WO2005017505A2 - Diagnostic d'un trouble atopique - Google Patents

Diagnostic d'un trouble atopique Download PDF

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Publication number
WO2005017505A2
WO2005017505A2 PCT/GB2004/003518 GB2004003518W WO2005017505A2 WO 2005017505 A2 WO2005017505 A2 WO 2005017505A2 GB 2004003518 W GB2004003518 W GB 2004003518W WO 2005017505 A2 WO2005017505 A2 WO 2005017505A2
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gene
polymorphism
polymorphisms
atopic
fcεri
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PCT/GB2004/003518
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English (en)
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WO2005017505A3 (fr
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William Osmond Charles Cookson
Miriam Fleur Moffat
Michael Richard Hill
James Arnold Traherne
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Isis Innovation Limited
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Publication of WO2005017505A2 publication Critical patent/WO2005017505A2/fr
Publication of WO2005017505A3 publication Critical patent/WO2005017505A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Definitions

  • Atopy is a common familial syndrome that is due to interacting genetic and environmental factors.
  • the atopic diseases include asthma, atopic dermatitis and allergic rhinitis and affect more than 10% of individuals in western populations (1 ).
  • Atopy is characterised by increased total serum Immunoglobulin E (IgE) concentrations and by elevations of IgE specific to common allergens such as house dust mite (HDM) proteins and grass pollen.
  • IgE Immunoglobulin E
  • Allergen-specific IgE may be detected by ELISA or RAST measurement of serum titres, and by prick skin tests (PST) in which minute amounts of allergen are introduced into the epidermis and the resulting skin wheal is quantified.
  • PST prick skin tests
  • the complex relationships between atopic diseases and these intermediate phenotypes can be dissected genetically in multivariate models (2, 3), and quantitative phenotypes are effective surrogates for disease in linkage and association studies.
  • the high affinity receptor for IgE Fc ⁇ RI
  • the Fc ⁇ RI- ⁇ protein acts as an amplifying element of the high-affinity ⁇ g ⁇ . receptor response to activation (12) and in addition stabilises the expression of the receptor on the mast cell surface (4). Polymorphism in Fc ⁇ RI- ⁇ is therefore in an ideal position to modify Fc ⁇ RI signalling in response to allergens.
  • Fc ⁇ RI- ⁇ is composed of seven exons and six introns, spanning approximately 11 Kb (13).
  • Initial sequencing of the coding regions of Fc ⁇ RI- ⁇ detected polymorphisms within exon 6 (L181I and L183V), which is strongly associated with atopic asthma and measures of atopy in British and Australian subjects (14). Although these variants have been reported in Kuwaiti Arabs (15),
  • WO02/062946 discloses human and mouse proteins that span the cell membrane at least four times and share high levels of sequence identity with Fc ⁇ RI - ⁇ , CD20 and HTm4. These proteins are stated to reveal a new gene family, designated as MS4A.
  • Fc ⁇ RI- ⁇ gene designated as MS4A2
  • MS4A2 is disclosed as being useful in the treatment of atopic disorders, this is in the context of evaluating drugs that modulate the MS4A2 protein function.
  • WO97/08338 discloses the E237G polymorphism in exon 7 of Fc ⁇ RI- ⁇ . A method for diagnosing atopy based upon the identification of this polymorphism is also disclosed.
  • WO95/05481 discloses the identification of specific polymorphisms at amino acids 181 and 183, in exon 6 of Fc ⁇ RI - ⁇ . Van Hage-Hamsten et al, Clin. Exp. Allergy, 2002; 32: 838-842 and Kim et al, Clin. Exp.
  • a method for detecting whether a subject has or is predisposed to an atopic disease comprises: determining the presence in the subject of any of the genetic polymorphisms disclosed in Table 1.
  • an isolated polynucleotide useful for diagnosing whether a subject has or is predisposed to an atopic disease comprises at least 15 contiguous nucleic acids derived from a region of the MS4A2 gene that comprises one or more of the polymorphisms shown in Table 1.
  • a diagnostic kit comprises a polynucleotide as defined above.
  • Figure 1 shows the Fc ⁇ RI- ⁇ /MS4A2 genomic structure and sequence polymorphism. Base A of the ATG initiator Met codon of Fc ⁇ RI- ⁇ is denoted nucleotide +1. Dinucleotide repeats are in brackets.
  • Figure 2 shows the Linkage Disequilibrium within Fc ⁇ RI- ⁇ / MS4A2. Pairwise estimations of D' are shown from unrelated subjects (the parents), on a scale of 1 (complete LD: red) to 0 (blue). Marker positions are shown as a schematic rather than at actual distances apart.
  • the lower insert illustrates the distribution of LD with true distances.
  • the present invention utilises known methods of genetic analysis to determine whether a particular subject has, or is predisposed to, an atopic disease.
  • genetic predisposition refers to an increased likelihood that a given subject has or is likely to develop an atopic disease, given the presence of a particular genomic sequence (polymorphism).
  • atopic disease is intended to refer to the related group of diseases, such as, asthma, atopic dermatitis and allergic rhinitis.
  • allele is used herein to refer to variants of a nucleotide sequence.
  • a biallelic polymorphism has two forms; designated herein as "allele 1 " and "allele 2". Diploid organisms may be homozygous or heterozygous for an allelic form.
  • haplotype is used herein to refer to a combination of alleles present on an individual chromosome.
  • polymorphism refers to the occurrence of two or more alternative genomic sequences or alleles between or among different genomes or subjects.
  • a single nucleotide polymorphism is a single base pair change. Typically, a SNP is the replacement of one nucleotide by another nucleotide at the polymorphic site.
  • dbSNP accession number is given where available (www.ensembl.org); the superscript (a) refers to dinucleotide repeats.
  • the study panels were not genotyped for -3264, -3226, -528, +1798, +11430, +12400.
  • the polymorphisms are shown in brackets. Having identified the SNPs, it will be apparent to the skilled person how to detect polymorphisms for a particular subject, to make a diagnosis. Methods for the detection of a polymorphism are known in the art, and include: polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) (e.g.
  • SSCP Single-stranded conformation polymorphism
  • the method for detecting the presence of a polymorphism comprises: contacting an isolated genetic sample containing the MS4A2 gene, or a portion thereof containing a putative polymorphism, with an oligonucleotide that hybridises to the gene or gene portion if the polymorphism is present; and determining whether hybridisation has occurred.
  • the oligonucleotides can be labelled with a detectable label, e.g. a fluorophore, so that those oligonucleotides that hybridise to the mutated gene can be identified.
  • a preferred method for the identification of the presence of a SNP is to use the LightCycler system (Lohmann et al., Biochemica, 2000; (4): 23-28) developed by Roche Molecular Biochemicals.
  • the LightCycler system enables the amplification and real-time detection of a polynucleotide, allowing accurate quantification.
  • the system permits the detection and genotyping of single nucleotide polymorphisms by utilising a function known as melting curve analysis. During the melting curve analysis the LightCycler instrument monitors the temperature-dependent hybridisation of sequence specific hybridisation probes to single stranded DNA.
  • a genetic sample is contacted with two oligonucleotides designed to hybridise at adjacent sites at the polymorphic region.
  • a ligase reaction is then carried out to ligate those oligonucleotides that are hybridised and the ligated product detected in a subsequent detection step.
  • This method is disclosed in US Patent No.6027889.
  • An alternative detection method is to use what are referred to in the art as "Molecular beacons".
  • Molecular beacons are oligonucleotides designed for the detection and quantification of target nucleic acids.
  • the oligonucleotides usually comprise self-hybridising portions that, in the absence of a target nucleic acid, form a stem-loop structure.
  • a fluorescent moiety and a quencher moiety are attached at each end of the oligonucleotide, and are positioned adjacently when the oligonucleotide is in the stem-loop orientation. Fluorescence is effectively prevented by the quencher moiety in this orientation.
  • the loop portion of the oligonucleotide is complementary to a specific target nucleic acid and, in the presence of the target, hybridisation to the target occurs disrupting the stem loop orientation, separating the fluor and quencher, resulting in an increase in detectable fluorescence.
  • hybridisation probes for use in the LightCycler system, or any hybridisation based system.
  • the design of suitable polynucleotide/hybridisation probes will be apparent to the skilled person.
  • the probes will usually comprise the polymorphic site, e.g. the SNP.
  • the polynucleotides/hybridisation probes may be detectably labelled, e.g. fluorescently labelled, using methods and labels known in the art, e.g. as used in the detection methods referred to above.
  • the polynucleotides/hybridisation probes may be immobilised to a support material, for use in a diagnostic assay.
  • Suitable support materials are known in the art and include, ceramics, plastics, glass and silicon materials.
  • Methods for immobilising polynucleotides to a support material are also known in the art.
  • Polynucleotide array technology are suitable for use in the invention, for screening of biological samples.
  • Arrays that include the desired immobilised polynucleotides can be produced on a customised basis by various companies, including HySeq. In general, the arrays employ immobilised polynucleotide probes that are complementary to target sequences from a biological sample (e.g. from a subject).
  • the target sequence will include a polymorphism as disclosed herein.
  • the polynucleotides to be used as probes in a diagnostic method will usually complete at least an 8, 10, 15, 20 or 50 consecutive nucleic acid sequence derived from the appropriate MS4A2 region, including one or more of the polymorphic sites disclosed herein.
  • Polynucleotides may also be designed to act as primers to amplify polynucleotides that may comprise a polymorphism.
  • One or more polynucleotides may be used to characterise/determine more than one different SNP.
  • linkage analysis The association between the presence of polymorphisms in the MS4A2 gene and atopic disease was identified by studying the correlation between the transmission of genetic markers and the prevalence of atopic disease throughout generations within a family (so-called linkage analysis).
  • Linkage Analysis When data are available from successive generations there is the opportunity to study the degree of linkage between pairs of loci. With loci that are genetic markers, a genetic map can be established, and the strength of linkage between markers and disease states can be calculated and used to indicate the relative positions of markers and genes affecting those disease states.
  • the classical method for linkage analysis is the logarithm of odds (LOD) score method (Morton et al., Am. J. Hum. Genet., 1955; 7: 277-318).
  • Example MATERIALS AND METHODS Physical Mapping Human genomic PAC clones containing Fc Rl- I MS4A2 sequence were identified through hybridisation based library screening using a 690bp cDNA clone, covering exons 2 to 7 of MS4A2, and a 662bp genomic PCR product covering the 5 ' untranslated region and exon 1. Positive clones were mapped by FISH to confirm their chromosomal location. A restriction map was generated from the isolated PAC clones to derive a consensus contig.
  • Fc Rl- was located by hybridising the 690bp cDNA probe onto the restriction fragments of the clones.
  • a vectorette PCR technique adapted from Munroe et al. (50) was used to extend the sequence of K ⁇ ster et al. (13) and isolate (CA) n repeats.
  • DNA sequencing used fluorescently labelled dye-terminator chemistry and an Applied Biosystems 377 sequencer. This provided an additional 3213 bases of sequence upstream and 3580 bases of sequence downstream ofthe previously described sequence (13). All sequences were aligned (GAP4 program, STADEN package) to produce 18098 bases of continuous sequence for polymorphism detection, as shown in the attached sequence listing.
  • Panel 2 contained 380 subjects in 67 nuclear and 7 extended pedigrees from the UK, recruited through probands attending hospital clinics with symptoms of asthma or atopic disease (51 ). Phenotvping The same protocols were used to test both panels of families. Prick Skin Tests to House Dust Mite (HDM) and mixed grass pollen (less the response of negative controls), specific IgE titres to HDM and Timothy Grass and the total serum IgE were measured as previously described (30). A "Skin Test Index (PSTI)” was calculated as the sum of the prick skin test results to HDM and grass mix (95% of individuals who were atopic reacted either to HDM, or to grass pollen or both). A “RAST index (RASTI)” was defined as the sum of the RAST scores for the serum IgE concentration specific to the same two allergens. Genotyping SNPs were genotyped by RFLP analysis of PCR products. The ⁇ -
  • a stepwise procedure was performed in which the most significantly associated SNP was included as a covariate in the QTDT analysis. The analysis was then repeated, and the next most significantly associated remaining SNP was included as an additional covariate, until no significant associations remained.
  • Haplotypes were generated by the MERLIN program (54). Pair-wise D' measurements were made between SNPs from the parental (i.e. unrelated subject) haplotypes and linkage disequilibrium (LD) across the locus was plotted by the GOLD program (55). For each marker pair, GOLD plotted the colour coded pairwise disequilibrium statistics at their Cartesian co-ordinates, and the plots were completed by interpolation.
  • CpG islands were detected by searching for high-scoring segments using an ungapped Smith-Waterman algorithm (56, 57) in which each CpG dinucleotide scores +20 and all other dinucleotides score -1 (PERL source code available on request).
  • a permutation test was used to determine statistically significant CpG islands: in order to model the dependence between nearby nucleotides, the sequence was divided into non-overlapping 10bp segments, the order of which was permuted. The highest-scoring CpG island in the permuted sequence was recorded, and process was repeated 1000 times until the empirical distribution of CpG island scores could be estimated with precision.
  • the ⁇ +6858 polymorphism (E237G (18)) confers the only coding change found.
  • Six of the sequence variants have previously been reported in the literature, ⁇ -211 (originally named -109 (33)), ⁇ +1343 (Rsal-ex2 (14, 27)), the dinucleotide repeat ⁇ +5026 (FCERIB (5, 8)), ⁇ +3934 (33), ⁇ +6858 (E237G (18) and ⁇ +9424 (Rsal-ex7 (27)).
  • dbSNP accession numbers had previously been assigned to 18 of the SNPs detected (Table 1 ). We did not find the previously reported L181I and L183V polymorphisms (14).
  • SNPs were associated to the PSTI/RASTI in both panels (Table 2). These corresponded approximately to the leader sequences and intron II; introns III, V and VI; the distal 3'UTR and contiguous sequences; and SNPs in the distal end ofthe region. In general, the associations were stronger in Panel 1. An association was observed in position -854 in the Panel 1 subjects but not in Panel 2, and weak associations were observed within the predicted F2 promoter only within the Panel 2 subjects. A stepwise procedure was then performed to determine if SNPs in these regions independently contributed to the phenotype.
  • the ⁇ +3934*2 SNP (or closely neighbouring markers) is therefore present on most positively associated haplotypes: however the weakly positive association with *1 *1 *1 *1 and the disproportionate strength of the association to the rare haplotype *2*2*1 *1 provide further evidence that the ⁇ +3934*2 cluster is not the only determinant of positive associations with the locus.
  • RASTI as covariate (results not shown). This is consistent with reduced numbers of subjects (because transmission tests do not measure the relationship between phenotype and genotype in parents).
  • a test for the presence of maternal effects for the RASTI was positive in the Panel 2 subjects (P ⁇ 0.01) but not in Panel 1. Association to maternally derived alleles was then examined (Table 2). Strong associations were seen to the RASTI and PSTI independently, but not in combination (Table 2 shows the results of testing the association to RASTI: the PSTI gave similar results).
  • TF binding sites were altered by the presence of SNPs, using the Matlnspector program (34).
  • IRF-2 Interferon regulatory factor 2
  • Table 4 TFs corresponding to atopy-associated SNPs are shading. SNPs are shown in bold in the consensus recognition sequence.
  • haplotypes also do not suggest that a single SNP is responsible for association of atopy phenotypes to this locus. Although most ofthe SNPs in the body of the gene were in partial LD with each other, the LD was incomplete and irregularly distributed and declined with distance. These results are not consistent with the haplotype block hypothesis
  • Fc ⁇ RI- ⁇ chain is not essential for Fc ⁇ RI function and does not possess autonomous cell activation capacity, but it augments the surface expression of the receptor (22) and acts as a 12 to 30 fold amplifier of Fc ⁇ RI- ⁇ mediated cell activation signals (12, 22, 41 ).
  • Receptor function may therefore be modified by variation in the level of ⁇ chain expression, or in the level of the recently recognised truncated form, ⁇ ⁇ , which regulates receptor surface expression (38).
  • IRF-2 Interferon regulatory factor 2
  • IRF-2 polymorphisms have been associated with atopic eczema (40) and IRF-2 knockout mice show defects in CD8+ T cells and spontaneous development of an inflammatory skin disease (41 ).
  • the two panels had a similar prevalence of atopy, measured by PSTI, and RASTI, but total serum IgE levels were higher and there were many more asthmatics in the panel that showed maternal effects (Panel 2).
  • the panels were of similar sizes, so the maternal effects in Panel 2 were not attributable to differences in power.
  • Parent-of-origin effects have been observed at other loci influencing allergic disease (8, 42, 43) and in other immunological disorders such as type I diabetes (44), Crohn's disease (45), rheumatoid arthritis (46) and IgA deficiency (47) .
  • the strength of parent-of-origin effects in type I diabetes had also been observed to differ among family collections from different populations (48). No mechanism has been identified for these phenomena.
  • Interaction between maternal and foetal immune systems, and genomic imprinting of disease genes are two possibilities (49). The two regions of increased CpG concentration that we have identified in Fc ⁇ RI- ⁇ provide a potential substrate for epigenetic effects.
  • the content of each of the publications referred to in the specification is incorporated herein by reference. References
  • IRE-bubble PCR a rapid method for efficient and representative amplification of human genomic DNA sequences from complex sources. Genomics, 19, 506-514.

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Abstract

L'invention concerne un procédé permettant de détecter si un sujet présente un trouble atopique ou s'il est prédisposé aux troubles atopiques. Ce procédé consiste à déterminer si ledit sujet présente l'un des polymorphismes génétiques identifiés dans le gène MS4A2.
PCT/GB2004/003518 2003-08-14 2004-08-16 Diagnostic d'un trouble atopique WO2005017505A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1876244A1 (fr) * 2005-04-04 2008-01-09 Asubio Pharma Co., Ltd. Calcul du risque relatif de survenue d'une dermité atopique par analyse du polymorphisme génique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008338A1 (fr) * 1995-08-29 1997-03-06 Isis Innovation Limited Atopie: diagnostic et therapie
WO2001014588A1 (fr) * 1999-08-24 2001-03-01 Genaissance Pharmaceuticals, Inc. Isogenes cibles de medicament: polymorphismes dans le gene de la chaine beta du recepteur e d'immunoglobuline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008338A1 (fr) * 1995-08-29 1997-03-06 Isis Innovation Limited Atopie: diagnostic et therapie
WO2001014588A1 (fr) * 1999-08-24 2001-03-01 Genaissance Pharmaceuticals, Inc. Isogenes cibles de medicament: polymorphismes dans le gene de la chaine beta du recepteur e d'immunoglobuline

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
COX H E ET AL: "ASSOCIATION OF ATOPIC DERMATITIS TO THE BETA SUBUNIT OF THE HIGH AFFINITY IMMUNOGLOBULIN E RECEPTOR" BRITISH JOURNAL OF DERMATOLOGY, XX, XX, vol. 138, 1998, pages 182-187, XP002933012 ISSN: 0007-0963 cited in the application *
DATABASE DBSNP 27 July 2000 (2000-07-27), XP002302000 retrieved from NCBI Database accession no. RS513986 *
HILL M R ET AL: "A NEW VARIANT OF THE BETA SUBUNIT OF THE HIGH-AFFINITY RECEPTOR FORIMMUNOGLOBULIN E (FCEPSILONRI-BETA E237G): ASSOCIATIONS WITH MEASURES OF ATOPY AND BRONCHIAL HYPER-RESPONSIVENESS" HUMAN MOLECULAR GENETICS, OXFORD UNIVERSITY PRESS, SURREY, GB, vol. 5, no. 7, 1 July 1996 (1996-07-01), pages 959-962, XP000616300 ISSN: 0964-6906 cited in the application *
HIZAWA NOBUYUKI ET AL: "A common FCER1B gene promoter polymorphism influences total serum IgE levels in a Japanese population" AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 161, no. 3 part 1, March 2000 (2000-03), pages 906-909, XP002301997 ISSN: 1073-449X *
PALMER L J ET AL: "FC-epsilon-R1-beta polymorphism and total serum IgE levels in endemically parasitized Australian Aborigines" AMERICAN JOURNAL OF HUMAN GENETICS, vol. 61, no. 1, 1997, pages 182-188, XP001203480 ISSN: 0002-9297 *
ROHRBACH M ET AL: "Screening of the Fc epsilon RI-beta-gene in a Swiss population of asthmatic children: no association with E237G and identification of new sequence variations." DISEASE MARKERS. NOV 1998, vol. 14, no. 3, November 1998 (1998-11), pages 177-186, XP009038510 ISSN: 0278-0240 cited in the application *
SHIRAKAWA T ET AL: "ASSOCIATION BETWEEN ATOPY AND VARIANTS OF THE BETA SUBUNIT OF THE HIGH-AFFINITY IMMUNOGLOBULIN E RECEPTOR" NATURE GENETICS, NEW YORK, NY, US, vol. 7, 1 June 1994 (1994-06-01), pages 125-130, XP000198191 ISSN: 1061-4036 cited in the application *
TRAHERNE JAMES A ET AL: "LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta." HUMAN MOLECULAR GENETICS, vol. 12, no. 20, 15 October 2003 (2003-10-15), pages 2577-2585, XP002301999 ISSN: 0964-6906 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1876244A1 (fr) * 2005-04-04 2008-01-09 Asubio Pharma Co., Ltd. Calcul du risque relatif de survenue d'une dermité atopique par analyse du polymorphisme génique
EP1876244A4 (fr) * 2005-04-04 2009-09-23 Asubio Pharma Co Ltd Calcul du risque relatif de survenue d'une dermité atopique par analyse du polymorphisme génique
US8071307B2 (en) 2005-04-04 2011-12-06 Asubio Pharma Co., Ltd. Method of detecting relative risk for the onset of atopic dermatitis by gene single nucleotide polymorphism analysis

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