which are rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs 1919100, rs28667150, rs1790543, rs1392720678, rs 11661223, rs200504002, rs 378803399874, rs174465, rs 535773 and rs12905.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of a biomarker combination in risk prediction of susceptible population of highly myopic men.
Background
Myopia refers to the condition that parallel rays of light are focused on the retina after passing through an eye dioptric system under the condition of adjusting relaxation, and cannot be clearly imaged on the retina. Myopic eyes with a diopter of-6D (D means diopter) or more are highly myopic. Myopic eyes have been recognized to have a certain genetic tendency, especially for high myopia. The patients with genetic factors are older and more than 600 degrees. However, there are also high myopia and no family history. High myopia is an autosomal recessive inheritance.
In infancy, the eyes are smaller and therefore they all look farsighted, but with age the axis of the eyes is gradually lengthened until they grow normally after age 6. If the patient develops excessively, myopia develops, which is called simple myopia and usually begins at school age, usually below 600 ℃. The development stops by about 20 years old. If the progression is rapid in childhood, more rapid by the age of 15 to 20, and then more gradual, myopia is usually greater than 600 degrees, which may be 2000 to 2500 or 3000 degrees. This myopia is called high myopia or progressive myopia or pathological myopia. Degenerative retinal choroidopathies can occur in the near-sightedness in the late years, so that the vision can gradually decline, and the eyesight cannot be corrected by glasses. People who engage in word work or other short-distance work have more myopia, and more myopia in young students, and the prevalence rate of the myopia is obviously increased from the fifth and sixth grade of primary school. This phenomenon indicates that the occurrence and progression of myopia is closely related to near work. Especially, the eyeball of the teenager is in the growth and development stage, the regulation capability is strong, the extensibility of the spherical wall is large, and the regulation and the integration function during the near-distance work such as reading and the like cause that the internal rectus muscle exerts certain pressure on the eyeball and the intraocular pressure is possibly increased.
Disclosure of Invention
In order to make up for the defects of the prior art, the invention aims to solve the technical problems existing at present, and provides a biomarker combination for risk prediction of susceptible population of high-myopia male through sequencing analysis of all exons, so that the problems of limitation, ethnic difference, sex difference and the like existing in the prior art are solved, and then large-scale high-myopia risk general screening of male population is accurately, quickly and low in cost.
In order to solve the problems, the invention adopts the following technical scheme:
one object of the invention is to provide a SNP combination for detecting a population susceptible to high myopia in men, wherein the SNP combination comprises one, more or all of rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678, rs1160961223, rs200504002, rs373399874, rs 465, rs535788073 and rs12905.
Further, the SNP combination is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075 and rs3815045.
Further, the SNP combination is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678 and rs 11661223.
Further, the SNP combination is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678, rs 11661223, rs200504002, rs373399874, rs 880174465, rs 535773 and rs12905.
The term "SNP (single nucleotide polymorphism)" used throughout the present specification means a single-base polymorphism that is frequently and stably distributed throughout the genome due to a general mutation occurring in one of a plurality of DNA bases occurring at a single site of a chromosome, whereby a human body is genetically polymorphic. In the present invention, the "SNP site" may be used in combination with "SNP".
The invention also aims to provide a kit for detecting the male population susceptible to high myopia, which comprises a reagent or an instrument for detecting the genotype of the SNP combination.
The term "susceptible population" used in the present invention refers to a population which is low in immunity and is susceptible to infection due to the presence of a certain susceptibility gene, and some genotypes which are associated with the occurrence of diseases and correspond to genetic constitutions which are unfavorable for health, and we refer to the disease susceptibility gene, wherein the susceptible population lacks immunity to certain infection, and the population which is susceptible to infection and the pathogen of the infectious disease lack specific immunity and is susceptible to infection.
The term "high myopia" as used throughout the specification of the present invention may also be referred to as pathological myopia, malignant myopia, and high myopia when the degree of myopia is above 600.
The high myopia susceptible population is a subject for predicting the occurrence risk of high myopia, and the subject with the risk value of any one, a plurality of or all risk genotypes in the SNP combination higher than a threshold (cutoff) is more likely to become a high myopia patient, namely the high myopia susceptible population.
Further, the reagent or apparatus for detecting the SNP site includes a reagent or apparatus used in the following method: taqMan probe method, sequencing method, chip method, flight mass spectrometer detection, restriction fragment length polymorphism method, single strand conformation polymorphism method, allele specific PCR, SNaPshot method, SNPlex method, denaturing high performance liquid chromatography, denaturing gradient gel electrophoresis method.
The term "allele" or "allele" as used throughout the specification is intended to refer to multiple forms of a gene located at the same genetic position on homologous chromosomes. A duality gene is used to indicate diversity, e.g., a SNP has more than two alleles, e.g., has two alleles.
Further, the reagent may also include specific primers or probes designed for any, several or all of the members of the SNP combinations described above.
Further, the product may also include a reagent or instrument for collecting a sample from a subject.
Further, the subject is a juvenile.
Further, the sample includes: cell supernatant, cell lysate, platelets, serum, plasma, vitreous humor, lymph fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, extracts of buccal swabs, saliva, sputum, tears, sweat, mucus, tumor lysate, tissue culture fluid, tissue extracts, homogenized tissue, tumor tissue, cell extracts.
Further, the sample is an extract of a swab of the mouth.
A third aspect of the invention provides a system for detecting a population susceptible to male high myopia, the system comprising data processing means for determining the likelihood of high myopia in a subject using the genotype detection results of any one or more of the aforementioned SNP combinations.
Further, the data processing apparatus includes the following multigenic risk score calculation formula for processing data:
wherein the multiple gene risk scores
Is m SNP effect values
The weighted sum of (a) and (b),
effect coefficient, X, representing the genotype of the jth SNP j Indicates the jth SNP genotype.
Further, the PRS scoring higher than 0.013 is rated as higher risk.
Further, the calculating of the likelihood of occurrence of high myopia in the subject is a determination of the likelihood of future high myopia in the subject.
Further, the system includes a collection device for collecting information about the processed sample from the subject.
Further, the subject is a juvenile.
Further, the system also comprises an output device for outputting the prediction result.
Further, the system also comprises a detection storage device for the genotype of the SNP locus.
Further, the sample comprises cell supernatant, cell lysate, platelets, serum, plasma, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, oral swab extract, saliva, sputum, tears, sweat, mucus, tumor lysate, tissue culture fluid, tissue extract, homogenized tissue, tumor tissue, cell extract.
Further, the sample is an extract of a buccal swab.
In the context of the present invention, the term "sample" as used refers to a composition obtained or derived from a subject comprising cells and/or other molecular entities to be characterized and/or identified, for example, according to physical, biochemical, chemical and/or physiological characteristics. For example, a sample refers to any sample derived from a subject that is expected or known to contain the cellular and/or molecular entities to be characterized.
In a fourth aspect, the present invention provides a method of detecting a population susceptible to male high myopia, the method comprising detecting a genetic variation in a nucleic acid-containing sample isolated from a subject indicative of male susceptibility to high myopia, the method comprising:
1) Contacting the sample with a reagent capable of detecting a genetic variation in a gene, said gene comprising an allele of a SNP site as set forth above;
2) Obtaining the genotype result of the SNP locus;
3) Diagnosing the susceptibility degree of the male high myopia according to the genotype of the SNP locus in the detection result, which comprises the following specific steps:
rs9513522 is a SNP of the DOCK9 gene, whose allele is a;
rs533280354 is an SNP of the FKBP5 gene, when its allele is a;
rs9517546 is a SNP for the DOCK9 gene, when its allele is G;
rs35985881 is an SNP of the FAM65B gene, when its allele is C;
rs35730227 is an SNP of FAM65B gene whose allele is G;
rs72839911 is a SNP of the FAM65B gene, when its allele is A;
rs6054605 is the SNP of SLC52A3 gene, when the allele is A;
rs2233580 is a SNP of the PAX4 gene whose allele is T;
rs2234075 is the SNP of the ETV7 gene, when its allele is A;
rs3815045 is the SNP of RAB3IL1 gene, when its allele is A;
rs191479100 is SNP of CARMN gene, when its allele is T;
rs28667150 is SNP of DPF3 gene, when its allele is G;
rs1790543 is SNP of TENM4 gene, when its allele is C;
rs1392720678 is a SNP of the SLC26A8 gene, whose allele is G;
rs1160961223 is the SNP of SLC26A8 gene, when its allele is a;
rs200504002 is SNP of LRRC16B gene, when its allele is A;
rs373399874 is the SNP of SRPK1 gene, and when the allele is C;
rs174465 is SNP of FADS3 gene, when its allele is C;
rs535788073 is a SNP of the EXD3 gene, when the allele is a;
rs12905 is SNP of IL1RL1 gene, and when the allele is A or the combination of more than two of the genes is adopted, the risk of the onset of the prediction of the male high myopia is increased;
rs9513522 is a SNP of the DOCK9 gene, whose allele is G;
rs533280354 is the SNP of FKBP5 gene, when its allele is G;
rs9517546 is a SNP of DOCK9 gene, when its allele is A;
rs35985881 is an SNP of the FAM65B gene, when its allele is T;
rs35730227 is an SNP of the FAM65B gene, whose allele is a;
rs72839911 is an SNP of the FAM65B gene, when its allele is G;
rs6054605 is the SNP of SLC52A3 gene, when its allele is G;
rs2233580 is an SNP of the PAX4 gene, when its allele is C;
rs2234075 is the SNP of the ETV7 gene, when its allele is G;
rs3815045 is the SNP of RAB3IL1 gene, when its allele is G;
rs191479100 is a SNP of the CARMN gene, when its allele is G;
rs28667150 is the SNP of DPF3 gene, when its allele is A;
rs1790543 is SNP of TENM4 gene, when its allele is G;
rs1392720678 is a SNP of the SLC26A8 gene, when its allele is a;
rs1160961223 is the SNP for the SLC26A8 gene, when its allele is G;
rs200504002 is SNP of LRRC16B gene, when its allele is G;
rs373399874 is the SNP of SRPK1 gene, when its allele is T;
rs174465 is SNP of FADS3 gene, when its allele is T;
rs535788073 is an SNP of the EXD3 gene when the allele is G;
rs12905 is an SNP of the IL1RL1 gene, and when the allele is G or a combination of two or more of the two genes, the risk of the onset of the prediction of the male high myopia is reduced.
The term "diagnosis" as used throughout the specification of the present invention means to determine whether or not there is a possibility of onset of high myopia in a specific human body, and if there is a possibility of onset, to determine whether or not the possibility of onset of high myopia is relatively higher than that in an unspecified large number of persons (normal population).
Further, the method includes a PRS calculation formula for calculating the risk of a male for high myopia.
Further, the PRS calculation formula is:
wherein the multiple gene risk scores
Is m SNP effect values
The weighted sum of (a) and (b),
effect factor, X, representing the genotype of the jth SNP j Indicates the jth SNP genotype.
Further, the PRS scoring higher than 0.013 is rated as higher risk.
A fifth aspect of the invention provides an application comprising:
1) The application of the SNP combination in preparing products for detecting male high-myopia susceptible people.
2) The kit for detecting the highly myopic male susceptible population and the application of the system in preparing the product for detecting the highly myopic male susceptible population are disclosed.
Drawings
FIG. 1 is a graph of a correlation analysis of genotypes found in a cohort male population;
FIG. 2 is a ROC plot of different SNP site combinations.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
According to an embodiment of the present invention, the SNP site combination for diagnosing high myopia according to the present invention can diagnose high myopia, or predict the risk of developing high myopia, or predict the prognosis of high myopia, but is not limited thereto.
Examples
1. Experimental materials and methods
Oral swab sampling was performed on teenager male population with high myopia and normal control population. Subsequently, the collected buccal swab sample is subjected to genetic material DNA extraction, and the extracted DNA is subjected to whole exon sequencing. The total number of the teenager male high myopia population is 4832, the total number of the normal contrast population is 5762, all the populations are divided into a discovery queue and a verification queue, and the grouping condition is shown in table 1.
Table 1 discovery queue and validation queue information
| Independent queues | People with high myopia | Control population |
| Discovery queue | 4097 | 3993 |
| Verification queue (cohort) | 735 | 1769 |
| Total number of samples | 4832 | 5762 |
2. Discovery queue detection
1) And (4) carrying out whole exon sequencing on the discovery queue, carrying out quality control, comparison and variation detection on sequencing data, and detecting a 1975544 variation site.
2) Correlation analysis (logistic regression) was performed on the male cohort to find variation sites with large frequency difference between the highly myopic population and the normal population, and the results are shown in fig. 1.
3) And after removing the sites with strong linkage on the positions, selecting the most significant 20 sites in the results of the association analysis of the discovery queue for verification analysis.
The 20 bits and their P values in the discovery queue correlation analysis are shown in table 2.
TABLE 2 SNP site specific information for 20 cohort association analyses
3. Validation queue validation
20 sites in Table 1 were selected for Polygenic Risk Score (PRS), and the discrimination effect of these site combinations on the validation cohort was examined.
Combining 20 SNP sites from small to large according to P values, drawing a verification queue Receiver Operating Curve (ROC) by using R package ggplot2, analyzing AUC values, sensitivity and specificity, and judging the diagnosis efficiency of the high myopia under the condition of single index and combination, wherein the result is shown in figure 2.
Combining SNP1 to SNP10, with PRS10 as the outcome of discrimination of the calculated risk for the validation cohort, AUC =0.622;
combining SNP1 to SNP15, with PRS15 as the outcome of discrimination for the calculated risk for the validation cohort, AUC =0.634;
combining SNP1 to SNP20, the discrimination result for the calculated risk for the validation cohort was PRS20 with AUC =0.646.
The PRS20 combined with 20 SNP loci has an AUC value of 0.646, a sensitivity of 0.581 and a specificity of 0.624, and shows higher efficacy on the phenotypic diagnosis of male high myopia from candidate risk pathogenic variant loci of a male high myopia genetic cohort.
4. Risk assessment formula for male susceptible population
The PRS score is rated higher than 0.013 for higher risk according to the PRS calculation. The formula is as follows:
in mathematical form, estimated multigene risk scores
Is m SNP effect values
The weighted sum of (a) and (b),
effect factor, X, representing the genotype of the jth SNP j Indicates the jth SNP genotype.
The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.
Claims (10)
1. An SNP combination for detecting a population susceptible to male high myopia, which is characterized by comprising one, more or all of rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678, rs1160961223, rs200504002, rs373399874, rs174465, rs 535773 and rs 88012905;
preferably, the combination of SNPs is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045;
preferably, the combination of SNPs is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678, rs1160961223;
preferably, the combination of SNPs is rs9513522, rs533280354, rs9517546, rs35985881, rs35730227, rs72839911, rs6054605, rs2233580, rs2234075, rs3815045, rs191479100, rs28667150, rs1790543, rs1392720678, rs 11661223, rs200504002, rs373399874, rs174465, rs 535773, rs12905.
2. A kit for detecting a population susceptible to male high myopia, the kit comprising a reagent or an apparatus for detecting the genotype of the SNP combination according to claim 1.
3. The kit according to claim 2, wherein the reagent or apparatus for detecting SNP sites comprises reagents or apparatuses used in the following methods: taqMan probe method, sequencing method, chip method, flight mass spectrometer detection, restriction fragment length polymorphism method, single strand conformation polymorphism method, allele specific PCR, SNaPshot method, SNPlex method, denaturing high performance liquid chromatography, denaturing gradient gel electrophoresis method.
4. The kit of claim 3, wherein the reagents further comprise specific primers or probes designed for any one, several or all members of the SNP combination of claim 1.
5. The kit of claim 4, wherein the product further comprises a reagent or instrument for collecting a sample from a subject;
preferably, the subject is a juvenile.
6. The kit of claim 5, wherein the sample comprises: cell supernatant, cell lysate, platelet, serum, plasma, vitreous fluid, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, extracts of buccal swabs, saliva, sputum, tears, sweat, mucus, tumor lysate, tissue culture fluid, tissue extracts, homogenized tissue, tumor tissue, cell extracts;
preferably, the sample is an extract of a buccal swab.
7. A system for detecting a population susceptible to male high myopia, the system comprising data processing means for determining the likelihood of high myopia in a subject using genotype measurements for any one or more of the SNP combinations set forth in claim 1;
preferably, the data processing apparatus comprises the following multi-gene risk score calculation formula for processing data:
wherein the multiple gene risk scores
Is m SNP effect values
The weighted sum of (a) and (b),
effect factor, X, representing the genotype of the jth SNP j Represents the jth SNP genotype;
preferably, the PRS scores higher than 0.013 with a higher risk rating;
preferably, said calculating the likelihood of occurrence of high myopia in the subject is determining the likelihood of future high myopia in the subject;
preferably, the system comprises a collecting device for collecting information on a sample of the subject;
preferably, the subject is a juvenile;
preferably, the system further comprises an output device for outputting the prediction result;
preferably, the system further comprises a storage device for detecting the genotype of the SNP site.
8. The system of claim 7, wherein the sample comprises cell supernatant, cell lysate, platelets, serum, plasma, vitreous humor, lymph fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, buccal swab extract, saliva, sputum, tears, sweat, mucus, tumor lysate, tissue culture fluid, tissue extract, homogenized tissue, tumor tissue, cell extract;
preferably, the sample is an extract of a buccal swab.
9. A method of detecting a genetic variation in a nucleic acid-containing sample isolated from a subject indicative of male susceptibility to high myopia in a human susceptible to male high myopia, the method comprising:
1) Contacting the sample with a reagent capable of detecting a genetic variation in a gene comprising an allele of the SNP site of claim 1;
2) Obtaining the detection result of the genotype of the SNP site according to claim 1;
3) Diagnosing the susceptibility degree of the male high myopia according to the genotype of the SNP locus in the claim 1 in the detection result, which comprises the following specific steps:
rs9513522 is a SNP of the DOCK9 gene, whose allele is a;
rs533280354 is an SNP of the FKBP5 gene, when its allele is a;
rs9517546 is a SNP of DOCK9 gene, when its allele is G;
rs35985881 is an SNP of the FAM65B gene with the allele C;
rs35730227 is an SNP of FAM65B gene, when its allele is G;
rs72839911 is a SNP of the FAM65B gene, when its allele is A;
rs6054605 is the SNP of the SLC52A3 gene when its allele is A;
rs2233580 is a SNP of the PAX4 gene whose allele is T;
rs2234075 is a SNP of the ETV7 gene, when its allele is A;
rs3815045 is the SNP of RAB3IL1 gene, when its allele is A;
rs191479100 is SNP of CARMN gene, when its allele is T;
rs28667150 is SNP of DPF3 gene, when its allele is G;
rs1790543 is SNP of TENM4 gene, when its allele is C;
rs1392720678 is the SNP of SLC26A8 gene when its allele is G;
rs1160961223 is the SNP for the SLC26A8 gene, when its allele is a;
rs200504002 is an SNP of LRRC16B gene, when its allele is A;
rs373399874 is the SNP of SRPK1 gene, when its allele is C;
rs174465 is SNP of FADS3 gene, when its allele is C;
rs535788073 is an SNP of the EXD3 gene when the allele is A;
rs12905 is SNP of IL1RL1 gene, and when the allele is A or the combination of more than two of the A alleles, the predicted onset risk of the male high myopia is increased;
rs9513522 is a SNP of the DOCK9 gene, whose allele is G;
rs533280354 is SNP of FKBP5 gene, when its allele is G;
rs9517546 is a SNP for the DOCK9 gene, when its allele is a;
rs35985881 is an SNP of the FAM65B gene, when its allele is T;
rs35730227 is an SNP of FAM65B gene, when its allele is a;
rs72839911 is an SNP of FAM65B gene, when its allele is G;
rs6054605 is the SNP of SLC52A3 gene, when its allele is G;
rs2233580 is an SNP of the PAX4 gene, when its allele is C;
rs2234075 is the SNP of the ETV7 gene, when its allele is G;
rs3815045 is the SNP of RAB3IL1 gene, when its allele is G;
rs191479100 is a SNP of the CARMN gene, when its allele is G;
rs28667150 is the SNP of DPF3 gene, when its allele is A;
rs1790543 is the SNP of the TENM4 gene, when its allele is G;
rs1392720678 is an SNP of the SLC26A8 gene whose allele is a;
rs1160961223 is the SNP of SLC26A8 gene, when its allele is G;
rs200504002 is SNP of LRRC16B gene, when its allele is G;
rs373399874 is the SNP of SRPK1 gene, when its allele is T;
rs174465 is SNP of FADS3 gene, when its allele is T;
rs535788073 is an SNP of the EXD3 gene when the allele is G;
rs12905 is SNP of IL1RL1 gene, and when the allele is G or the combination of more than two of the SNP, the risk of the onset of the prediction of the male high myopia is reduced;
preferably, the method comprises a PRS calculation formula for calculating the risk of a male to suffer from high myopia;
preferably, the PRS calculation formula is:
wherein the multiple gene risk scores
Is m SNP effect values
The weighted sum of (a) and (b),
the effect coefficient of the jth SNP genotype is shown,X j represents the jth SNP genotype;
preferably, the PRS scores higher than 0.013 with a higher risk rating.
10. Use according to any one of the following, wherein said use comprises:
1) Use of the combination of SNPs according to claim 1 for the preparation of a product for detecting a population susceptible to male high myopia;
2) The kit for detecting the high myopia susceptible male human body as claimed in claim 2, and the use of the system as claimed in claim 7 in the preparation of products for detecting the high myopia susceptible male human body.
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