WO2017007275A1 - Composition for determining nasal phenotype - Google Patents

Abstract

The present invention relates to a composition for determining a nasal phenotype, and more specifically, the present invention relates to: a marker, for determining the nasal phenotype, comprising an SNP linked to the nasal phenotype; a composition, for determining the nasal phenotype, comprising a means for detecting the marker; a kit, for determining the nasal phenotype, comprising the composition; a microarray, for determining the nasal phenotype, comprising the marker; and a method for providing information for determining the nasal phenotype utilizing the composition and kit. The marker according to the present invention is a specific genetic marker for determining size from among the nasal phenotypes, and thus can be used to objectively determine the size of a nose, and as such, can be widely utilized to determine the physical constitution and manage health effectively, and can be effectively used in crime investigations, such as in creating a facial composite.

Description

Nose phenotype composition

The present invention relates to a composition for determining a nasal phenotype, and more particularly, the present invention relates to a nasal phenotype determination marker comprising an SNP associated with a nasal phenotype, and a composition for determining a nasal phenotype comprising a means for detecting the marker. The present invention relates to a nasal phenotype determination kit comprising a composition, a nasal phenotype determination microarray including the marker, and a nasal phenotype determination method using the composition or kit.

As interest in quality of life increases with the improvement of living standards, the preference for proactive health management such as health status measurement and proper exercise management is increasing. Among the various information required for such management, the most important is information such as the constitution of the subject and the current state of health. Since the subject's current health condition is constantly changing according to the subject's surroundings and living environment, it is practically difficult to perform health care using this as a variable, but since the subject's constitution is hardly changed, There is a need for development of methods to use.

In this regard, Sasang medicine suggests that it is effective to change the treatment method according to the constitution even for the same disease or symptom, and divides the human constitution into four according to the deviation of the five intestines. The identification of constitution based on the ideology is used to find and confirm each constitution through the Sasang Constitutional Medicine Program (QSSCCII) certified by the Sasang Constitutional Medicine Association. However, since such a conventional method often depends on the subjective judgment of the diagnoser, there is a limit in the reliability. Therefore, studies for determining the constitution based on more objective facts are actively conducted.

Facial phenotypes are one of the most prominent phenotypes that represent differences between individuals. While it is clear that it is regulated by genetic characteristics, the mechanism of action of the gene on facial phenotypic determination is little known. In addition, research on the association between the genetic risk of disease and the genetic features of facial phenotype is insufficient.

In this situation, GWAS studies on the nose phenotype, one of the face phenotypes, were reported by Patemoster L. et al. (Am J Hum Genet 90, 478-485, 2012) and Liu F. et al. PLoS Genet 8, e1002932) and the like. However, the results of studies on Europeans whose genetic traits differ significantly from those of Asians, including Koreans, are currently insufficient.

On the other hand, montages in criminal investigations are used when pictures of criminals to be arranged are not available. The current method used to create a montage finds the characteristics and similarities of the criminal based on the memory of the people who witnessed the criminal's face, and looks like outlines, eyes, nose, mouth, ears, jaw, eyebrows and hair. Select, synthesize and replicate. The basic picture is shown back to the eyewitness, and the correction is repeated until it matches the image of the culprit. However, because the witness's memory could be distorted, the montage created by current methods often did not match the arrested criminal's face. Thus, the need for montages to be based on more objective facts, such as the arrest of criminals by DNA analysis of suspects, has emerged.

The present inventors have diligently researched to develop a method for deriving the heredity inherent in the nasal phenotype. As a result, the inventors have discovered SNPs associated with the nasal phenotype. In addition to deriving the genetic influence of the confirmed that the crime can be used for investigation, the present invention was completed.

It is an object of the present invention to provide a marker for determining a nasal phenotype comprising an SNP associated with a nasal phenotype.

Another object of the present invention to provide a composition for determining the nasal phenotype comprising a means for detecting the marker.

Another object of the present invention to provide a kit for determining the nasal phenotype comprising the composition.

Another object of the present invention to provide a microarray for determining the nose phenotype comprising the marker.

Still another object of the present invention is to provide a method for determining nasal phenotype using the composition or kit.

Another object of the present invention is to provide the use of SNPs associated with nasal phenotypes for nasal phenotype determination.

The marker of the present invention is a specific gene marker that determines the size of the nose phenotype, and can be used as a means for objectively evaluating the size of the nose, so that it can be widely used for constitution determination and effective health care, as well as montage It can be actively used for criminal investigation such as writing.

1 is a schematic diagram showing phenotypes that characterize the side nose.

Figure 2 is a schematic diagram showing the process of discovering the SNP of the present invention.

Figure 3 is a diagram showing the results of analyzing the SNP of the present invention in East Asia HapMap results.

FIG. 4 is a graph showing a regional plot of the chromosome associated region 17 for the nose angle phenotype (ln_PA_12_14_21).

One embodiment of the invention (a) the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1, the 301th base is A or G, a poly consisting of 5 to 1,000 consecutive bases comprising the 301th base Nucleotides; (b) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2, wherein the 301th base is C or T; (c) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 3, wherein the 301th base is C or T; (d) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4, wherein the 301th base is C or G; (e) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 5, wherein the 301th base is C or A; And (f) a polynucleotide selected from the group consisting of polynucleotides complementary to any of the polynucleotides of (a) to (f).

The polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1 may include rs3105176 which is an SNP, the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2 may include rs2159042, which is an SNP, the base of SEQ ID NO: 3 The polynucleotide consisting of the sequence may include rs2024070 SNP, the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4 may include rs2193054 SNP, the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 5 May include rs2058742, which is an SNP.

Marker for determining the nasal phenotype provided by the present invention, the polynucleotide of SEQ ID NO: 1 wherein the base corresponding to the 301th is A or G; The polynucleotide of SEQ ID NO: 2 wherein the base corresponding to the 301st is C or T; The polynucleotide of SEQ ID NO: 3 wherein the base corresponding to the 301st is C or T; The polynucleotide of SEQ ID NO: 4 wherein the base corresponding to the 301st is C or G; The polynucleotide of SEQ ID NO: 5 wherein the base corresponding to the 301st is C or A; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, and the polynucleotide of SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, and the polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, and the polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T; The polynucleotide of SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G; The polynucleotide of SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G; The polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G; The polynucleotide of SEQ ID NO: 1, wherein the base corresponding to the 301th is A or G, SEQ ID NO: 2, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 2, where the base corresponding to the 301th is C or T, the SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G; The polynucleotide of SEQ ID NO: 2, where the base corresponding to the 301th is C or T, SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; The polynucleotide of SEQ ID NO: 3, wherein the base corresponding to the 301th is C or T, SEQ ID NO: 4, wherein the base corresponding to the 301th is C or G, and the polynucleotide of SEQ ID NO: 5, wherein the base corresponding to the 301th is C or A; SEQ ID NO: 1, where the 301th base is A or G, SEQ ID NO: 1, where 301 is the base number C, or T, SEQ ID NO: 2, 301, which corresponds to SEQ ID NO: 3, and 301, the base C or T. The polynucleotide of SEQ ID NO: 4 with a base of C or G; SEQ ID NO: 1, where the 301th base is A or G, SEQ ID NO: 1, where 301 is the base number C, or T, SEQ ID NO: 2, 301, which corresponds to SEQ ID NO: 3, and 301, the base C or T. The polynucleotide of SEQ ID NO: 5 with a base of C or A; SEQ ID NO: 1, where the 301th base is A or G, SEQ ID NO: 1, where 301 is the base number C, or T, SEQ ID NO: 2, 301, which corresponds to SEQ ID NO: 4 and 301, the base C or G. The polynucleotide of SEQ ID NO: 5 with a base of C or A; SEQ ID NO: 1, where the 301th base is A or G, SEQ ID NO: 3, where 301 is the base C or T, SEQ ID NO: 3, 301, which corresponds to SEQ ID NO: 4, and 301, the base corresponding to C or G The polynucleotide of SEQ ID NO: 5 with a base of C or A; SEQ ID NO: 2, where the 301th base is C or T, SEQ ID NO: 3, where the 301 base is C or T, SEQ ID NO: 3, 301, which corresponds to SEQ ID NO: 4, and 301, the base C or G. The polynucleotide of SEQ ID NO: 5 with a base of C or A; Or SEQ ID NO: 1, where the 301th base is A or G, SEQ ID No. 1, 301, which corresponds to SEQ ID NO: 2, or 301, where the base corresponding to the 301 th, C or T, corresponds to SEQ ID NO: 3,301. A polynucleotide of SEQ ID NO: 4 having a base of C or G and SEQ ID NO: 5 having a base corresponding to 301 th C or A may be included.

The term "nose phenotype" of the present invention refers to the nose area, nose angle, nose height and nose length that are formed when three points are designated on the side surface of the nose. For continuous variables. The phenotype of the nasal morphology is also useful in discriminating constitution in Sasang Constitutional Medicine, and is also a major variable in the Sasang constitutional analysis tool (SCAT).

In one experimental example of the present invention, in the polynucleotides of SEQ ID NOs: 1 to 5 including SNPs, the individual having the 301th base G in the polynucleotide of SEQ ID NO: 1 has a relatively larger nose size than the individual having the base A. A tendency to decrease was identified; In the polynucleotide of SEQ ID NO: 2, the individual having the 301th base of C was found to have a tendency to increase in nose size relative to the individual having the base of T; In the polynucleotide of SEQ ID NO: 3, the individual having the 301th base of C was found to have a tendency to increase in nose size relative to the individual having the T of the base; In the polynucleotide of SEQ ID NO: 4, an individual whose base 301 is C has a tendency to increase in nose size relative to an individual whose base is G; In the polynucleotide of SEQ ID NO: 5, the individual having the 301th base A was found to have a tendency to decrease the nose size relatively than the individual having the C base.

Among the genetic mutations of the polynucleotides including the five SNPs, the incidence of alleles that increase the nose height and size is known to be higher in Westerners than in Asians including Koreans. Thus, the experimental example can explain some of the racial differences between the nose and Westerners with a big nose.

In addition, the nasal influence of the polynucleotide containing the five SNPs may have a medically important meaning. Among the polynucleotides containing five SNPs, the SNPs contained in the polynucleotide of SEQ ID NO: 1 located on chromosome 8 are present in the VPS13B gene, which performs membrane-mediated transport and protein classification in cells. It means a gene encoding a potential membrane protein. The genes play a role in the development of the eye, blood system and central nervous system, and mutations in the genes can cause Cohen syndrome and the like. The nucleotide sequence of the VPS13B gene may be obtained from a known database such as GenBank of NCBI. For example, the nucleotide sequence of GenBank Accession HF584359.1, NM_017890.4, etc. may be used. It may comprise a polynucleotide consisting of.

Subsequently, the SNPs contained in the polynucleotides of SEQ ID NOs: 2 to 5 located on chromosome 17 among the polynucleotides containing five SNPs are SOX9 (sex determining region Y)-which is a gene involved in the differentiation of chondrocytes. box 9) Located near the gene. Mutations in the gene can cause actin dysplasia or robin syndrome. The nucleotide sequence of the SOX9 gene can be obtained from a known database such as GenBank of NCBI. For example, the SOX9 gene can be a gene represented by GenBank Accession NM_000346.3, NG_012490.1, or the like.

The term "polynucleotide consisting of the nucleotide sequences of SEQ ID NOs: 1 to 5" of the present invention refers to the nose area, nose angle, nose height and nose length among the nose phenotypes. As a polymorphic sequence including a polymorphic site of a gene involved in the polymorphic sequence, the polymorphic sequence means a sequence including a polymorphic site including SNP in a polynucleotide sequence. The polynucleotide sequence may be DNA or RNA.

The term "polymorphism" of the present invention refers to a case in which two or more alleles exist at one locus, and among polymorphic sites, a single base polymorphism ( single nucleotide polymorphism (SNP). As a specific example, the polymorphic marker has two or more alleles that exhibit a frequency of at least 1%, more preferably at least 5% or 10% in the selected population.

The term "allele" in the present invention means several types of genes that exist at the same locus of homologous chromosomes. Alleles are also used to indicate polymorphism, for example, SNPs have two kinds of bialleles.

Another embodiment of the present invention provides a composition for determining nasal phenotype, comprising an agent capable of detecting or amplifying the nasal phenotype determination marker.

As used herein, the term "agent capable of detecting or amplifying a marker" refers to an agent capable of specifically binding to and recognizing SNP contained in the nasal phenotype judgment marker, or specifically, an agent capable of amplifying the SNP. May be a probe capable of specifically binding to a polymorphic site including an SNP, a polynucleotide comprising the SNP marker, or a primer capable of specifically amplifying a complementary polynucleotide thereof.

As used herein, the term "probe" refers to a nucleic acid fragment, such as RNA or DNA, which is capable of forming a specific binding with an mRNA, which may be a few bases to several hundred bases, and is labeled. The presence or absence of a specific mRNA can be confirmed. Probes may be prepared in the form of oligonucleotide probes, single stranded DNA probes, double stranded DNA probes, RNA probes, and the like.

In the present invention, a probe used to bind to and recognize an SNP marker includes a sequence complementary to a polynucleotide sequence including an SNP, but is not limited thereto, and may be in a DNA, RNA or DNA-RNA hybrid form. . In addition, a fluorescent labeling factor, a radiolabeling factor, or the like may be additionally attached to the 5 'or 3' end of the probe for visual recognition.

As used herein, the term “primer” refers to a base sequence having a short free 3 ′ hydroxyl group, which can form complementary templates and base pairs and is a starting point for copying template strands. By a short sequence that functions as a point. Primers used for amplifying the SNP markers in the present invention may be prepared using appropriate conditions (e.g., four different nucleoside triphosphates and polymerizers such as DNA, RNA polymerase or reverse transcriptase) in appropriate buffers and under appropriate temperatures. It may be a single-stranded oligonucleotide that can serve as a starting point for directing DNA synthesis. The appropriate length of the primer may vary depending on the purpose of use, but may generally be used in a size of 15 to 30 nucleotides. The primer sequence need not be completely complementary to the polynucleotide comprising the SNP marker or its complementary polynucleotide, and may be used if it is complementary enough to hybridize.

In addition, primers may be modified, for example methylation, capping, substitution of nucleotides or modifications between nucleotides, for example, uncharged linkages such as methyl phosphonate, phosphoester, phosphoramidate, Carbamate, etc.) or charged linkers (eg, phosphorothioate, phosphorodithioate, etc.).

Another embodiment of the present invention provides a nasal phenotype determination kit comprising the composition. Specifically, the kit may be, but is not limited to, RT-PCR (Reverse Transcription Polymerase Chain Reaction) kit, DNA analysis (eg, DNA chip) kit.

Kit of the present invention can determine the nasal phenotype by using the composition to confirm the base of the SNP provided by the present invention by amplification, or to check the expression level of mRNA. As a specific example, the kit provided in the present invention may be a kit including essential elements necessary for performing RT-PCR.

For example, RT-PCR kits, in addition to each primer pair specific for the SNP, RT-PCR kits can be used in test tubes or other suitable containers, reaction buffers (variable pH and magnesium concentrations), deoxynucleotides (dNTPs) Enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. It may also include primer pairs specific for the gene used as a quantitative control.

As another example, the kit of the present invention may be a DNA chip kit for nasal phenotype determination including essential elements necessary for performing a DNA chip.

The term "DNA chip" of the present invention means one of the DNA microarray which can identify each base of hundreds of thousands of DNA at a time.

The DNA chip kit is a substrate in which a nucleic acid species is attached in a gridded array to a glass surface, which is generally not larger than a flat solid support plate, typically a microscope slide. Multiple hybridization reactions occur between nucleic acids on a chip and complementary nucleic acids contained in a solution treated on a chip surface, thereby enabling mass parallel analysis.

Another embodiment of the present invention provides a nasal phenotype determination microarray comprising the nasal phenotype determination marker.

Specifically, the microarray is a polynucleotide consisting of 5 to 1,000 consecutive bases including (a) the 301th base is A or G in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1, and the 301th base. ; (b) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2, wherein the 301th base is C or T; (c) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 3, wherein the 301th base is C or T; (d) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4, wherein the 301th base is C or G; (e) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 5, wherein the 301th base is C or A; And (f) at least one polynucleotide selected from the group consisting of polynucleotides complementary to the polynucleotides of (a) to (f).

The microarray may include DNA or RNA polynucleotides. The microarray consists of conventional microarrays except that the polynucleotide of the present invention is included in the probe polynucleotide.

Methods for preparing microarrays by immobilizing probe polynucleotides on substrates are well known in the art. The probe polynucleotide refers to a polynucleotide capable of hybridization, and refers to an oligonucleotide capable of sequence-specific binding to the complementary strand of a nucleic acid. The probe of the present invention is an allele specific probe in which polymorphic sites exist in nucleic acid fragments derived from two members of the same species, and hybridize to DNA fragments derived from one member, but not to fragments derived from other members. . In this case, hybridization conditions show significant differences in hybridization strength between alleles, and should be sufficiently stringent to hybridize to only one of the alleles. This can lead to good hybridization differences between different allelic forms. The probe of the present invention may be used in a nasal phenotype determination method by detecting an allele. The determination method includes detection methods based on hybridization of nucleic acids such as Southern blot and the like, and may be provided in a form that is pre-bound to the substrate of the DNA chip in a method using a DNA chip. Said hybridization can usually be carried out under stringent conditions, for example salt concentrations below 1 M and temperatures above 25 ° C. For example, conditions of 5 × SSPE (750 mM NaCl, 50 mM Na Phosphate, 5 mM EDTA, pH 7.4) and 25-30 ° C. may be suitable for allele specific probe hybridization.

The process of immobilizing the probe polynucleotides associated with the nasal phenotype judgment of the present invention on a substrate can also be readily performed using this prior art. In addition, the hybridization of nucleic acids on microarrays and detection of hybridization results are well known in the art. The detection is accomplished by labeling a nucleic acid sample with a labeling substance capable of generating a detectable signal comprising, for example, a fluorescent substance such as Cy3 and Cy5, and then hybridizing onto a microarray and generating from the labeling substance. The hybridization result can be detected by detecting the signal.

Another embodiment of the invention amplifies a polymorphic site comprising (a) a polynucleotide consisting of the nucleotide sequences of SEQ ID NOS: 1-5 from the DNA of a sample isolated from an individual or a SNP of a complementary polynucleotide thereof Making a step; And (b) determining the base of the amplified polymorphic site. At this time, the DNA of the separated sample can be obtained from a sample separated from the individual.

As described above, the marker for determining the nasal phenotype provided by the present invention includes each SNP included in the polynucleotides of SEQ ID NOs: 1 to 5, which can determine the nose size in the nasal phenotype.

It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 1 is larger than the individual whose base is G; It is determined that an individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 2 is C has a larger nose size than an individual whose base is T; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 3 is C has a larger nose size than the individual whose base is T; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 4 is C has a larger nose size than the individual whose base is G; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 5 is C can be determined to have a larger nose size than the individual whose base is A.

Further, it is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 1 is G has a smaller nose size than the individual whose base is A; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 2 is T is determined to have a smaller nose size than the individual whose base is C; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 3 is T has a smaller nose size than the individual whose base is C; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 4 is G has a smaller nose size than the individual whose base is C; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 5 is A can be determined to have a smaller nose size than the individual whose base is C.

Therefore, by determining the base of each SNP, it is possible to objectively predict or determine the nasal phenotype, particularly the size of the individual comprising the SNP. As such, the nose phenotype of an object predicted or determined objectively may be provided as nasal phenotype information that is used as a basis for determining the ideological constitution of the individual.

The term "individual" of the present invention refers to a person who is a subject to determine a nasal phenotype, and the nasal phenotype can be determined by analyzing the base of the polymorphic site including the SNP using an isolated sample obtained from the person. Can be. The sample may be hair, urine, blood, various body fluids, separated tissues, samples such as isolated cells or saliva, but is not particularly limited thereto.

Amplifying the polymorphic site of the SNP from the DNA of step (a) can be used by any method known to those skilled in the art. For example, the target nucleic acid can be amplified by PCR and purified. Ligase chain reaction (LCR) (Wu and Wallace, Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988)), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989)) and self-sustaining sequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87, 1874 (1990)) and nucleic acid based sequence amplification (NASBA).

Determining the base of the amplified polymorphic site of step (b) of the method is sequence analysis, microarray hybridization, allele specific PCR, dynamic allele hybridization technique (dynamic allele-). specifichybridization (DASH), PCR prolongation analysis, PCR-SSCP, PCR-RFLP analysis or TaqMan technique, SNPlex platform (Applied Biosystems), mass spectrometry (e.g. Sequenom's MassARRAY system), mini-sequencing method , Bio-Plex system (BioRad), CEQ and SNPstream system (Beckman), Molecular Inversion Probe array technology (e.g., Affymetrix GeneChip), and BeadArray Technologies (e.g., Illumina GoldenGate and Infinium assays) It may be, but is not particularly limited thereto. Alleles can be identified in the polynucleotide comprising the SNP by the above methods or by other methods available to those skilled in the art. Determining the base of such a mutation site may be preferably performed through a DNA chip.

The TaqMan method comprises the steps of: (1) designing and constructing a primer and a TaqMan probe to amplify a desired DNA fragment; (2) labeling probes of different alleles with FAM dye and VIC dye (Applied Biosystems); (3) using the DNA as a template and performing PCR using the primers and probes described above; (4) after the PCR reaction is completed, analyzing and confirming the TaqMan assay plate with a nucleic acid analyzer; And (5) determining the base of the polynucleotides of step (1) from the analysis result.

The sequencing assay can use conventional methods for sequencing and can be performed using an automated genetic analyzer. In addition, allele-specific PCR refers to a PCR method for amplifying a DNA fragment in which the mutation is located with a primer set including a primer designed with the base at which the mutation site is located as the 3 'end. The principle of the method is, for example, when a specific base is substituted from A to G, PCR by designing a primer containing A as the 3 'terminal base and a reverse primer capable of amplifying a DNA fragment of a suitable size. When the reaction is performed, when the base of the mutation position is A, the amplification reaction is normally performed, and a band of the desired position is observed. When the base is substituted with G, the primer may complementarily bind to template DNA. The amplification reaction is not performed properly because the 3 'end is not complementary. DASH may be performed by a conventional method, preferably by a method by Prince et al.

PCR extension assays, on the other hand, first inactivate DNA fragments containing bases in which a single nucleotide polymorphism is located by amplifying a pair of primers, and then deactivating all nucleotides added to the reaction, followed by specific extension primers, dNTP mixtures. By adding a didioxynucleotide, a reaction buffer and a DNA polymerase to carry out the primer extension. At this time, the extension primer is a 3 'end of the base immediately adjacent to the 5' direction of the base where the mutation site is located, the dNTP mixture excludes a nucleic acid having the same base as the didioxynucleotide, the didioxynucleotide is a mutation It is selected from one of the base types shown. For example, if there is a substitution from A to G, when a mixture of dGTP, dCTP and TTP and ddATP are added to the reaction, the primer is extended by DNA polymerase at the base where the substitution takes place and after several bases A The primer extension is terminated by ddATP at the position where the base first appears. If the substitution has not occurred, since the extension reaction is terminated at the position, it is possible to determine the base type showing the mutation by comparing the length of the extended primer.

In this case, as the detection method, when the fluorescent primer is labeled with an extended primer or didioxynucleotide, the mutation can be detected by detecting fluorescence using a gene analyzer (for example, Model 3700, manufactured by ABI, etc.) used for general sequencing. In the case of using unlabeled extension primers and didioxynucleotides, genetic variation of the SNP can be detected by measuring molecular weight using a matrix assisted laser desorption ionization-time of flight (MALDI-TOF) technique. .

Another embodiment of the present invention provides the use of a SNP associated with a nasal phenotype for nasal phenotype determination.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and the scope of the present invention is not to be construed as being limited by these examples.

Example  1: Screening Subjects and Setting Lateral Nose Phenotype Criteria

Example  One- 1: research  Target Screening

The subjects of the present invention consisted of three large population groups, and the group was collected in the Anseong-Ansan area group, the group collected for constitution diagnosis in a number of oriental hospitals, and the group collected regardless of the constitution diagnosis in two oriental hospitals. It was a group. In the group, a total of 9,416 persons were collected among the 20-year-olds with lateral nose phenotypes among the facial phenotypes, except for cancer patients who could affect the facial phenotypes, of which 3,897 were males and 5,519 females. .

Specifically, the Anseong-Ansan area group was a collection group that collected facial phenotypes in cooperation with the Korean Genome and Epidemiology Study (KoGES) project from 2009 to 2012 (hereafter, the discovery group). It consists of 2,962 women and women.

The subjects collected for the purpose of constitution diagnosis in many oriental hospitals were collected from 21 oriental hospitals from 2007 to 2012 as part of the Korea Constitution Multicenter Study (KCMS) project (hereafter, validation). 1 group), consisting of 678 males and 1,220 females out of a total of 1898.

Regardless of the constitution diagnosis, the subjects were collected from two oriental hospitals during the two years from 2011 to 2012 (hereinafter, validation 2 group), which consists of 585 men and 1,337 women out of 1,922.

Example  1-2: Set the detailed criteria for the side nose phenotype

The face phenotype is determined by traits such as area, angle, and distance by connecting major feature points based on photographs of the front and side. Of these, the phenotypes representing the characteristics of the side noses were connected to the feature points specified in the side photographs of the study subjects.

As shown in FIG. 1, the area of the nose is a triangular area (PArea_12_14_21) connecting 12, 14, and 21 and has one phenotype, and the length of the nose is between 12 and 21 (PD_12_21), 12, 14, or 14 It has three phenotypes as vertical lines (PDV_12_14, PDV_14_21) connecting 21 and 21, and the height of the nose has two phenotypes as horizontal lines (PDH_12_14, PDH_14_21) connecting 14 and 12 or 21. The nose angle has three phenotypes: the nose contour partial angle PA_12_14_21 consisting of 12, 14, and 21, the acute angle PAi_14_12 of 12, 14, and the acute angle PA_14_21 of 14 and 21.

The ln-transformation of phenotypes with severe tails and long tails of the lateral nasal phenotypes were made similar to the normal distribution. These phenotypes were 6 out of 9 phenotypes, corresponding to nose area (ln_PArea_12_14_21), nose length phenotypes (ln_PD_12_21, ln_PDV_14_21), nose height (ln_PDH_14_21), and nose angle phenotypes (ln_PA_14_21, ln_PA_12_14_21). .

Samples showing outliers in each of the face phenotypes were excluded from the analysis because they may lower the reliability of the statistical results. The nasal phenotype extraction can be found in two previous publications published in 2012 (Do et al., BMC Complementary and Alternative Medicine 2012, 12: 85; and Do et al., Integrative Medicine Research 2012, 1: 26-). 35).

Example  2: Single nucleotide polymorphism (SNP) allele genotyping

Allotyping (genotyping) of SNPs was performed by two methods. The discovery population determined SNP alleles using Affymetrix Genome-Wide Human SNP array 5.0 (Affymetrix).

Genotyping of the validation 1 and 2 groups was determined via unlabeled oligonucleotide probe (UOP). In other words, DNA strands that complementarily bind at the SNP position, when the temperature is gradually increased in a real-time PCR (LightCycler 480) device, compared to DNA strands that are not complementary at the SNP position (melting, Melting) is used at a relatively high temperature. As a result, the melting pattern through UOP genotyping has three types according to major homozygotes, heterozygotes, and minor homozygotes, and thus SNP alleles can be determined.

In the discovery population, the lower call rate (≤95%), the lower minor allele frequency (<5%), and the SNP deviating from the Hardy-Weinberg equilibrium among the total 500,568 SNPs on the Affymetrix SNP array. Except for p <0.0001), 311,944 SNPs were used in the genome-wide association study (GWAS) to identify associations with facial phenotypes.

The validation 1 group was first tested for facial phenotypic associations of candidate SNPs selected with cutoff of p <5.0 x 10 ^-6 in the GWAS analysis of the discovery population (cutoff p-value: 0.1). The first validation was performed on the SNPs in the second validation group (cutoff p-value: 0.05).

Example  3: Statistical Association Analysis

GWAS analysis of the lateral nose phenotype was performed by multiple linear regression analysis in the discovery population, with gender, age, body mass index (BMI), and collection area as correction variables. PLINK (version 1.07) was used as the analysis program used for GWAS analysis. Quantile-quantile plots and genome-regulated inflation factors (λ) were used to determine whether there was a population stratification within the study population. Manhattan plots showed SNP sites that were associated with each chromosome. Quantile-quantile plots and Manhattan plots were analyzed using the R program (version 3.0.2).

In the validation analysis of the validation 1 and 2 groups, similar to the GWAS analysis, multiple linear regression analysis was performed on the lateral nose phenotype with gender, age, and BMI as the correction variable or collection region (in the validation 2 group). It was. In this case, PLINK or R program was used.

The meta-analysis program, version 2.0 (Biostat), was used to meta-analyze the results of the discovery and validation groups 1 and 2 separately, and the fixed effect model results were taken.

The significance level of the SNP associations for integration meta-analysis p <5.0 × 10 ^{- 8} were to, when selecting a candidate SNP associated in each group was set to a cut-off p-value referred to in Example 2.

Hardy-Wineberg equilibrium was analyzed by chi-square analysis, and linkage disequilirium (LD) analysis between SNPs was analyzed using the Haploview (version 4.2) program.

In the above, the contents confirmed through the above examples are summarized in the following experimental examples.

Experimental Example  1: SNP Excavation Process Associated with Lateral Nose Phenotype

The excavation process of the lateral nasal phenotype associated SNPs is listed in FIG. 2. GWAS analysis was performed on a discovery population in which nine continuous variables with lateral nose phenotypes were determined (discovery step), and the SNPs to be tested for association were determined to have a p value of <5.0 x 10 ^-6 . Among the first selected GWAS SNPs, SNPs within 250 kb were considered to be connected to each other, and only those having significant significance were selected through the validation step (validation 1 and 2).

Candidate GWAS SNPs, which were finally selected at the discovery stage, were determined for additional Sino alleles by additional genotyping in the validation 1 and 2 populations, and then analyzed for association with the flank nose phenotype.

By integrating the associations between the discovery and validation stages through meta-analysis techniques for these SNPs, we presented the genetic influence on the lateral nose phenotype.

Experimental Example  2: lateral nasal phenotype associated with SNP Marker  Analysis

As a result of GWAS analysis (discovery stage) of 5,596 discovery populations, a total of 34 GWAS SNPs with p values <5.0 x 10 ^-6 and significant within 250 kb were selected and each phenotype was selected. Six groups were selected for the nose area, five for the nose length, nine for the nose height, and 14 for the nose angle. Of the 34 SNPs, the number of purely related SNPs was 22, except for the redundancy of the SNPs with repeated associations with various phenotypes.

SNP Marker Assay Associated with Lateral Nose Phenotype in the Discovery Population

#	Group #	Group	CHR	SNP	Minorallel	MAF	n	BETA	SE	p
One	One	In_PArea_12_14_21	17	rs11078212	C	0.076	5351	0.029	0.006	1.50E-06
2	2	In_PArea_12_14_21	17	rs2024070	C	0.485	5351	0.021	0.003	1.29E-10
3	3	In_PArea_12_14_21	17	rs2058742	T	0.283	5351	-0.017	0.004	3.02E-06
4	4	In_PArea_12_14_21	17	rs2159042	C	0.487	5351	0.021	0.003	1.47E-10
5	5	In_PArea_12_14_21	3	rs6445445	C	0.483	5184	-0.017	0.003	2.48E-07
6	6	In_PArea_12_14_21	13	rs7330390	C	0.291	5334	-0.017	0.004	1.67E-06
7	One	In_PD_12_21	5	rs318070	C	0.267	5370	-0.008	0.002	4.02E-06
8	2	In_PD_12_21	11	rs6591148	T	0.413	5375	0.007	0.001	3.75E-06
9	3	PDV_12_14	10	rs12573823	A	0.416	5295	-0.337	0.073	4.09E-06
10	4	PDV_12_14	20	rs2092846	T	0.314	5371	0.366	0.079	3.25E-06
11	5	In_PDV_14_21	4	rs6851773	G	0.094	5335	-0.022	0.005	1.94E-06
12	One	In_PDH_14_21	13	rs7330390	C	0.291	5375	-0.017	0.004	3.90E-06
13	2	PDH_12_14	9	rs10817791	C	0.362	5303	0.307	0.065	2.28E-06
14	3	PDH_12_14	17	rs2024070	C	0.485	5418	0.330	0.064	2.18E-07
15	4	PDH_12_14	17	rs2159042	C	0.487	5418	0.339	0.064	9.54E-08
16	5	In_PDH_14_21	6	rs12212993	C	0.089	5392	-0.026	0.006	3.53E-06
17	6	In_PDH_14_21	17	rs2024070	C	0.485	5392	0.017	0.003	3.61E-07
18	7	In_PDH_14_21	17	rs2058742	T	0.283	5392	-0.023	0.004	9.77E-10
19	8	In_PDH_14_21	17	rs2159042	C	0.487	5392	0.017	0.003	6.87E-07
20	9	In_PDH_14_21	17	rs2193054	C	0.463	5392	0.019	0.003	1.93E-08
21	One	In_PA_12_14_21	12	rs10744843	A	0.276	5347	-0.007	0.001	1.54E-10
22	2	In_PA_12_14_21	17	rs2024070	C	0.485	5353	-0.006	0.001	3.00E-09
23	3	In_PA_12_14_21	17	rs2058742	T	0.283	5353	0.007	0.001	6.41E-09
24	4	In_PA_12_14_21	17	rs2159042	C	0.487	5353	-0.006	0.001	5.22E-09
25	5	In_PA_12_14_21	17	rs2193054	C	0.463	5353	-0.007	0.001	1.43E-11
26	6	PAi_14_21	16	rs4787778	C	0.257	5425	-0.490	0.104	2.63E-06
27	7	PAi_14_21	17	rs6503196	G	0.154	5426	-0.601	0.131	4.76E-06
28	8	PAi_14_21	5	rs9327968	C	0.216	5415	-0.528	0.110	1.74E-06
29	9	PAi_14_21	6	rs9395049	T	0.351	5421	0.438	0.095	4.20E-06
30	10	In_PA_14_21	12	rs11054145	C	0.235	5391	0.013	0.003	3.34E-06
31	11	In_PA_14_21	7	rs12666591	C	0.087	5405	0.021	0.004	7.75E-07
32	12	In_PA_14_21	17	rs2058742	T	0.283	5405	0.013	0.003	9.92E-07
33	13	In_PA_14_21	17	rs2193054	C	0.463	5405	-0.014	0.002	1.56E-08
34	14	In_PA_14_21	8	rs3105176	C	0.415	5256	0.014	0.002	3.72E-08

(Group: phenotypic group; CHR: chromosome number; MAF: minor allele frequency; SE: standard error)

Primary validation of lateral nose phenotype associations in the Validation 1 population for 34 candidate GWAS SNPs

#	Group #	Group	SNP	CHR	Minorallel	MAF	n	BETA	SE	p
One	One	In_PArea_12_14_21	rs2159042	17	C	0.487	1784	0.013	0.006	2.90E-02
2	2	In_PArea_12_14_21	rs2024070	17	C	0.485	1773	0.011	0.006	4.98E-02
3	One	PDV_12_14	rs2092846	20	T	0.314	1808	0.254	0.138	6.63E-02
4	One	In_PDH_14_21	rs2159042	17	C	0.487	1787	0.019	0.005	5.08E-04
5	2	In_PDH_14_21	rs2024070	17	C	0.485	1776	0.019	0.005	5.93E-04
6	3	In_PDH_14_21	rs2193054	17	C	0.463	1787	0.011	0.005	4.98E-02
7	4	In_PDH_14_21	rs2058742	17	T	0.283	1785	-0.013	0.006	3.12E-02
8	One	In_PA_12_14_21	rs2159042	17	C	0.487	1782	-0.006	0.002	1.14E-03
9	2	In_PA_12_14_21	rs2024070	17	C	0.485	1770	-0.006	0.002	2.90E-03
10	3	In_PA_12_14_21	rs2193054	17	C	0.463	1781	-0.009	0.002	4.60E-07
11	4	In_PA_12_14_21	rs2058742	17	T	0.283	1779	0.010	0.002	9.32E-07
12	5	PAi_14_21	rs9327968	5	C	0.216	1832	-0.496	0.191	9.40E-03
13	6	PAi_14_21	rs9395049	6	T	0.351	1835	0.289	0.164	7.85E-02
14	7	In_PA_14_21	rs3105176	8	C	0.415	1807	0.008	0.005	8.39E-02
15	8	In_PA_14_21	rs2193054	17	C	0.463	1813	-0.008	0.005	7.49E-02
16	9	In_PA_14_21	rs2058742	17	T	0.283	1811	0.012	0.005	1.41E-02

(Group: phenotypic group; CHR: chromosome number; MAF: minor allele frequency; SE: standard error)

Secondary validation of the lateral nose phenotype association in the Validation 2 population for 16 SNPs validated in Validation 1

#	Group #	Group	SNP	CHR	Minorallel	MAF	n	beta	SE	p
One	One	In_PArea_12_14_21	rs2159042	17	C	0.487	1897	0.016	0.004	2.95E-04
2	2	In_PArea_12_14_21	rs2024070	17	C	0.485	1897	0.015	0.004	8.77E-04
3	One	In_PDH_14_21	rs2159042	17	C	0.487	1903	0.017	0.004	7.64E-05
4	2	In_PDH_14_21	rs2024070	17	C	0.485	1903	0.016	0.004	1.13E-04
5	3	In_PDH_14_21	rs2193054	17	C	0.463	1903	0.015	0.004	3.43E-04
6	4	In_PDH_14_21	rs2058742	17	T	0.283	1903	-0.011	0.005	1.87E-02
7	One	In_PA_12_14_21	rs2159042	17	C	0.487	1896	-0.006	0.001	2.71E-05
8	2	In_PA_12_14_21	rs2024070	17	C	0.485	1896	-0.007	0.001	2.68E-06
9	3	In_PA_12_14_21	rs2193054	17	C	0.463	1896	-0.005	0.001	1.59E-04
10	4	In_PA_12_14_21	rs2058742	17	T	0.283	1896	0.006	0.002	2.65E-04
11	5	In_PA_14_21	rs3105176	8	C	0.415	1896	0.007	0.004	3.76E-02
12	6	In_PA_14_21	rs2193054	17	C	0.463	1895	-0.012	0.004	6.02E-04

(Group: phenotypic group; CHR: chromosome number; MAF: minor allele frequency; SE: standard error)

Meta-analysis of 5 SNPs verified up to the 2nd stage

#	Group #	Group	SNP	CHR	Minorallel	MAF	n	P	beta	Q	I
One	One	In_PArea_12_14_21	rs2159042	17	C	0.487	9032	4.23E-14	0.0182	0.3554	3.33
2	2	In_PArea_12_14_21	rs2024070	17	C	0.485	9021	2.57E-13	0.0176	0.2306	31.84
3	One	In_PDH_14_21	rs2159042	17	C	0.487	9082	4.49E-13	0.0172	0.9322	0
4	2	In_PDH_14_21	rs2024070	17	C	0.485	9071	4.05E-13	0.0172	0.9321	0
5	3	In_PDH_14_21	rs2193054	17	C	0.463	9082	7.69E-12	0.0160	0.4611	0
6	4	In_PDH_14_21	rs2058742	17	T	0.283	9080	4.25E-11	-0.0173	0.1232	52.25
7	One	In_PA_12_14_21	rs2159042	17	C	0.487	9031	2.58E-15	-0.0060	0.9969	0
8	2	In_PA_12_14_21	rs2024070	17	C	0.485	9019	4.21E-16	-0.0061	0.9177	0
9	3	In_PA_12_14_21	rs2193054	17	C	0.463	9030	1.11E-19	-0.0068	0.1986	38.14
10	4	In_PA_12_14_21	rs2058742	17	T	0.283	9028	1.44E-16	0.0069	0.2063	36.65
11	5	In_PA_14_21	rs3105176	8	C	0.415	8959	3.07E-19	0.0111	0.2795	21.55
12	6	In_PA_14_21	rs2193054	17	C	0.463	9113	1.24E-11	-0.0124	0.5621	0

(Group: phenotypic group; CHR: chromosome number; MAF: minor allele frequency; SE: standard error)

As shown in Table 2, as a result of firstly verifying the lateral nasal phenotype association in the validation 1 group for 34 candidate GWAS SNPs (without considering duplicate associations), the SNPs in which the individual nasal phenotype association effects of SNPs are reproduced are 16 Came out as a dog. For each nose phenotype group, two were examined for nose area, one for nose length, four for nose height, and eight for nose angle, and the number of purely related SNPs excluding duplicate associations was eight.

As shown in Table 3, as a result of secondarily verifying the side nose phenotype association in the validation 2 group for 16 SNPs validated in validation 1 (without considering duplicate associations), a total of 12 SNP association effects were reproduced. It became. For each nose phenotype group, two were examined for nose area, zero for nose length, four for nose height, and six for nose angle, and the number of purely related SNPs excluding duplicate associations was five. In addition, as a result of performing a meta-analysis on the five SNPs verified up to the second, as shown in Table 4, all the statistically significant p value was <5.0 x 10 ^-8 .

As a result, a total of 5 SNPs showed significant association in the Korean nasal phenotype with one rs3105176 on chromosome 8 and four rs2159042, rs2024070, rs2193054, and rs2058742 on chromosome 17. Since the SNPs of chromosome 17 of the present invention are adjacent to each other in position, it is possible to determine whether the nasal phenotype associations of SNPs are independent of each other by analyzing LDs between these SNPs. As shown in FIG. 3, which shows the results of analyzing the SNPs between SNPs using East Asian HapMap results, the SNPs of chromosome 17 showed strong association imbalance (LD) between rs2159042 and rs2024070, and weak LDs between rs2193054 and rs2058742. There was no LD between the SNP and the two subsequent SNPs. In other words, although the nasal phenotype association of each pair of SNPs with LD relationship is not independent, there is no LD between rs2159042, rs2024070 LD group, and rs2193054, rs2058742 LD group. Therefore, it could be concluded that there are three SNPs that are independent of the lateral nasal phenotype, two on chromosome 17 (rs2024070 and rs2193054) and one on chromosome 8 (rs3105176).

Experimental Example  3: lateral nasal phenotype associated with SNP Marker  Interpret the results

Larger noses tended to increase nose area and nose height, while smaller nose angles tended. Looking at the minor allele effects of these five SNPs, three (rs2159042, rs2024070, rs2193054) tended to increase the nose size, and two (rs2058742, rs3105176) tended to decrease the nose size.

The SOX9 (sex determining region Y-box 9) gene is located near chromosome 17 SNPs. Interestingly, this gene is involved in the differentiation of chondrocytes, and mutations in this gene cause campomelic dysplasia and, among other phenotypic changes, lower nasal bridges in the nasal form. It is known that this is. In addition, a gene called VPS13B (vacuolar protein sorting 13 homolog B (yeast)) near rs3105176 of chromosome 8 is known to cause cohen syndrome due to mutation, and the ratio of various phenotypic changes of the syndrome It is reported that there is a tendency to increase. Thus, the influence of these SNPs on the nasal morphology is likely to have medical significance.

In addition, as shown in Table 5 below, among the genetic variation of these five SNPs, the frequency of influent alleles that increases the nose size is three out of five (C of rs2159042, C of rs2024070, A of rs3105176). Since it is known to be higher in Caucasians than Asians, including Koreans, it can be said that Caucasians explain some of the ethnic differences in noses compared to Asians.

Frequency of alleles that influence the size of the nose among the genetic variants of the five SNPs

CHR	SNP	Allel	Minorallel	Minor allel nose height effect	Minor allel frequency
					The present invention	HCB	JPT	CEU
17	rs2159042	C / T	C	+	0.487	0.407	0.506	0.951
17	rs2024070	C / T	C	+	0.485	0.419	0.512	0.951
17	rs2193054	C / G	C	+	0.463	0.512	0.442	0.518
17	rs2058742	C / A	A	-	0.283	0.233	0.297	0.354
8	rs3105176	A / G	G	-	0.415	0.384	0.390	0.164

A regional plot of chromosome 17 associated with the lateral nose phenotype is shown in FIG. 4 for the nose angle phenotype, ln_PA_12_14_21, as an example. If we draw the peak SNP, rs2193054, on both sides of 1Mb, SNPs with p <5.0 x 10 ^-8 are present in the vicinity of two chromosomes, and rs2193054 and rs2058742 are located near the middle peak SNP, and another ahead of it. The rs2159042 and rs2024070 are located at the associated site. Except for these SNPs, all other SNPs near SOX9 are shown to be p <1.0 × 10 ⁻⁶ .

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (10)

1. (a) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1 and A or G;

   (b) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2, wherein the 301th base is C or T;

   (c) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 3, wherein the 301th base is C or T;

   (d) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4, wherein the 301th base is C or G;

   (e) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 5, wherein the 301th base is C or A; And

   (f) Nose phenotype determination marker comprising a polynucleotide selected from the group consisting of polynucleotides complementary to any one of the polynucleotides of (a) to (e).
2. The method of claim 1,

   The nose phenotype is one or more selected from the group consisting of area, length, height and angle of the nose.
3. A nasal phenotype determination composition comprising an agent capable of detecting or amplifying the nasal phenotype determination marker of claim 1.
4. Nasal phenotype determination kit comprising the composition of claim 3.
5. The method of claim 4, wherein

   The kit is an RT-PCR kit or a DNA chip kit.
6. A microarray for determining a nasal phenotype comprising the marker of claim 1.
7. (a) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 1 and A or G;

   (b) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2, wherein the 301th base is C or T;

   (c) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 3, wherein the 301th base is C or T;

   (d) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4, wherein the 301th base is C or G;

   (e) a polynucleotide consisting of 5 to 1,000 consecutive bases including the 301th base in the polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 5, wherein the 301th base is C or A; And

   (f) A nasal phenotype judgment microarray comprising at least one polynucleotide selected from the group consisting of polynucleotides complementary to the polynucleotides of (a) to (e).
8. (a) amplifying a polymorphic site comprising a SNP of a polynucleotide consisting of the nucleotide sequences of SEQ ID NOs: 1 to 5 or complementary polynucleotides thereof from DNA of a sample isolated from an individual; And

   (b) determining the base of the amplified polymorphic site, nasal phenotype determination method.
9. The method of claim 8,

   It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 1 is larger than the individual whose base is G; It is determined that an individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 2 is C has a larger nose size than an individual whose base is T; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 3 is C has a larger nose size than the individual whose base is T; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 4 is C has a larger nose size than the individual whose base is G; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 5 is C is determined to have a larger nose size than the individual whose base is A.
10. The method of claim 8,

    It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 1 is G has a smaller nose size than the individual whose base is A; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 2 is T is determined to have a smaller nose size than the individual whose base is C; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 3 is T has a smaller nose size than the individual whose base is C; It is determined that the individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 4 is G has a smaller nose size than the individual whose base is C; The individual whose base corresponding to the 301th polynucleotide of SEQ ID NO: 5 is A is determined to have a smaller nose size than the individual whose base is C.

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