JP7267198B2 - Methods for Determining Susceptibility to Side Effects of Retinoids - Google Patents

Description

The present invention relates to a method for determining the susceptibility of a subject to retinoid side effects based on genetic elements by SNP analysis, a computer for determining the susceptibility to retinoid side effects, and a program for controlling the computer. Based on the determined susceptibility of the subject to retinoid side effects, it is possible to develop methods for alleviating susceptibility, provide beauty guidance services, and select cosmetics.

Retinol, which is one of natural vitamin A, is an endogenous substance that naturally exists in the human body, and is involved in a wide range of physiological functions such as growth, reproduction, vision, and infection prevention through conversion to retinal and retinoic acid. In addition to retinol, retinal, retinoic acid, and derivatives thereof are known as compounds that exhibit the action of vitamin A, and these are collectively called retinoids. The effects of retinoids on the skin include promotion of turnover due to stratum corneum exfoliation, epidermal thickening due to promotion of proliferation and induction of differentiation of keratinocytes, increased production of elastic fibers such as collagen and elastin in dermal fibroblasts, and sebum due to suppression of sebaceous gland function. It is known to reduce secretion as well as improve pigmentation by excretion of melanin granules. Therefore, retinoids are incorporated into cosmetics and pharmaceuticals for the purpose of anti-wrinkle, whitening, and anti-blemish effects.

On the other hand, retinoids are irritating to the skin, and their side effects may include redness, epidermal hyperplasia, edema, blisters, erythema, burns, itching, burn sensitivity, and epidermal desquamation. Such side effects often occur when using skin external preparations that contain retinoids at high concentrations or highly physiologically active retinoids such as tretinoin. On the other hand, the susceptibility to side effects of retinoids varies greatly depending on the subject of use. (Non-Patent Document 1: J Drugs in Dermatology (2011), vol. 10, Issue 5, page 483-489)

J Drugs in Dermatology (2011), vol. 10, Issue 5, pages 483-489 J. Clin Invest. 2013; 123 (9): 3941-3951 Plos One 2013; 8(10):e78203 Comprehensive Genetic Polymorphism (SNP) Journal of Pharmacology (2005), pp.125, 148-152

Since the anti-wrinkle, whitening, and anti-blemish effects of retinoids are extremely useful for cosmetic and medical purposes, it is useful to determine susceptibility to side effects of retinoids in advance. Therefore, there is a need to develop methods for determining susceptibility to retinoid side effects.

The present inventors performed SNP analysis on subjects for the purpose of determining susceptibility to side effects of retinoids. As a result, 55 SNPs related to sensitivity to retinoid side effects were identified, leading to the present invention.

Accordingly, the present invention provides the following inventions:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038
Detecting at least one SNP selected from the group consisting of
A method for determining susceptibility to retinoid side effects, comprising the step of determining susceptibility to retinoid side effects based on the detected SNPs.

In yet another aspect, the invention provides a computer for determining susceptibility to side effects of retinoids comprising:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038
a storage unit storing information on at least one SNP selected from the group consisting of
an input unit for inputting the user's DNA information;
a processing unit that detects the presence of stored SNPs in the input DNA information;
A computer comprising an output unit that outputs a susceptibility to retinoid side effects based on detected SNPs. A further aspect of the invention relates to a method and/or a control program for controlling such a computer, and also to a storage medium storing such a control program. Such storage media are preferably non-volatile media.

In yet another aspect, the present invention provides 8286474, rs112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs80067170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, A nucleic acid reagent for detecting at least one SNP selected from the group consisting of rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038, for determination of susceptibility to retinoid side effects It also relates to kits.

The present invention also relates to methods of determining susceptibility to retinoid side effects and methods of providing cosmetics, pharmaceuticals, and beauty regimens based on computer-determined susceptibility to determine susceptibility to retinoid side effects.

Further, the present invention provides the following:
applying a candidate agent;
Altered expression of at least one gene selected from the group consisting of: CAPN2, OR14I1, LYPD8, OSTN, LOC643675, FHDC1, TENM2, LOC105375854, SHC3, KCNMA1, ST3GAL4, LINGO1, NSMCE1, and LOC105372121 in the applied cells and assessing changes in action of the functional protein translated from the gene. Based on said changes in expression and function, determining the regulation of retinoid susceptibility of the candidate drug.
It also relates to methods of screening for candidate agents.

INDUSTRIAL APPLICABILITY According to the present invention, it becomes possible to determine susceptibility to side effects of retinoids, and to provide cosmetics and pharmaceuticals, and beauty methods and therapeutic methods based on the determined susceptibility.

FIG. 1 is a process flow diagram of a computer controlled program for determining susceptibility to side effects of retinoids. FIG. 2 is a schematic diagram of a computer that determines susceptibility to retinoid side effects. FIG. 3 is a Manhattan plot diagram showing the results of a genome-wide association study {Genome-Wide Association Study (GWAS)} that evaluated SNPs associated with retinoid sensitivity.

The present invention relates to a method for determining susceptibility to retinoid side effects, comprising the steps of detecting a SNP associated with susceptibility to retinoid side effects, and determining the susceptibility to retinoid side effects based on the detected SNP. Here, SNPs associated with susceptibility to side effects of retinoids include the following: 58310152, rs58286474, rs112273273, rs73380909, rs73380910, rs73380913 , rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145653129, rs1903895, rs2574810, rs6480852, rs49 7578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs80067170, rs78606856, rs12100559 , rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs At least one SNP selected from the group consisting of 150302670 and rs763038 is used.

In the present invention, retinoid refers to vitamin A such as retinol, retinal, and retinoic acid, and derivatives thereof. The derivative can be any derivative that has vitamin A activity, including retinol acetate, retinol palmitate, retinyl esters, and the like. Retinoic acid is known to have stereoisomers such as all-trans retinoic acid (tretinoin), 9-cis retinoic acid and 13-cis retinoic acid, and tretinoin in particular is known to have high potency.

Side effects of retinoids include teratogenicity, proinflammatory, stratum corneum abrasion, and inflammation-induced hyperpigmentation. Among these side effects, the present invention particularly relates to side effects when used as an external preparation for skin, ie, inflammation induction, stratum corneum peeling, and inflammation-induced pigmentation. Skin irritation may include desquamation, erythema, redness, and dermatitis.

Susceptibility to retinoid side effects can be categorized arbitrarily. For example, it can be classified into two or more groups, such as a group with and without susceptibility, and in some cases, three groups of high, low, and no susceptibility, or more groups, such as 4 groups or 5 groups. . Sensitivity can be determined according to the type and number of SNPs detected. As an example, when classifying into 3 groups, out of 55 types of SNPs, if a certain number or more of SNPs are detected, it can be determined that the sensitivity is high, and if a certain number of SNPs are not detected, it can be determined that the sensitivity is high. can be determined to be low. For example, when 20 or more, optionally 30 or more, or even 40 or more SNPs are detected, it can be determined that the sensitivity is high. Among the 55 SNPs, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, and rs2247880 are SNPs involved in the control region of the KCNMA1 gene on chromosome 10. Here, the KCNMA1 gene is related to K ion channels and is known to suppress the action of a stimulatory receptor called TRPV1 activated by retinoids (Non-Patent Document 2: J. Clin Invest. 2013 123 (9): 3941-3951, Non-Patent Document 3: Plos One 2013; 8 (10): e78203). Therefore, genes involved in the regulation of the KCNMA1 gene are highly likely to contribute to the side effects of retinoids. Therefore, when one or more, preferably 5 or more, and more preferably 8 or more of these SNPs are detected, it can be determined that the susceptibility to retinoid side effects is high. Susceptibility to retinoid side effects can be determined by non-physicians, for example, by non-medical personnel such as estheticians, cosmetologists, counselors, and by medical personnel such as clinical laboratory technicians. The method of the invention can also be referred to as a non-diagnostic method.

In the present invention, SNPs are indicated by rs numbers (Reference SNP ID numbers). Detailed information (location and mutation on the chromosome) of SNPs corresponding to each rs number is managed by the US National Center for Biotechnology Information (NCBI). nih.gov/).

Details of the SNPs identified in the present invention that are involved in susceptibility to retinoid side effects are as follows:

Detection of SNPs may be performed by any known method. As an example, subject's biological samples such as saliva, blood, mucous membranes, tissue fragments, hair, etc. are purified from subject's nucleic acid according to standard methods, and SNPs are detected in the purified nucleic acid. Therefore, the method for determining susceptibility to retinoid side effects of the present invention may further include a sample preparation step and a nucleic acid purification step. In the SNP detection step, any method can be used as long as it enables detection of SNPs in purified nucleic acids. The SNP can be detected by sequencing around the position of the SNP of interest, or it can be detected using a PCR-based technique, a technique using DNA probes, or a technique using mass spectrometry. can also PCR-based techniques include the SNP typing method, the TaqMan PCR method, the single nucleotide extension method, the Pyrosequencing method, the Exonuclease Cycling Assay method, and the like. Techniques using DNA probes include the Invader method (Comprehensive Genetic Polymorphism Analysis (SNP), Nihon Pharmacological Journal, 125, 148-152, 2005). A SNP may be associated with another SNP in linkage disequilibrium. A target SNP can be detected by detecting a SNP in linkage disequilibrium with the target SNP. Therefore, in the present invention, SNP detection is not limited to direct detection of a target SNP, but also includes detection of a target SNP by detecting an SNP in linkage disequilibrium. and

It is also possible to detect the presence of SNPs involved in susceptibility to retinoid side effects based on an individual's base sequence that has already been sequenced or a list of individual SNPs determined from the base sequence. In this case, the presence of the SNP can be detected by examining the sequence at the position where the SNP exists in the base sequence data that has already been determined. exists or not. Therefore, SNP detection in this case may be performed by inputting base sequence data or an individual SNP list into a computer in which SNP information is stored. In a more preferred mode, the input is input from the terminal via the Internet, the SNP is detected on the server, and the detection result can be output to the terminal via the Internet.

Subjects whose susceptibility to retinoid side effects is detected according to the present invention may be of any race. More preferably, the target race is yellow (Mongoloid).

In another aspect of the invention, the invention relates to a computer for determining susceptibility to side effects of retinoids. Such a computer is capable of performing the method of determining susceptibility to side effects of retinoids described above. In a further method of the invention, the invention also relates to a computer-controlled method or program for determining the susceptibility to side effects of a retinoid of the invention, as well as a storage medium storing said program. A computer of the present invention includes a storage unit, an input unit, an output unit, and a processing unit.

The storage unit includes memory devices such as RAM, ROM, and flash memory, fixed disk devices such as hard disk drives, and portable storage devices such as flexible disks and optical disks. The storage unit stores data and instructions input from the input unit, results of arithmetic processing performed by the processing unit, programs, databases, and the like used for various processes of the computer. The computer program may be installed via a computer-readable recording medium such as CD-ROM, DVD-ROM, or the Internet. The computer program is installed in the storage unit using a known setup program or the like. In the present invention, the storage unit is rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs582 86474, rs112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs 814014, rs137908383, rs186198501, rs7933887, rs80067170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, Information about at least one SNP selected from the group consisting of rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038 is stored. Information on these SNPs may further include information on SNPs in linkage disequilibrium with the SNPs. Information about SNPs can include sequence information.

The input section includes an interface. The interface may be connected to, for example, an operation unit such as a keyboard and mouse, a communication unit such as a LAN or port, and an external storage device such as a CD-ROM, DVD-ROM, BD-ROM, or memory stick. Information about the SNP may be input from the input unit and stored in the storage unit. In addition, the target sequence information or SNP list is input from the input unit. The input sequence information or SNP list may be temporarily stored in the storage unit, or may be directly sent to the processing unit. The target sequence information may be the entire genome sequence of the target, or may be only a partial sequence of interest. An instruction for processing in the processing section can be given from the input section via the operation section.

The processing unit detects the presence of SNPs in the target sequence information. More specifically, the processing unit extracts SNPs related to susceptibility to retinoid side effects contained in the target sequence information from the SNP sequence information stored in the storage unit and the target sequence information input from the input unit. Presence can be detected. comparing the SNP sequence information stored in the storage unit with the target sequence information input from the input unit, or comparing the target sequence information input from the input unit with the SNP sequence information stored in the storage unit; The search can detect the presence of SNPs related to susceptibility to retinoid side effects. The processing unit can also detect whether SNPs related to susceptibility to side effects of retinoids exist in the input target SNP list. The processing unit executes various arithmetic processing according to programs stored in the storage unit. Arithmetic processing is performed by a CPU or processor included in the processing unit. This CPU or processor includes functional modules that control an input section, a storage section, and an output section, and can perform various controls. Each of these units may be composed of an independent integrated circuit, microprocessor, firmware, or the like. Information about the presence of SNPs detected by the processing unit may be temporarily stored in the storage unit, or may be displayed as is by the processing unit on the output unit. Also, when a plurality of SNPs exist, the degree of susceptibility to retinoid side effects can be determined according to the number and type of SNPs.

The output unit is configured to output information about the degree of susceptibility to side effects of retinoids stored in the storage unit for SNPs detected by the arithmetic processing performed by the data processing unit. The output unit can also output a warning to a subject determined to be highly susceptible to stop using retinoid-containing cosmetics in addition to or instead of the information about the degree of sensitivity. In addition to or instead of the information about the degree of susceptibility, the output unit can also present cosmetics with an appropriate retinoid content according to the susceptibility to side effects of retinoids. The output unit may be a display device such as a liquid crystal display that directly displays the result of arithmetic processing, an output means such as a printer, or an interface unit for outputting to an external storage device or via a network. may In still another aspect, a purchase button can be displayed together with the presented cosmetics, and the subject may be configured to be able to purchase the product by clicking the purchase button.

In a preferred aspect of the present invention, the computer of the present invention constitutes a server, and the input section and output section are each connected to a network via an interface section. In this case, individual terminals connected to the network can provide genome information and partial sequence information of the genome, and the provided sequence information is processed by the server. In the server, the presence of SNPs related to susceptibility to retinoid side effects is detected, and together with the detected SNPs, the susceptibility to retinoid side effects corresponding to the number or type of detected SNPs can be output to the terminal through the network.

Although sensitivity to retinoid side effects can be determined by detecting a single SNP, it is preferable to determine sensitivity by detecting a plurality of SNPs from the viewpoint of achieving higher sensitivity. In order to determine susceptibility based on the detection of multiple SNPs, for example, clarifying whether the SNP has a positive or negative effect on the susceptibility and assigning points according to its presence, This is done by calculating the SNP score. By predetermining the relationship between the SNP score and susceptibility, the susceptibility can be determined from the SNP score.

When susceptibility is determined by the method for determining susceptibility to side effects of retinoids of the present invention, counseling can be provided based on information about susceptibility. Accordingly, one aspect of the invention also relates to methods of counseling. During such counseling, advice can be provided on the cosmetics and medicines to be used. As an example, a subject determined to be highly sensitive to the side effects of retinoids can be warned against using cosmetics containing retinoids. Also, such a subject can be provided with a cosmetic containing no or reduced retinoids with or without the warning. Cosmetics containing retinoids can be provided to subjects determined to have low susceptibility to side effects of retinoids. The content and amount of retinoid used can be changed according to retinoid sensitivity. In another aspect, a subject determined to be highly susceptible to side effects of retinoids is provided with a method for alleviating retinoid sensitivity, a cosmetic guidance service for alleviating sensitivity, and a method for selecting cosmetics for alleviating sensitivity. can be provided. Cosmetics or pharmaceuticals enriched with retinoid emollients can also be provided to alleviate sensitivities. Therefore, the present invention relates to a cosmetic or therapeutic method comprising determining susceptibility by a method for determining susceptibility to side effects of retinoids, and selecting and providing appropriate cosmetics or pharmaceuticals based on the susceptibility.

Another aspect of the invention also relates to a kit for determining susceptibility to retinoid side effects. The kit includes: rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs582 86474, rs112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468 , rs117142738, rs10086126, rs145653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs1 37908383, rs186198501, rs7933887, rs80067170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200 , rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038, or nucleic acid reagents for detecting SNPs in linkage disequilibrium thereof. Such kits may further include nucleic acid extraction reagents and purification reagents. It may also contain instructions describing the relationship between the detected SNPs and susceptibility.

Examples of such nucleic acid reagents include primers capable of selectively amplifying SNPs, DNA polymerase, dNTPs, and optionally amplification buffers. Primers capable of amplifying SNPs can be arbitrarily designed for each SNP.

When using a nucleic acid probe as the nucleic acid reagent, the kit may further contain a probe detection reagent. Such nucleic acid probes may be unimmobilized probes, or those immobilized on DNA chips can be used to simultaneously detect a plurality of SNPs. Such nucleic acid probes may be labeled so as to detect specific SNPs.

Genes in which there are SNPs associated with susceptibility to side effects of retinoids identified in the present invention can also be identified. Such genes include at least one gene selected from the group consisting of CAPN2, OR14I1, LYPD8, OSTN, LOC643675, FHDC1, TENM2, LOC105375854, SHC3, KCNMA1, ST3GAL4, LINGO1, NSMCE1, and LOC105372121. Since these genes are related to susceptibility to retinoid side effects, the expression changes of these genes after application of candidate drugs can be used as indicators to screen drugs that can act on retinoid susceptibility. can be done. It is also possible to evaluate changes in the action of functional proteins translated from genes and to screen candidate drugs that modulate those changes. Actions on retinoid susceptibility include alleviation of retinoid susceptibility and conversely, increasing retinoid susceptibility. Whether the candidate agent screened for being able to alter the gene expression described above has an effect of alleviating retinoid susceptibility or an vice versa effect of increasing retinoid susceptibility depends on the type of gene and its mechanism. It can be determined, and can be easily determined by performing a secondary screening. In addition, a candidate drug is a candidate drug that exhibits a retinoid sensitivity-relieving action or, conversely, a retinoid sensitivity-increasing action by changing the action of a functional protein, and can control the change in the action. As a secondary screening, for example, determination can be made by using retinoid-containing cosmetics in combination with a subject.

As an example of the screening method,
applying a solution comprising the candidate agent;
determining a change in expression of a gene in cells to which it has been applied; and determining, based on said change in expression, the effect of the candidate drug on retinoid sensitivity.

Also, as another example of the screening method,
applying a solution comprising the candidate agent;
Evaluating the effect on the action of the functional protein in the cells to which it is applied; and Determining the effect of the candidate drug on retinoid sensitivity based on changes in the action of the functional protein.

Furthermore, as a further example of a screening method,
applying a solution comprising the candidate agent;
determining the expression of the gene in the applied cells;
A method of screening a candidate drug, comprising the steps of: evaluating the effect on the action of the functional protein in the applied cells; and determining the effect of the candidate drug on retinoid sensitivity based on said altered expression and altered action of the functional protein. Regarding.

The step of applying the solution containing the candidate agent may be applied to cultured cells or applied to skin. For gene expression, gene expression levels may be measured for individual genes by a technique such as RT-PCR, or changes in gene expression may be identified using an array. As a control, the gene expression or the action of the functional protein is measured using a solution that does not contain only the candidate drug, and the gene expression and the action of the protein are compared in the cells to which the solution containing the candidate drug is applied. Thus, changes in expression and actions can be determined. Control measurements may be predetermined by performing experiments in advance, or may be performed simultaneously.

Changes in the actions of functional proteins may be identified based on an evaluation system that quantitatively evaluates each function. When the functional protein is an enzyme, the change in action of the functional protein can be evaluated by measuring the change in enzymatic activity. In that case, for example, the retinoid sensitivity of the candidate drug can be evaluated using the specific substrate of the enzyme and using the degradation activity as an index. When a functional protein acts on other substances (especially proteins) to affect cell functions, the interaction with other substances can be used as an index to evaluate changes in the action of the functional protein. A functional protein may exhibit its function by changing its localization, and changes in localization can be used as an index to evaluate changes in the action of the functional protein. In that case, for example, depending on the localization of a given organelle such as the nucleus or Golgi apparatus, the cell membrane, the cytoplasm, or the extracellular position, changes in the action of the functional protein can be evaluated, thereby determining retinoid sensitivity of the candidate drug. can be evaluated. In addition, phenotypic changes such as cell proliferation and changes in intracellular ion concentration that occur as a result of interactions with other proteins and changes in localization can be used as indicators.

All documents mentioned herein are hereby incorporated by reference in their entirety.

The embodiments of the invention described below are for illustrative purposes only and are not intended to limit the scope of the invention. The technical scope of the present invention is limited only by the description of the claims. Modifications of the present invention, such as additions, deletions and replacements of constituent elements of the present invention, can be made without departing from the gist of the present invention.

test 1
For 150 test subjects, in addition to usual skin care, a retinol-containing beauty essence was applied twice a day (morning and night) over the entire face, centering on the left and right corners of the eyes and cheeks, for two weeks. After continuous application for 2 weeks, photographs of appearance were taken, interviews were conducted, and skin findings were determined.

test 2
A half-face test was conducted on 80 subjects, using a serum containing retinol as a test sample in addition to regular skin care, and a control sample with a formulation in which only retinol was removed from the test sample. . Specifically, placebo-controlled randomized test samples and control samples were applied twice daily (morning and night) for 9 weeks on separate left and right faces, respectively. Appearance photographs were taken before the start of the test and after 9 weeks, interviews were conducted, and skin findings were determined.

test 3
For 360 subjects, in addition to daily skin care, a retinol-containing beauty essence was applied to the entire face twice a day (morning and night) for 4 weeks, focusing on the left and right corners of the eyes and cheeks. After 4 weeks of continuous application, photographs of appearance were taken, interviews were conducted, and skin findings were determined.

Determination of Retinol Sensitivity Based on the results obtained in Tests 1, 2, and 3, retinol sensitivity was classified into a responder group and a healthy group. Specifically, the healthy group relates to the group of subjects who had no trouble with the administration of the retinol sample. The response group relates to a group of subjects who experienced skin troubles to retinol with clearly observed side effects.

Saliva was collected from the subjects, DNA was purified, and subjected to SNP array analysis. For SNP array analysis, genotyping was performed using Japonica array (Toshiba Corporation). Imputation was performed on the genotyping results, and the SNP results of the subjects were comprehensively acquired. A genome-wide association analysis was performed on the genotyping results and the SNP results after imputation in the retinol-responsive group and the healthy group. A Manhattan plot was prepared with chromosome number on the axis (Fig. 3). Fifty-five species listed in Table 2 below were identified as SNPs with p-values <10 ⁻⁵ .

Claims (15)

the following:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, detecting at least one SNP selected from the group consisting of rs28363677, rs16948876, rs17753299, rs150302670, and rs763038;
A method for non-diagnostic determination of susceptibility to side effects of retinoids, comprising the step of determining susceptibility to side effects in external application of retinoids to the skin according to the type or number of detected SNPs. 2. The non-diagnostic determination method of Claim 1, wherein said SNP is selected from the group consisting of: rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, and rs2247880. 3. A method for providing a method for using a cosmetic according to the susceptibility to side effects of external application of retinoid on the skin determined by the method according to claim 1 or 2. 3. A method for providing a cosmetic, which comprises selecting a cosmetic based on susceptibility to retinoid side effects determined by the method according to claim 1 or 2. A computer for determining susceptibility to side effects of retinoids comprising:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038
a storage unit storing information on at least one SNP selected from the group consisting of
an input unit for inputting the user's DNA information;
a processing unit that detects the presence of stored SNPs in the input DNA information;
A computer, comprising: an output unit that outputs susceptibility to side effects of topical retinoids on the skin based on the detected SNPs. 6. The computer according to claim 5, wherein said computer is a server, said input section is a communication section, and said output section is a communication section. 7. The computer of claim 5 or 6, wherein said SNP is selected from the group consisting of: rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, and rs2247880. A computer controlled program for determining susceptibility to side effects of retinoids, comprising a storage unit, an input unit, a processing unit, and an output unit, the program comprising:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, storing in a storage unit information on at least one SNP selected from the group consisting of rs28363677, rs16948876, rs17753299, rs150302670, and rs763038, and information on sensitivity to side effects of retinoids associated with the SNP when externally applied to the skin;
Input the user's DNA information from the input unit,
causing the processing unit to detect the presence of the stored SNP in the input DNA information;
causing a processing unit to determine susceptibility to retinoid side effects based on the detected SNPs;
causing the output unit to output sensitivity information to retinoid side effects;
Said program. 9. The program according to claim 8, wherein said computer is a server, said input section is a communication section, and said output section is a communication section. 10. The program of claim 8 or 9, wherein said SNPs are selected from the group consisting of: rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, and rs2247880. the following:
rs117761959, rs35515429, rs35736558, rs61840347, rs12754142, rs9290978, rs28501222, rs117675886, rs117758125, rs875705, rs58310152, rs58286474, rs 112273273, rs73380909, rs73380910, rs73380913, rs12655922, rs17068781, rs278015, rs17068796, rs73381002, rs59490468, rs117142738, rs10086126, rs145 653129, rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, rs2247880, rs814014, rs137908383, rs186198501, rs7933887, rs800 67170, rs78606856, rs12100559, rs150171951, rs2060609, rs2060608, rs1349250, rs145745344, rs57595200, rs8008945, rs12907778, rs151092710, rs28363677, rs16948876, rs17753299, rs150302670, and rs763038
A kit for determining susceptibility to side effects in external application of retinoids to the skin, comprising a nucleic acid reagent for detecting at least one SNP selected from the group consisting of: 12. The kit of claim 11, wherein said kit further comprises nucleic acid extraction and purification reagents. 13. The kit according to claim 11 or 12, wherein said nucleic acid reagent is a primer capable of selectively amplifying SNPs, and said kit further comprises polymerase and dNTP. 13. The kit of claim 11 or 12, wherein said nucleic acid reagent is a nucleic acid probe, and said kit further comprises a probe detection reagent. 15. The kit of any one of claims 11-14, wherein said SNP is selected from the group consisting of: rs1903895, rs2574810, rs6480852, rs497578, rs562187, rs531402, rs2574801, rs2247887, and rs2247880.

Images