WO1999037761A1 - Novel sequence variants of the human beta2-adrenergic receptor gene and use thereof - Google Patents
Novel sequence variants of the human beta2-adrenergic receptor gene and use thereof Download PDFInfo
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- WO1999037761A1 WO1999037761A1 PCT/DE1998/003818 DE9803818W WO9937761A1 WO 1999037761 A1 WO1999037761 A1 WO 1999037761A1 DE 9803818 W DE9803818 W DE 9803818W WO 9937761 A1 WO9937761 A1 WO 9937761A1
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- beta2
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- sequence
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- variants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
Definitions
- the invention relates to new sequence variants of the human beta2-adrenergic receptor gene and their use for the diagnosis of a spectrum of diseases, in particular for the determination of hypertension dispositions and for the development of therapeutic agents on the basis of pharmacogenetic principles.
- the human beta2-adrenergic receptor is an important component of the sympathetic nervous system and, as such, regulates a spectrum of central and peripheral functions, e.g. Cardiovascular functions, metabolic functions, central nervous functions and neurosecretion. It is the target of pharmaceuticals / therapeutic agents with a wide range of indications, which are among the most commonly prescribed drugs.
- This receptor could play a role in the pathogenesis / pathophysiology of a number of common diseases, e.g. hypertension and other cardiovascular diseases, various neuropsychiatric diseases such as Depression, and metabolic diseases such as Obesity (Insel PA (Ed) (1987) Adrenergic receptors in man, Marcel Dekker, New York, Basel).
- the aim of the invention is to determine variants, polymorphisms, mutations and resulting haplotypes in the DNA sequence of the human beta2-adrenergic receptor gene and to determine their correlations with disease dispositions. Based on these correlations, a method for diagnosing these disease predispositions, for predicting severity, course and survival time, a system for predicting individual responsiveness to beta2 active therapeutic agents, for developing individually specific beta2 receptor agonists and antagonists, and a system for developing a new one Class of beta2 effective therapeutic agents, as well as the development of test systems for researching pathophysiological relationships and development of the above-mentioned therapeutic agents.
- an individually optimal therapeutic agent can be predicted or developed for each beta2 genotype.
- the object is achieved according to the claims, the subclaims are preferred variants. 2
- the invention then relates to the sequence of the human beta2-adrenergic receptor gene, which is at positions 159, 245, 565, 934, 1120, 1221, 1541, 1568, 1633, 1666, 1839, 2078, 2110, 2640, and 2826 in whole or is partially mutated.
- sequences are particularly important:
- the invention furthermore relates to a method for determining disease dispositions, it being possible for all sequences and variants of the beta2-adrenergic receptor gene from the individual mutation to all possible combinations of all variants (including any absolute number of variants which can be included) to be genotyped and enable the corresponding statements about disease dispositions.
- the method is characterized in that the DNA of a test subject is isolated and genotyped at least in one of the exchanged positions and subsequently compared with the reference DNA sequence.
- Embodiments are preferred in which at least position 1633, at least the three positions 1541, 1633 and 1666 or the four last-mentioned positions (1541, 1568, 1633 and 1666) or at the seven positions 245, 565 934, 11541, 1568, 1633 and genotyped in 1666. 3
- the method can also be varied by genotyping at least 3 of the 4 positions 1541, 1568, 1633 and 1666 and subsequently comparing them with the reference DNA sequence. Genotyping of positions 1541, 1633 and 1666 is preferred here.
- Genotyping is performed by sequencing or by other methods that are suitable for the detection of point mutations. This includes PCR-based genotyping methods such as B. allele-specific PCR, other genotyping methods using ohgonucleotides (examples would be 'dot blotting' or 'oligonucleotide ligation assays' (OLA)), methods using restriction enzymes, and' single nucleotide polymorphism '(SNP) analysis using' matrix assisted laser desorption / ionization mass spectrometry (MALDI), as well as in principle any future method for variant detection including chip technology in all its technological versions.
- PCR-based genotyping methods such as B. allele-specific PCR, other genotyping methods using ohgonucleotides (examples would be 'dot blotting' or 'oligonucleotide ligation assays' (OLA)), methods using restriction enzymes, and' single nucleotide polymorphism '
- the method according to the invention is suitable for determining a broad spectrum of the most diverse disease dispositions.
- a disposition for high blood pressure e.g. to determine a disposition for high blood pressure (or the prediction of the range of individual blood pressure values as such), and other cardiovascular diseases, including myocardial infarction and stroke, in the broadest sense the development of end-stage renal failure (requiring dialysis).
- Another preferred embodiment variant allows e.g. the determination of a disposition for neuropsychiatric diseases such as depression and anxiety disorders, attention deficit disorder (with hyperactivity), eating disorders, e.g. for anorexia nervosa and bulimia, or disorders caused by post-traumatic stress; or for diseases of the autonomic nervous system, e.g. Bradbury-Eggleston, Sky-Drager and Riley-Day syndrome as well as selective noradrenergic and baroreceptor dispositions, or migraines.
- neuropsychiatric diseases such as depression and anxiety disorders, attention deficit disorder (with hyperactivity), eating disorders, e.g. for anorexia nervosa and bulimia, or disorders caused by post-traumatic stress
- diseases of the autonomic nervous system e.g. Bradbury-Eggleston, Sky-Drager and Riley-Day syndrome as well as selective noradrenergic and baroreceptor dispositions, or migraines.
- Another area of application is the determination of a disposition for metabolic diseases such as obesity (as well as familial 'morbid obesity'), including a prediction of the weight range as such or a disposition for weight change, and finally a prediction of the ratio of the body measurements as such, as they are e.g. Express 'body mass index' (BMI). 4
- the method also allows the course and severity of diseases to be determined, and the prediction of survival after serious medical diseases, e.g. after myocardial infarction, heart failure and / or stroke.
- a further preferred embodiment variant enables the determination of an individually different reactivity of the autonomic nervous system, in particular on endogenous and exogenous stress (as expressed, for example, in particular by an individually different disposition to changes in blood pressure and / or heart rate (deflections) on endogenous and exogenous stress comes), or by individually different blood pressure changes to endogenously or exogenously induced changes in the salt concentration in the blood (individually different salt sensitivity or resistance), and in the broadest sense also by individually different salt and water regulation or reabsorption in the kidney (related volume regulation ) is expressed.
- Another important object of the invention is the use of the claimed sequence variants a) for predicting the individually different responsiveness to previously known therapeutic agents (beta2 receptor ligands) and the individually different responsiveness to the endogenous ligands adrenaline and noradrenaline; b) preferably for the development of individually specific beta2 receptor agonists and antagonists; c) in particular also for the development of a new class of therapeutic agents which are directed to the beta2 receptor gene at the 5 'regulatory region, promoter region, in particular e.g. attack the leader peptide and act by regulating transcription, translation and by influencing their efficiency, primarily by regulating expression.
- another object of the invention is the prediction of individual habituation to drug administration (tachyphylaxis), as well as a different disposition for drug side effects. Overall, it is possible to predict individually optimal therapeutic agents, which are based on different mechanisms of action.
- kits or methods can advantageously be used to predict individual disease disposition or individual responsiveness to various beta2 therapeutics.
- Cultures (cells) that express the various combinations of individual ß2 variants mentioned can thus serve as test models for the development of individually specific therapeutic agents (ß2 agonists and antagonists, as well as beta2 expression-regulating DNA therapeutic agents). This corresponds to test models in vitro, but also in vivo test models are included (transgenic animals that carry these individual receptor variants).
- the three mutations described have a significant effect on phenotypic parameters such as heart rate, noradrenaline concentrations, blood pressure changes on experimentally induced physical and mental stress, 'coping styles' and personality dimensions, as well as weight and weight change.
- phenotypic parameters such as heart rate, noradrenaline concentrations, blood pressure changes on experimentally induced physical and mental stress, 'coping styles' and personality dimensions, as well as weight and weight change.
- an association of the leader peptide mutation with hypertension was also shown.
- beta2-agonist-induced vasodilation and beta2 receptor mutations, preferably at position 16 of the amino acid sequence and a relationship between beta2-receptor expression in fibroblast cultures of genotyped individuals and beta2 receptor mutations, preferably at position 16 of the amino acid sequence, could be established.
- Combination 1 1541 T (Cys Allel), 1568 T, 1633 A (Arg Allel), 1666 C (Gin Allel)
- Combination 2 1541 C (Arg Allel), 1568 C, 1633 G (Gly Allel), 1666 G (Glu Allele)
- combination 3 1541 T (Cys Allele), 1568 T, 1633 G (Gly Allele), 1666 C (Gin Allele)
- Combination 1 was observed significantly more frequently in individuals who were inherited with hypertension and is therefore a genetic risk factor.
- Detection of specific beta2 'haplotypes' consisting of seven variants Taking all variants into account, 'haplotypes' consisting of seven variants (including the three mutations mentioned) could be extracted; The calculations were based on the goal of identifying 'haplotypes' from the entirety of the genome which were sufficient to distinguish the patient group from the control group. A specific 'haplotype', combination 1, can be observed more frequently in cases of genetic hypertension, and this can be extended to other phenotypes.
- Combination 1 245 G, 565 G, 934 A, 1541 T (Cys allele), 1568 T, 1633 A (Arg allele),
- Combination 2 245 A, 565 A, 934 G, 1541 C (Arg allele), 1568 C, 1633 G (Gly allele),
- Combination 3 245 G, 565 G, 934 G, 1541 T (Cys Allel), 1568 T, 1633 G (Gly Allel),
- the multiplex PCR sequencing method was used for the collection of the entire polymorphic spectrum of the beta2-receptor gene.
- the entire promoter region known to date and the coding region were divided into eight fragments and amplified by means of PCR (see FIG. 1). These PCR fragments were pooled and sequenced simultaneously.
- the fragments of the terrination reactions were separated on a sequence gel and transferred to a nylon membrane by direct transfer electrophoresis (DTE).
- DTE direct transfer electrophoresis
- the individual sequence ladders were decoded by successive hybridization with specific oligonucleotides.
- fragment II was amplified with hooves of the two primers ADRBR-F2: 5 ' -GCATACCCCCGCTCCAGATAAA-3 ' and ADRBR-R2: 5 ' -GCACGCACATACAGGCACAAATAC-3 ' .
- fragment III it was the two primers ADRBR-F3: 5 ' -GGCCGCGTTTCTGTGTTGG-3 ' and ADRBR-R3: 5 ' -AGTGCGTTCTGCCCGTTATGTG-3 ' .
- fragment VIII the two primers ADRBR-F8: 5 ' -GGTACTGTGCCTAGCGATAAC-3 ' and ADRBR-R8: 5 ' - TAAAATACCCCGTGTGAGCAAATAAGAG-3 ' .
- the reaction conditions for these four fragments were as follows: 10 x PCR buffer (100 mM Tris-HCl, 15 mM MgCl 2 x 6 H 2 O, 500 mM KC1, pH 8.3), dNTP 2 mM, 30 ⁇ M Primer F, 30 ⁇ M primer R, 50 ng genomic DNA and 5 U of a Taq DNA polymerase. Three fragments were amplified with the following temperature profile: 94 ° C for 4 min; 35 cycles: 94 ° C 30 sec, 60 ° C 30 sec, 72 ° C 1 min and finally 72 ° C 10 min.
- Fragment IV was generated using the two primers ADRBR-F4: 5 - GGGGAGGGAAAGGGGAGGAG-3 ' and ADRBR-R4: 5 ' -
- TACCCTCAAGTTAAATAGTCTGTT-3 used.
- the conditions for these two PCR reactions were as follows: 10 x PCR buffer (160 mM (NH 4 ) 2 SO 4 , 0.1% Tween-20, 500 mM KOH, pH), dNTP 2 mM, 30 ⁇ M Primer F , 30 ⁇ M Primer R, 50 ng genomic DNA and 4 U of a mixture of the Taq DNA polymerase and a thermostable inorganic pyrophosphatase from Thermits thermophilus.
- Fragment V was amplified using the two primers ADRBR-F5: 5 - ATGCGCCGGACCACGAC-3 ' and ADRBR-R5: 5 - GTAGAAGGACACGATGGA-3, fragment VI using the two primers ADRBR-F6: 5 - GCTACTTTGCCATTACTTCACC-3 ' and ADRBR-R6: 5 ' -
- AAATCTGGGCTCCGGCAGTAGATAAG-3 ' AAATCTGGGCTCCGGCAGTAGATAAG-3 ' .
- These two fragments were amplified using Perkin Elmer's 'AmpliTaq Gold Kit'.
- the temperature profile for these two fragments was as follows: 94 C 10 min; 35 cycles: 94 C 30 sec, 56 ° C [fragment V] or 58 ° C [fragment VI] 30 sec, 72 ° C 1 min and finally 72 ° C 10 min.
- the sequencing was done using the 'Thermo Sequenase cycle sequencing kit' from Amersham.
- the PCR primers described above were used as sequencing primers.
- the sequencing was carried out in four multiplex pools.
- Pool 1 contained the sequencing primers ADRBR-Fl, ADRBR-F3, ADRBR-F5 and ADRBR-F7;
- Pool 2 the sequencing primers ADRBR-Rl, ADRBR-R3, ADRBR-R5 and ADRBR-R7.
- the PCR fragments I, III, V and VII were used in both sequencing pools.
- Pool 3 on the other hand, contained the sequencing primers ADRBR-F2, F4, F6 and F8;
- Pool 4 the sequencing primers ADRBR-R2, R4, R6 and R8.
- the fragments ⁇ , IV, VI and VIII were inserted into these two pools.
- Parola AL and KobUa BK The peptide product of a 5 ' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis. J Biol Chem. 269 (6): 4497-505 (1994).
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Abstract
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU25107/99A AU2510799A (en) | 1997-12-30 | 1998-12-30 | Novel sequence variants of the human beta2-adrenergic receptor gene and use thereof |
EP98966818A EP1044268A1 (en) | 1997-12-30 | 1998-12-30 | Novel sequence variants of the human beta2-adrenergic receptor gene and use thereof |
Applications Claiming Priority (2)
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DE19758401 | 1997-12-30 | ||
DE19758401.2 | 1997-12-30 |
Publications (1)
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WO1999037761A1 true WO1999037761A1 (en) | 1999-07-29 |
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PCT/DE1998/003818 WO1999037761A1 (en) | 1997-12-30 | 1998-12-30 | Novel sequence variants of the human beta2-adrenergic receptor gene and use thereof |
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EP (1) | EP1044268A1 (en) |
AU (1) | AU2510799A (en) |
DE (1) | DE19860930A1 (en) |
WO (1) | WO1999037761A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000022166A2 (en) * | 1998-10-14 | 2000-04-20 | Pyrosequencing Ab | Genes for assessing cardiovascular status and compositions for use thereof |
US6197505B1 (en) | 1997-04-04 | 2001-03-06 | Pyrosequencing Ab | Methods for assessing cardiovascular status and compositions for use thereof |
WO2001067862A1 (en) * | 2000-03-10 | 2001-09-20 | University Of Cincinnati | Adrenergic receptor overexpression in airway tissues for the treatment of airway obstructive diseases |
EP1280814A1 (en) * | 2000-04-13 | 2003-02-05 | Genaissance Pharmaceuticals, Inc. | Association of beta2 adrenergic receptor haplotypes with drug response |
US6586183B2 (en) | 2000-04-13 | 2003-07-01 | Genaissance Pharmaceuticals, Inc. | Association of β2-adrenergic receptor haplotypes with drug response |
EP1417338A1 (en) * | 2001-07-16 | 2004-05-12 | Price Foundation Limited | Genes and snps associated with eating disorders |
US6861217B1 (en) * | 1998-11-25 | 2005-03-01 | Genaissance Pharmaceuticals, Inc. | Variation in drug response related to polymorphisms in the β2-adrenergic receptor |
WO2006031181A1 (en) * | 2004-09-13 | 2006-03-23 | Astrazeneca Ab | Methods for identifying a patient as a candidate for treatment with a long acting beta agonist and for predicting a patient’s response to long acting beta2 agonist therapy by analysing polymorphisms in the beta2-adrenergic receptor gene |
EP1782321A2 (en) * | 2004-07-23 | 2007-05-09 | The University of North Carolina at Chapel Hill | Methods and materials for determining pain sensitivity and predicting and treating related disorders |
EP2055776A1 (en) * | 2006-11-30 | 2009-05-06 | Arkray, Inc. | Primer set for amplification of obesity gene, reagent for amplification of obesity gene comprising the primer set, and use of the primer set |
-
1998
- 1998-12-30 AU AU25107/99A patent/AU2510799A/en not_active Abandoned
- 1998-12-30 WO PCT/DE1998/003818 patent/WO1999037761A1/en not_active Application Discontinuation
- 1998-12-30 DE DE19860930A patent/DE19860930A1/en not_active Withdrawn
- 1998-12-30 EP EP98966818A patent/EP1044268A1/en not_active Withdrawn
Non-Patent Citations (11)
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HALL I.: "Beta-2 adrenoceptor polymorphisms: are they clinically important ?", THORAX, vol. 51, 1996, pages 351 - 353, XP002106246 * |
KOBILKA B K ET AL: "Functional activity and regulation of human beta 2 - adrenergic receptors expressed in Xenopus oocytes.", JOURNAL OF BIOLOGICAL CHEMISTRY, (1987 NOV 15) 262 (32) 15796-802. JOURNAL CODE: HIV. ISSN: 0021-9258., United States, XP002106245 * |
LARGE V. ET AL.: "Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function", JOURNAL OF CLINICAL INVESTIGATION, vol. 100, no. 12, 1997, pages 3005 - 3013, XP002106243 * |
LIGGETT S.: "Polymorphisms of the beta-2 adrenergic receptor and asthma", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 156, no. 4, October 1997 (1997-10-01), pages S156 - S162, XP002106240 * |
MCGRAW D W ET AL: "Polymorphisms of the 5' leader cistron of the human beta2 - adrenergic receptor regulate receptor expression.", JOURNAL OF CLINICAL INVESTIGATION, (1998 DEC 1) 102 (11) 1927-32. JOURNAL CODE: HS7. ISSN: 0021-9738., United States, XP002106249 * |
PAROLA A L ET AL: "The peptide product of a 5' leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis.", JOURNAL OF BIOLOGICAL CHEMISTRY, (1994 FEB 11) 269 (6) 4497-505. JOURNAL CODE: HIV. ISSN: 0021-9258., United States, XP002106244 * |
SCOTT M G ET AL: "Identification of novel polymorphisms within the promoter region of the human beta2 adrenergic receptor gene.", BRITISH JOURNAL OF PHARMACOLOGY, (1999 FEB) 126 (4) 841-4. JOURNAL CODE: B00. ISSN: 0007-1188., ENGLAND: United Kingdom, XP002106250 * |
TIMMERMANN B ET AL: "Novel DNA sequence differences in the beta2 - adrenergic receptor gene promoter region.", HUMAN MUTATION, (1998) 11 (4) 343-4. JOURNAL CODE: BRD. ISSN: 1059-7794., United States, XP002106247 * |
TIMMERMANN B. ET AL: ".beta.-2 Adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study", KIDNEY INTERNATIONAL, (1998) 53/6 (1455-1460). REFS: 32 ISSN: 0085-2538 CODEN: KDYIA5, United States, XP002106248 * |
TURKI J ET AL: "Myocardial signaling defects and impaired cardiac function of a human beta 2 - adrenergic receptor polymorphism expressed in transgenic mice.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, (1996 SEP 17) 93 (19) 10483-8. JOURNAL CODE: PV3. ISSN: 0027-8424., United States, XP002106241 * |
TURKI J. ET AL.: "GENETIC POLYMORPHISMS OF THE BETA2-ADRENERGIC RECEPTOR IN NOCTURNAL AND NONNOCTURNAL ASTHMA", JOURNAL OF CLINICAL INVESTIGATION, vol. 95, 1995, pages 1635 - 1641, XP002106242 * |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6197505B1 (en) | 1997-04-04 | 2001-03-06 | Pyrosequencing Ab | Methods for assessing cardiovascular status and compositions for use thereof |
WO2000022166A3 (en) * | 1998-10-14 | 2000-09-14 | Pyrosequencing Ab | Genes for assessing cardiovascular status and compositions for use thereof |
WO2000022166A2 (en) * | 1998-10-14 | 2000-04-20 | Pyrosequencing Ab | Genes for assessing cardiovascular status and compositions for use thereof |
US6861217B1 (en) * | 1998-11-25 | 2005-03-01 | Genaissance Pharmaceuticals, Inc. | Variation in drug response related to polymorphisms in the β2-adrenergic receptor |
WO2001067862A1 (en) * | 2000-03-10 | 2001-09-20 | University Of Cincinnati | Adrenergic receptor overexpression in airway tissues for the treatment of airway obstructive diseases |
EP1280814A1 (en) * | 2000-04-13 | 2003-02-05 | Genaissance Pharmaceuticals, Inc. | Association of beta2 adrenergic receptor haplotypes with drug response |
EP1280814A4 (en) * | 2000-04-13 | 2003-05-14 | Genaissance Pharmaceuticals | Association of beta2 adrenergic receptor haplotypes with drug response |
US6586183B2 (en) | 2000-04-13 | 2003-07-01 | Genaissance Pharmaceuticals, Inc. | Association of β2-adrenergic receptor haplotypes with drug response |
EP1417338A1 (en) * | 2001-07-16 | 2004-05-12 | Price Foundation Limited | Genes and snps associated with eating disorders |
EP1417338A4 (en) * | 2001-07-16 | 2005-06-29 | Price Foundation Ltd | Genes and snps associated with eating disorders |
EP1782321A4 (en) * | 2004-07-23 | 2009-11-04 | Univ North Carolina | Methods and materials for determining pain sensitivity and predicting and treating related disorders |
US11085081B2 (en) | 2004-07-23 | 2021-08-10 | The University Of North Carolina At Chapel Hill | Methods and materials for determining pain sensitivity and predicting and treating related disorders |
EP1782321A2 (en) * | 2004-07-23 | 2007-05-09 | The University of North Carolina at Chapel Hill | Methods and materials for determining pain sensitivity and predicting and treating related disorders |
EP2484780A1 (en) * | 2004-07-23 | 2012-08-08 | The University of North Carolina At Chapel Hill | Methods and materials for determining pain sensibility and predicting and treating related disorders |
JP2008512114A (en) * | 2004-09-13 | 2008-04-24 | アストラゼネカ・アクチエボラーグ | To identify a patient as a candidate for treatment with a long-acting beta agonist and to analyze the polymorphism in the beta 2-adrenergic receptor gene, Method for predicting response |
WO2006031181A1 (en) * | 2004-09-13 | 2006-03-23 | Astrazeneca Ab | Methods for identifying a patient as a candidate for treatment with a long acting beta agonist and for predicting a patient’s response to long acting beta2 agonist therapy by analysing polymorphisms in the beta2-adrenergic receptor gene |
EP2055776A4 (en) * | 2006-11-30 | 2009-11-25 | Arkray Inc | Primer set for amplification of obesity gene, reagent for amplification of obesity gene comprising the primer set, and use of the primer set |
US8021845B2 (en) | 2006-11-30 | 2011-09-20 | Arkray, Inc. | Probes for detecting obesity gene |
EP2055776A1 (en) * | 2006-11-30 | 2009-05-06 | Arkray, Inc. | Primer set for amplification of obesity gene, reagent for amplification of obesity gene comprising the primer set, and use of the primer set |
Also Published As
Publication number | Publication date |
---|---|
EP1044268A1 (en) | 2000-10-18 |
DE19860930A1 (en) | 1999-09-16 |
AU2510799A (en) | 1999-08-09 |
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