DE102007041656A1 - Use of marker sequences for the diagnosis of rheumatoid arthritis, where the marker sequences of a complementary DNA (cDNA) from the specific sequence is determined in a patient - Google Patents

Abstract

Use of marker sequences for the diagnosis of rheumatoid arthritis, is claimed, where at least a marker sequence of a complementary DNA (cDNA) from the SEQ ID NO. 1-488 (not defined) or a protein obtained from the sequence, a partial sequence or a fragment of the sequence, is determined in a patient. Independent claims are included for: (1) diagnosing rheumatoid arthritis comprising introducing the marker sequences on a solid carrier and contacting with body fluids or tissue extracts of a patient and determining the interaction of the body fluids or tissue extracts with the marker sequences; (2) a procedure for the stratification, preferably for risk stratification or for the therapy control of a patient with rheumatoid arthritis, comprising determining the marker sequences in a patient; (3) an arrangement of marker sequences; (4) an assay, protein biochip consisting of the arrangement, where the marker sequences are applied on a solid carrier; (5) a diagnostic agent for the diagnosis of rheumatoid arthritis comprising the marker sequence; and (6) a target for the treatment and therapy of rheumatoid arthritis from the marker sequence.

Description

The The present invention relates to novel marker sequences for Rheumatoid arthritis and its diagnostic use, including one Method of screening for potential drugs for Rheumatoid arthritis using these marker sequences. Further concerns the invention provides a diagnostic device containing such marker sequences for rheumatoid arthritis, especially a protein biochip and its use.

protein biochips gain an increasing industrial importance in analytics and diagnostics as well as in pharmaceutical development. Have protein biochips established as screening tools.

Here, the fast and highly parallel detection of a variety of specific binding molecules is made possible in a single experiment. For the production of protein biochips, it is necessary to have the required proteins available. In particular, protein expression libraries have been established for this purpose. The high-throughput cloning of defined open reading frames is one possibility ( Heyman, JA, Cornthwaite, J., Foncerrada, L., Gilmore, JR, Gontang, E., Hartman, KJ, Hernandez, CL, Hood, R., Hull, HM, Lee, WY, Marcil, R., Marsh , EJ, Mudd, KM, Patino, MJ, Purcell, TJ, Rowland, JJ, Sindici, ML and Hoeffler, JP (1999) Genome-scale cloning and expression of individual open reading frames using topoisomerase I-mediated ligation. Genome Res, 9, 383-392; Kersten, B., Feilner, T., Kramer, A., Wehrmeyer, S., Possling, A., Witt, I., Zanor, MI, Stracke, R., Lueking, A., Kreutzberger, J., Lehrach , H. and Cahill, DJ (2003) Generation of Arabidopsis Protein Chip for Antibody and Serum Screening. Plant Molecular Biology, 52, 999-1010; Reboul, J., Vaglio, P., Rual, JF, Lamesch, P., Martinez, M., Armstrong, CM, Li, S., Jacotot, L., Bertin, N., Janky, R., Moore, T., Hudson, JR, Jr., Hartley, JL, Brasch, MA, Vandenhaute, J., Boulton, S., Endress, GA, Jenna, S., Chevet, E., Papasotiropoulos, V., Tolias, PP , Ptacek, J., Snyder, M., Huang, R., Chance, MR, Lee, H., Doucette strain, L., Hill, DE and Vidal, M. (2003) C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression. Nat Genet, 34, 35-41; Walhout, AJ, Temple, GF, Brasch, MA, Hartley, JL, Lorson, MA, van den Heuvel, S. and Vidal, M. (2000) GATEWAY recombinational cloning: application to the cloning of large numbers of open reading frames ORFeomes. Methods Enzymol, 328, 575-592 ). However, such an approach is strongly related to the progress of genome sequencing projects and the annotation of these gene sequences. Moreover, the determination of the expressed sequence is not always clear due to differential splicing events. This problem can be circumvented by the use of cDNA expression libraries ( Büssow, K., Cahill, D., Nietfeld, W., Bancroft, D., Scherzinger, E., Lehrach, H. and Walter, G. (1998) A method for global protein expression and antibody screening at high density filters of an arrayed cDNA library. Nucleic Acids Research, 26, 5007-5008; Büssow, K., Nordhoff, E., Lübbert, C., Lehrach, H. and Walter, G. (2000) A human cDNA library for high-throughput protein expression screening. Genomics, 65, 1-8; Holz, C., Lueking, A., Bovekamp, L., Gutjahr, C., Bolotina, N., Lehrach, H. and Cahill, DJ (2001) A human cDNA expression library in yeast enriched for open reading frames. Genome Res, 11, 1730-1735; Lueking, A., Holz, C., Gotthold, C., Lehrach, H. and Cahill, D. (2000) A system for dual protein expression in Pichia pastoris and Escherichia coli, Protein Expr. Purif., 20, 372- 378 ). Here, the cDNA of a particular tissue in a bacterial or a eukaryotic expression vector, such as. B. yeast, cloned. The vectors used for the expression are generally characterized by the fact that they carry inducible promoters, with which the timing of protein expression can be controlled. In addition, expression vectors have sequences for so-called affinity epitopes or proteins, which on the one hand allow the specific detection of the recombinant fusion proteins by means of an antibody directed against the affinity epitope, on the other hand, the specific purification via affinity chromatography (IMAC) allows.

For example, the gene products of a cDNA expression library of human fetal brain tissue in the bacterial expression system Escherichia coli in high density format were placed on a membrane and successfully screened with different antibodies. It could be shown that the proportion of full-length proteins is at least 66%. In addition, the recombinant proteins from the expression library could be expressed and purified at high throughput ( Brown P., Hu, Y., Shen, B., Halleck, A., Koundinya, M., Harlow, E. and LaBaer, J. (2002) Proteome-scale purification of human protein from bacteria. Proc Natl Acad Sci USA, 99, 2654-2659; Büssow (2000) supra; Lueking, A., Horn, M., Eickhoff, H., Büssow, K., Lehrach, H. and Walter, G. (1999) Protein microarrays for gene expression and antibody screening. Analytical Biochemistry, 270, 103-111 ). Such protein biochips based on cDNA expression libraries are the subject of particular WO 99/57311 and WO 99/57312 ,

Further, in addition to antigen-presenting protein biochips, antibody-presenting arrangements have also been described ( Lal et al (2002) Antibody arrays: An embryonic but growing technology, DDT, 7, 143-149; Kuznetsov et al. (2003), Antibody microarrays: An evaluation of production parameters, Proteo mics, 3, 254-264 ).

It however, there is a high need for indication-specific provide diagnostic devices such as a protein biochip.

marker sequences and their diagnostic use for the rheumatoid Arthritis, especially in the embodiment of a protein biochip as well as related tests for the screening of Active ingredients are not described in the prior art.

The The object of the present invention is therefore the provision of marker sequences and their diagnostic use.

The Provision of specific marker sequences allows a safe Diagnosis and stratification of patients with rheumatoid arthritis, in particular by means of a protein biochip.

Therefore For example, the invention relates to the use of marker sequences for diagnosis of rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-391 or in each case one protein coding for this or one each Partial sequence or fragment thereof (hereinafter: inventive Marker sequences) is determined on a patient to be examined.

The Marker sequences of the invention could by means of differential screening of samples from healthy volunteers with patient samples be identified with rheumatoid arthritis.

The term "Rheumatoid arthritis" is z. B. after Pschyrembel, de Gruyter, 261st edition (2007), Berlin Are defined.

In In another embodiment, at least 2 to 5 or 10, preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences on a patient to be examined.

In a further embodiment of the invention the marker sequences of the invention also combined with known biomarkers for this indication, be supplemented or extended.

In In a preferred embodiment, the determination is made the marker sequences outside the human body and the determination is made in an ex vivo / in vitro diagnosis.

In Another embodiment of the invention relates to Invention the use of marker sequences as diagnostic agents, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-391 or each one coding for it Protein or in each case a partial sequence or fragment thereof.

Further The invention relates to a method for the diagnosis of rheumatoid Arthritis, wherein a.) At least one marker sequence of a cDNA selected from the group SEQ 1-391 or one each for it coding protein or in each case a partial sequence or fragment of which is applied to a solid support and b.) with body fluid or tissue extract one Patient is brought into contact and c.) The evidence of an interaction the body fluid or tissue extract with the Marker sequences from a.) Is done.

Therefore The invention also relates to diagnostic agents for the diagnosis of rheumatoid Arthritis in each case selected from the group SEQ 1-391 or in each case a protein coding for it or in each case a partial sequence or fragment thereof.

Of the Evidence of such interaction can be, for example, by a probe, in particular by an antibody.

Therefore The invention also relates to the task of a diagnostic Device or an assay, in particular a protein biochip, which is used for rheumatoid arthritis Diagnosis or examination allowed.

Furthermore, the invention relates to a method for stratifying, in particular for risk stratification and / or therapy control of a patient with rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-391 or in each case a protein coding for this egg in the patient to be examined.

Further includes stratification of patients with rheumatoid arthritis in new or established subgroups of rheumatoid arthritis, as well the sensible selection of patient groups for clinical development of new therapeutics. The term therapy control also includes the classification of patients into responders and non-responders a therapy or its course of therapy.

"Diagnosis" For the purposes of this invention means the positive finding of rheumatoid arthritis by means of the invention Marker sequences and the assignment of patients to the rheumatoid Arthritis. The term diagnosis includes medical diagnostics and related studies, especially in vitro Diagnostics and laboratory diagnostics, also proteomics and nucleic acid blots. Further investigations can be made for protection and exclusion other diseases are needed. Therefore, the term includes Diagnosis also the differential diagnosis of rheumatoid arthritis by means of the marker sequences according to the invention as well as the prognosis of rheumatoid arthritis.

"Stratify (also: stratification) or therapy control "in the sense of this invention means that the inventive method Decisions to treat and treat the patient, be it hospitalization of the patient, use, effect and / or Dosage of one or more drugs, a therapeutic Measure or monitor disease progression as well as treatment course or etiology or classification a disease, eg. In a new or existing subtype or the differentiation of diseases and their patients.

In Another embodiment of the invention comprises Term "stratification" in particular the risk stratification with the prognosis of an "outcome" of an adverse health Event.

in the For purposes of this invention, "patient" is any Subject - human or mammal - understood, with the proviso that the subject on rheumatoid arthritis is examined.

The term "marker sequences" in the sense of this invention means that the cDNA or the respective polypeptide or protein obtainable therefrom are significant for rheumatoid arthritis For example, the cDNA or the respectively obtainable polypeptide or protein can interact with substances from the body fluid or tissue extract of a Patients with rheumatoid arthritis (eg, antigen (epitope) / antibody (paratope) interaction.) For the purposes of the invention, "at least one marker sequence of a cDNA selected from the group SEQ 1-391 or in each case a protein coding for it or in each case a partial sequence or fragment thereof is determined on a patient to be examined "that an interaction between the body fluid or tissue extract of a patient and the marker sequences according to the invention is detected. Such an interaction is z. B. a bond, in particular a binding substance to at least one marker sequence of the invention or in the case of a cDNA hybridization with a suitable substance under selected conditions, in particular stringent conditions ( z. As commonly defined in J. Sambrook, EF Fritsch, T. Maniatis (1989), Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Habor Laboratory Press, Cold Spring Habor, USA or Ausubel, "Current Protocols in Molecular Biology Green Publishing Associates and Wiley Interscience, NY (1989) ). An example of stringent hybridization conditions is: hybridization in 4 x SSC at 65 ° C (alternatively in 50% formamide and 4 x SSC at 42 ° C), followed by several washes in 0.1 x SSC at 65 ° C for a total of about one Hour. An example of less stringent hybridization conditions is hybridization in 4 x SSC at 37 ° C, followed by several washing steps in 1 x SSC at room temperature.

Such According to the invention, substances are part of a Body fluid, especially blood, whole blood, Blood plasma, blood serum, patient serum, urine, cerebrospinal fluid, Synovial fluid or a tissue extract of the patient.

In a further embodiment of the invention however, the marker sequences according to the invention in a significantly higher or lower expression rate or concentration that is present on rheumatoid arthritis points. This is done by means of proteomics or nucleic acid blots the relative expression rates ill / healthy of the invention Marker sequences for rheumatoid arthritis determined.

The Marker sequences have a further embodiment the invention via a detection signal, which to the the substance to be bound is addressed (eg antibody, nucleic acid). According to the invention is preferred for a Protein the recognition signal an epitope and / or paratope and / or Hapten and for a cDNA a hybridization or binding region.

The marker sequences according to the invention are the subject of Table A and can be identified by the respectively cited database entry (also by means of Internet:
http://www.ncbi.nlm.nih.gov/ ) are clearly identified (see Table A: Accession No. there).

According to the invention the marker sequences also include such modifications of the cDNA sequence and the corresponding amino acid sequence, such as chemical modification, such as citrullination, acetylation, phosphorylation, glycosylation or polyA strand and others relevant to the person skilled in the art known modifications.

In Another embodiment of the invention are also Partial sequences or fragments of the invention Includes marker sequences. In particular, those subsequences, the an identity of 95%, 90%, especially 80% or 70% having the marker sequences according to the invention.

In In another embodiment, the respective marker sequence in different amounts in one or more areas be represented a solid carrier. This allows a variation of sensitivity. The areas can each comprise a total of marker sequences, d. H. a sufficient number of different marker sequences, in particular 2 to 5 or 10 or more and optionally further nucleic acids and / or proteins, especially biomarkers. However, preferred are at least 96 to 25,000 (numerically) or more from different or the same marker sequences and other nucleic acids and / or proteins, especially biomarkers. Further preferred are more than 2,500, more preferably 10,000 or more different or the same marker sequences and, if necessary, further nucleic acids and / or proteins, especially biomarkers.

One Another object of the invention relates to an arrangement of marker sequences containing at least one marker sequence of a cDNA selected from the group SEQ 1-391 or one each for it coding protein. Preferably, the arrangement contains at least 2 to 5 or 10, preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences.

In the context of this invention, "arrangement" synonymously means "array" and insofar as this "array" is used to identify substances to marker sequences, this is to be understood as an "assay" or diagnostic device. In a preferred embodiment, the arrangement is such that the marker sequences represented on the array are in the form of a grid on a solid support. Further, such arrangements are preferred which allow a high density array of protein binders and spotting the marker sequences. Such high-density spotted arrangements are for example in the WO 99/57311 and WO 99/57312 disclosed and may be advantageously used in a robotic automated high-throughput method.

in the However, within the scope of this invention, the term "assay" includes or diagnostic device also such embodiments a device such as ELISA, Bead-based Assay, Line Assay, Western Blot, immunochromatographic methods (eg so-called lateral Flow immunoassays) or similar immunological single or multiplex detection method. A protein biochip in the sense of this Invention is the systematic arrangement of proteins on one solid carrier.

The Marker sequences of the assembly are on a solid support fixed, but preferably spotted or immobilized even printed, d. H. applied reproducibly. One or more marker sequences can multiply in the totality of all marker sequences be present and in different quantities based on have a spot. Furthermore, the marker sequences be standardized on the solid support (eg Serial dilution series of z. B. human globulins as internal calibrators for data normalization and quantitative evaluation).

Therefore For example, the invention relates to an assay or protein biochip from an arrangement containing inventive Marker sequences.

In a further embodiment, the marker sequences are present as clones. Such clones can be obtained, for example, by means of a cDNA expression library according to the invention ( Büssow et al. 1998 (supra) ). In a preferred embodiment, such expression libraries containing clones are obtained by means of expression vectors from an expressing cDNA library consisting of the cDNA marker sequences. These expression vectors preferably contain inducible promoters. The induction of expression may, for. Example by means of an inductor, such as IPTG done. Suitable expression vectors are described in Terpe et al. ( Terpe T Appl Microbiol Biotechnol. 2003 Jan; 60 (5): 523-33 ).

Expression libraries are known in the art, these can according to standard works, such as Sambrook et al, "Molecular Cloning, A laboratory handbook, 2nd edition (1989), CSH press, Cold Spring Harbor, New York getting produced. Further preferred are expression libraries which are tissue-specific (eg human tissue, in particular human organs). Furthermore, according to the invention also such expression libraries are included, which can be obtained by exontrapping. Instead of expression library can be spoken synonymously from an expression bank.

Also preferred are protein biochips or corresponding expression libraries which have no redundancy (so-called: Uniclone ^® library) and according to the teachings of WO 99/57311 and WO 99/57312 for example, can be produced. These preferred Uniclone libraries have a high content of non-defective, fully expressed proteins of a cDNA expression library.

in the Also within the scope of this invention, the clones can not finally, such as transformed bacteria, recombinant phage or transformed mammalian cells, Insects, fungi, yeasts or plants.

The Clones are fixed on a solid support, spotted or immobilized.

Therefore The invention relates to an arrangement wherein the marker sequences exist as clones.

additionally The marker sequences can be in the appropriate form in the form a fusion protein, which, for example, at least contains an affinity epitope or "tag". Of the Day can be such as c-myc, His-tag, Arg-tag, FLAG, alkaline phosphatase, V5 tag, T7 tag or strep tag, HAT tag, NusA, S-tag, SBP-tag, thioredoxin, DsbA, a fusion protein, preferably a cellulose-binding domain, green fluorescent Protein, maltose binding protein, calmodulin binding protein, Glutathione S-transferase or lacZ included.

In All embodiments include the term "solid support" designs such as a filter, a Membrane, a magnetic or fluorophore-labeled bead, a silicon wafer, glass, metal, plastic, a chip, a mass spectrometer Target or a matrix. However, a filter is preferred according to the invention.

When Filter is further preferred PVDF, nitrocellulose or nylon (z. Immobilon P Millipore, Protran Whatman, Hybond N + Amersham).

In a further preferred embodiment of the invention Arrangement this corresponds to a grid that the order of magnitude a microtiter plate (8-12 wells strips, 96 wells, 384 wells or more), a silicon wafer, a chip, one mass spectrometric targets or a matrix.

In In another embodiment, the invention relates to a Assay or protein biochip for identification and characterization a substance for rheumatoid arthritis, characterized that an arrangement or assay according to the invention with a.) At least one substance to be examined in contact and b.) a binding success is detected.

Further The invention relates to a method for identifying and characterizing a substance for rheumatoid arthritis, characterized that an arrangement or assay according to the invention with a.) At least one substance to be examined in contact and b.) a binding success is detected.

The substance to be examined may be any native or non-native Biomolecule, a synthetic chemical molecule, a mixture or substance library.

After this the substance to be examined contacts a marker sequence the evaluation of binding success, for example, using with commercially available image analysis software (GenePix Pro (Axon Laboratories), Aida (Ragtest), ScanArray (Packard Bioscience) he follows.

The visualization of protein-protein interactions according to the invention (for example protein on marker sequence, such as antigen / antibody) or corresponding "means for detecting the binding success" can be carried out, for example, by means of fluorescence labeling, biotinization, radioisotope labeling or colloidal gold or latex Particle labeling is carried out in a conventional manner. Detection of bound antibodies takes place using secondary antibodies labeled with commercial reporter molecules (eg Cy, Alexa, Dyomics, FITC or similar fluorescent dyes, colloidal gold or latex particles), or with reporter enzymes such as alkaline phosphatase, horseradish peroxidase , etc. and the corresponding colorimetric, fluorescent or chemiluminescent substrates. A reading takes place z. Example by means of a microarray laser scanner, a CCD camera or visually.

In In another embodiment, the invention relates to a Drug / drug or prodrug for rheumatoid arthritis developed and available by the use of the invention Assays or protein biochip.

Therefore The invention also relates to the use of an inventive Arrangement or assay for screening drugs for Rheumatoid arthritis.

Therefore relates to the invention in a further embodiment also a target for the treatment and therapy of rheumatoid Arthritis in each case selected from the group SEQ 1-391 or one protein coding for each.

In In another embodiment, the invention also relates the use of the marker sequences according to the invention, preferably in the form of an array, as an affinity material for performing an apheresis or iwS. a blood wash, being substances from body fluids of a Patients with rheumatoid arthritis, such as blood or plasma, to the bind marker sequences of the invention and thus the Body fluid can be selectively withdrawn.

Examples and figures:

ten or more patient samples were individually against a cDNA expression library screened. The rheumatoid arthritis-specific expression clones were determined by comparison with ten or more healthy ones Rehearse. The identity of the marker sequences was determined by DNA sequencing determined.

In 1 For example, differential screening between two protein biochips from each of a patient cDNA expression library and a healthy subject is shown. The differential clones are detected by fluorescence labeling and evaluated bioinformatorisch. Table A: seq No Well Accession No 1 331 00800_506_A06 2 332 00800_506_B06 gi | 5032030 | ref | NM_005778.1 | NM 005778 3 333 00800_506_F07 gi | 68299771 | ref | NM_001069.2 | NM 001069 4 334 00800_506_H06 gi | 29826324 | ref | NM_176801.1 | NM 176801 5 335 00800_506_L05 gi | 38201669 | ref | NM_016162.2 | NM 016162 6 336 00800_506_O02 gi | 4757715 | ref | NM_004890.1 | NM 004890 7 337 00800_506_O22 ref | NM_004559.2 || gi | 34098945 NM 004559 8th 338 00800_507_G20 ref | NM_004559.2 || gi | 34098945 NM 004559 9 339 00800_508_E13 ref | NM_004559.2 || gi | 34098945 NM 004559 10 340 00800_508_J22 ref | NM_004559.2 || gi | 34098945 NM 004559 11 341 00800_508_P06 ref | NM_004559.2 || gi | 34098945 NM 004559 12 342 00800_509_A21 gi | 32129198 | ref | NM_033082.1 | NM 033082 13 343 00800_510_M10 ref | NM_001409.2 || gi | 82524843 NM 001409 14 344 00800_514_C12 15 345 00800_514_C09 gi | 4758647 | ref | NM_004521.1 | NM 004521 16 346 00800_514_E19 gi | 30581140 | ref | NM_176783.1 | NM 176783 17 347 00800_517_F03 ref | NM_007177.1 || gi | 6005923 NM 007177 18 348 00800_517_J22 gi | 34147654 | ref | NM_002866.3 | NM 002866 19 349 00800_517_L10 ref | NM_005463.2 || gi | 14110410 NM 005463 20 350 00800_518_D04 gi | 58219047 | ref | NM_001010926.1 | NM 00101092 21 351 00800_518_F05 gi | 4757715 | ref | NM_004890.1 | NM 004890 22 352 00800_518_O10 gi | 21361156 | ref | NM_004838.2 | NM 004838 23 353 00800_519_B21 gi | 29801560 | ref | NT_011295.10 | Hs19_11452 NT 011295 24 354 00800_519_I19 gi | 56181386 | ref | NM_005861.2 | NM 005861 25 355 00800_519_J13 gi | 38372939 | ref | NM_001185.2 | NM 001185 26 356 00800_519_O15 gi | 89111136 | ref | NM_002475.3 | NM 002475 27 357 00800_520_A20 ref | NM_005463.2 || gi | 14110410 NM 005463 28 358 00800_520_J04 ref | NM_004559.2 || gi | 34098945 NM 004559 29 359 00800_523_J01 ref | | NM_017948.4 | gi | 46048233 NM 017948 30 360 00800_524_A11 ref | NM_182923.2 || gi | 41055203 NM 182923 31 361 00800_524_E08 32 362 00800_524_N07 ref | NM_004559.2 || gi | 34098945 NM 004559 33 363 00800_526_A08 gi | 54607123 | ref | NM_013286.3 | NM 013286 34 364 00800_528_A14 gi | 18390348 | ref | NM_000972.2 | NM 000972 35 365 00800_528_M16 gi | 10518498 | ref | NM_007219.2 | NM 007219 36 366 00800_528_O17 gi | 8051607 | ref | NM_002134.2 | NM 002134 37 367 00800_529_E16 gi | 20127557 | ref | NM_016410.2 | NM 016410 38 368 00800_529_H16 gi | 66392201 | ref | NM_002512.2 | NM 002512 39 369 00800_529_L17 gi | 7524353 | ref | NM_013974.1 | NM 013974 40 370 00800_529_M22 gi | 42544170 | ref | NM_001983.2 | NM 001983 41 371 00800_529_N10 gi | 21389576 | ref | NM_144679.1 | NM 144679 42 372 00800_530_E15 gi | 31341380 | ref | NM_174920.2 | NM 174920 43 373 00800_530_I03 gi | 4507398 | ref | NM_003199.1 | NM 003199 44 374 00800_531_K23 gi | 38679886 | ref | NM_003130.2 | NM 003130 45 375 00800_533_B01 46 376 00800_533_E20 gi | 56181386 | ref | NM_005861.2 | NM 005861 47 377 00800_533_E21 gi | 33286445 | ref | NM_007346.2 | NM 007346 48 378 00800_534_B04 49 379 00800_534_H02 gi | 89030746 | ref | NW_924573.1 | HsCraAAD602_390 NW 924573 50 380 00800_536_L24 gi | 56682958 | ref | NM_002032.2 | NM 002032 51 381 00800_536_P23 gi | 38257138 | ref | NM_002735.1 | NM 002735 52 382 00800_537_C08 gi | 22027497 | ref | NM_012295.2 | NM 012295 53 383 00800_538_C18 ref | NM_005463.2 || gi | 14110410 NM 005463 54 384 00800_538_K19 gi | 49640010 | ref | NM_001001894.1 | NM 001001894 55 385 00800_538_K05 ref | NM_182923.2 || gi | 41055203 NM 182923 56 386 00800_540_B18 ref | NM_005463.2 || gi | 14110410 NM 005463 57 387 00800_540_O08 gi | 83656780 | ref | NM_032025.3 | NM 032025 58 388 00800_541_B06 ref | NM_004559.2 || gi | 34,098,945 NM 004559 59 389 00800_541_G12 gi | 56181386 | ref | NM_005861.2 | NM 005861 60 390 00800_541_H07 gi | 51472974 | ref | NT_010393.15 | Hs16_10550 NT 010393 61 391 00800_541_H09 gi | 89111136 | ref | NM_002475.3 | NM 002475 62 392 00800_542_B07 gi | 113428394 | ref | XM_001129992.1 | XM 001129992 63 393 00800_542_C05 64 394 00800_42_E06 gi | 51472974 | ref | NT_010393.15 | Hs16_10550 NT 010393 65 395 00800_542_I05 ref | NM_004559.2 || gi | 34098945 NM 004559 66 396 00800_542_K03 gi | 83656780 | ref | NM_032025.3 | NM 032025 67 397 00800_544_E09 gi | 89031690 | ref | NT_017795.18 | Hs10_17951 NT 017795 68 398 00800_544_F15 gi | 12056467 | ref | NM_021991.1 | NM 021991 69 399 00800_544_H24 gi | 33286445 | ref | NM_007346.2 | NM 007346 70 400 00800_544_M10 gi | 89040669 | ref | NW_926018.1 | HsCraAAD602_520 NW 926018 71 401 00800_545_C01 gi | 51472974 | ref | NT_010393.15 | Hs16_10550 NT 010393 72 402 00800_545_E24 gi | 89111136 | ref | NM_002475.3 | NM 002475 73 403 00800_545_L14 ref | NM_025112.3 || gi | 50843811 NM 025112 74 404 00800_546_A08 gi | 89060463 | ref | NT_011726.13 | HsX_11883 NT 011726 75 405 00800_546_O15 gi | 71361681 | ref | NM_006185.2 | NM 006185 76 406 00800_547_N20 gi | 56682958 | ref | NM_002032.2 | NM 002032 77 407 00800_548_E10 ref | NM_004559.2 || gi | 34098945 NM 004559 78 408 00800_548_E13 ref | NM_004559.2 || gi | 34098945 NM 004559 79 409 00800_548_F15 gi | 40353728 | ref | NM_024832.3 | NM 024832 80 410 00800_548_J13 ref | NM_004559.2 || gi | 34098945 NM 004559 81 411 00800_548_J09 ref | NM_004559.2 || gi | 34098945 NM 004559 82 412 00800_549_D02 ref | NM_005463.2 || gi | 14110410 NM 005463 83 413 00800_549_H12 84 414 00800_549_N17 gi | 113430465 | ref | XR_018762.1 | XR 018762 85 415 00800_549_P03 gi | 42490757 | ref | NM_001789.2 | NM 001789 86 416 00800_550_A02 gi | 7705480 | ref | NM_016406.1 | NM 016406 87 417 00800_550_C08 88 418 00800_551_L21 gi | 56181386 | ref | NM_005861.2 | NM 005861 89 419 00800_552_D16 gi | 31317308 | ref | NM_012398.1 | NM 012398 90 420 00800_552_D02 ref | NM_004573.1 || gi | 4758937 NM 004573 91 421 00800_553_C06 gi | 47519746 | ref | NM_002751.5 | NM 002751 92 422 00800_553_E11 gi | 5032030 | ref | NM_005778.1 | NM 005778 93 423 00800_554_E05 gi | 17149845 | ref | NM_002013.2 | NM 002013 94 424 00800_554_G09 gi | 71361681 | ref | NM_006185.2 | NM 006185 95 425 00800_554_P20 gi | 89040669 | ref | NW_926018.1 | HsCraAADB02_520 NW 926018 96 426 00800_556_D15 gi | 89057118 | ref | NW_927173.1 | HsCraAADB02_624 NW 927173 97 427 00800_556_G22 gi | 113411825 | ref | XM_001126014.1 | XM 001126014 98 428 00800_556_J06 gi | 113428394 | ref | XM_001129992.1 | XM 001129992 99 429 00800_557_C03 ref | NM_004559.2 || gi | 34098945 NM 004559 100 430 00800_557_C07 ref | NM_004559.2 || gi | 34098945 NM 004559 101 431 00800_558_I07 ref | NM_004559.2 || gi | 34098945 NM 004559 102 432 00800_558_M02 gi | 56181386 | ref | NM_005861.2 | NM 005861 103 433 00800_559_B17 gi | 34147654 | ref | NM_002866.3 | NM 002866 104 434 00800_562_D06 gi | 22202618 | ref | NM_145918.1 | NM 145918 105 435 00800_562_N06 ref | NM_004559.2 || gi | 34098945 NM 004559 106 436 00800_562_O08 ref | NM_004559.2 || gi | 34098945 NM 004559 107 437 00800_562_P08 ref | NM_004559.2 || gi | 34098945 NM 004559 108 438 00800_563_H18 gi | 89040669 | ref | NW_926018.1 | HsCraAADB02_520 NW 926018 109 439 00800_564_J03 gi | 113428394 | ref | XM_001129992.1 | XM 001129992 110 440 00800_566_M11 gi | 83367078 | ref | NM_001402.5 | NM 001402 111 441 00800_568_J19 ref | NM_005463.2 || gi | 14110410 NM 005463 112 442 00800_568_L02 gi | 5032030 | ref | NM_005778.1 | NM 005778 113 443 00800_568_M18 ref | NM_002383.1 || gi | 13399295 NM 002383 114 444 00800_573_P23 ref | NM_016474.3 || gi | 31652250 NM 016474 115 445 00800_574_C10 gi | 33636763 | ref | NM_152345.3 | NM 152345 116 446 00800_574_G23 gi | 22202618 | ref | NM_145918.1 | NM 145918 117 447 00800_574_P09 gi | 54124342 | ref | NM_001005751.1 | NM 001005751 118 448 00800_577_A01 ref | NM_004559.2 || gi | 34098945 NM 004559 119 449 00800_577_I11 gi | 34335231 | ref | NM_001823.3 | NM 001823 120 450 00800_577_I13 ref | NM_004559.2 || gi | 34098945 NM 004559 121 451 00800_577_I14 ref | NM_005463.2 || gi | 14110410 NM 005463 122 452 00800_577_I16 ref | NM_001416.1 || gi | 4503528 NM 001416 123 453 00800_578_A04 gi | 113423957 | ref | XM_001132864.1 | XM 001132864 124 454 00800_578_C07 ref | NM_004559.2 || gi | 34098945 NM 004559 125 455 00800_578_G10 gi | 34335231 | ref | NM_001823.3 | NM 001823 126 456 00800_578_I17 ref | | NT_023666.17 | Hs8_23822 gi | 51466739 NT 023666 127 457 00800_578_I19 gi | 38201669 | ref | NM_016162.2 | NM 016162 128 458 00800_578_K04 ref | NM_004559.2 || gi | 34098945 NM 004559 129 459 00800_578_L14 gi | 38201669 | ref | NM_016162.2 | NM 016162 130 460 00800_578_N23 gi | 21361946 | ref | NM_030795.2 | NM 030795 131 461 00800_579_P10 ref | NM_001018097.1 || gi | 70166553 NM 001018097 132 462 00800_580_K15 gi | 68299771 | ref | NM_001069.2 | NM 001069 133 463 00800_580_P08 ref | NM_002383.1 || gi | 13399295 NM 002383 134 464 00800_581_N12 ref | NM_005463.2 || gi | 14110410 NM 005463 135 465 00800_581_P18 gi | 68299771 | ref | NM_001069.2 | NM 001069 136 466 00800_582_I11 gi | 89059359 | ref | NW_927628.1 | HsCraAADB02_665 NW 927628 137 467 00800_582_I09 gi | 56682958 | ref | NM_002032.2 | NM 002032 138 468 00800_583_A21 139 469 00800_583_E11 140 470 00800_583_E13 gi | 22212941 | ref | NM_016525.3 | NM 016525 141 471 00800_583_E07 142 472 00800_584_G07 gi | 57242754 | ref | NM_014944.3 | NM 014944 143 473 00800_584_J06 gi | 55925645 | ref | NM_014412.2 | NM 014412 144 474 00800_586_M11 gi | 23111017 | ref | NM_152856.1 | NM 152856 145 475 00800_586_M03 ref | NM_005463.2 || gi | 14110410 NM 005463 146 476 00800_587_A08 147 477 00800_587_C18 gi | 46391095 | ref | NM_152479.3 | NM 152479 148 478 00800_589_A19 gi | 40807453 | ref | NM_003434.3 | NM 003434 149 479 00800_589_A21 gi | 40807453 | ref | NM_003434.3 | NM 003434 150 480 00800_589_A07 gi | 57617038 | ref | NM_015140.2 | NM 015140 151 481 00800_589_F18 ref | NM_004559.2 || gi | 34098945 NM 004559 152 482 00800_589_L01 gi | 113430220 | ref | XM_377073.3 | XM 377073 153 483 00800_590_A24 gi | 13128995 | ref | NM_024040.1 | NM 024040 154 484 00800_590_C18 gi | 7705480 | ref | NM_016406.1 | NM 016406 155 485 00800_590_H21 gi | 51173146 | ref | NM_000232.3 | NM 000232 156 486 00800_590_O04 ref | NM_004559.2 || gi | 34098945 NM 004559 157 487 00800_591_D23 gi | 38679886 | ref | NM_003130.2 | NM 003130 158 488 00800_591_F16 ref | NM_005463.2 || gi | 14110410 NM 005463 159 489 00800_591_H12 gi | 58219047 | ref | NM_001010926.1 | NM 001010926 160 490 00800_591_K11 gi | 21464122 | ref | NM_003926.5 | NM 003926 161 491 00800_592_116 gi | 89111136 | ref | NM_002475.3 | NM 002475 162 492 00800_592_M16 gi | 34335231 | ref | NM_001823.3 | NM 001823 163 493 00800_594_A04 ref | NM_004559.2 || gi | 34098945 NM 004559 164 494 00800_594_C21 gi | 94721349 | ref | NM_004968.2 | NM 004968 165 495 00800_594_O02 ref | NM_004559.2 || gi | 34098945 NM 004559 166 496 00800_594_L21 gi | 34335231 | ref | NM_001823.3 | NM 001823 167 497 00800_594_M03 gi | 16554608 | ref | NM_022839.2 | NM 022839 168 498 00800_595_B19 gi | 47894110 | ref | NM_032246.3 | NM 032246 169 499 00800_595_K14 gi | 33286421 | ref | NM_182471.1 | NM 182471 170 500 00800_595_P16 gi | 56181386 | ref | NM_005861.2 | NM 005861 171 501 00800_596_F13 ref | NM_002306.1 || gi | 4504982 NM 002306 172 502 00800_596_F24 gi | 113423896 | ref | XM_942556.2 | XM 942556 173 503 00800_596_N21 ref | | NM_018434.4 | gi | 38176162 NM 018434 174 504 00800_596_P02 gi | 23111046 | ref | NM_152227.1 | NM 152227 175 505 00800_598_E15 ref | NM_004559.2 || gi | 34098945 NM 004559 176 506 00800_598_G03 gi | 45439300 | ref | NM_006352.3 | NM 006352 177 507 00800_598_H13 178 508 00800_598_L23 179 509 00800_598_L08 180 510 00800_598_M20 gi | 89057118 | ref | NW_927173.1 | HsCraAAD602_624 NW 927173 181 511 00800_598_O05 gi | 34335231 | ref | NM_001823.3 | NM 001823 182 512 00800_598_P19 ref | NM_004559.2 || gi | 34098945 NM 004559 183 513 00800_599_H07 ref | NM_004559.2 || gi | 34098945 NM 004559 184 514 00800_599_N03 gi | 83641890 | ref | NM_002046.3 | NM 002046 185 515 00800_599_P14 ref | NM_182923.2 || gi | 41,055,203 NM 182923 186 516 00800_600_E13 gi | 89111136 | ref | NM_002475.3 | NM 002475 187 517 00800_600_J10 188 518 00800_600_N24 gi | 4502004 | ref | NM_001622.1 | NM 001622 189 519 00800_600_N08 gi | 16306505 | ref | NM_012115.2 | NM 012115 190 520 00800_601_C03 gi | 34147654 | ref | NM_002866.3 | NM 002866 191 521 00800_601_D08 gi | 56181386 | ref | NM_005861.2 | NM 005861 192 522 00800_601_E12 gi | 32129198 | ref | NM_033082.1 | NM 033082 193 523 00800_601_G18 gi | 51036581 | ref | NM_015330.1 | NM 015330 194 524 00800_601_P03 gi | 4758219 | ref | NM_004699.1 | NM 004699 195 525 00800_602_I09 ref | NM_004559.2 || gi | 34098945 NM 004559 196 786 00800_505_I09 gi | 27764862 | ref | NM_001636.1 | NM 001636 197 787 00800_506_M11 gi | 88942368 | ref | NT_021937.18 | Hs1_22093 NT 021937 198 788 00800_507_I08 199 789 00800_507_M15 gi | 46370065 | ref | NM_000127.2 | NM 000127 200. 790 00800_508_J06 gi | 50086623 | ref | NM_033547.3 | NM 033547 201 791 00800_509_D09 gi | 8392890 | ref | NM_000477.3 | NM 000477 202 792 00800_509_O21 gi | 51473210 | ref | NT_037887.4 | Hs16_37891 NT 037887 203 793 00800_512_O19 ref | NM_006160.2 || gi | 21314637 NM 006160 204 794 00800_513_E09 205 795 00800_513_M16 gi | 20302149 | ref | NM_007260.2 | NM 007260 206 796 00800_513_M06 gi | 57222567 | ref | NM_005937.2 | NM 005937 207 797 00800_513_N07 gi | 37546193 | ref | NT_011630.14 | HsX_11787 NT 011630 208 798 00800_514_A15 gi | 22219473 | ref | NM_003824.2 | NM 003824 209 799 00800_515_C22 210 800 00800_517_F04 ref | | NT_008413.17 | Hs9_8570 gi | 89029256 NT 008413 211 801 00800_523_B20 ref | | NT_009775.16 | Hs12_9932 gi | 89035772 NT 009775 212 802 00800_523_I13 gi | 31543190 | ref | NM_032333.2 | NM 032333 213 803 00800_524_D10 gi | 40807483 | ref | NM_030815.2 | NM 030815 214 804 00800_524_E18 gi | 30581146 | ref | NM_006814.2 | NM 006814 215 805 00800_524_E24 gi | 38201669 | ref | NM_016162.2 | NM 016162 216 806 00800_526_A22 gi | 86788141 | ref | NM_130442.2 | NM 130442 217 807 00800_526_C01 218 808 00800_526_O05 gi | 66392201 | ref | NM_002512.2 | NM 002512 219 809 00800_528_D24 gi | 51317357 | ref | NM_052880.3 | NM 052880 220 810 00800_528_H06 gi | 83641894 | ref | NM_031157.2 | NM 031157 221 811 00800_528_L06 gi | 10938021 | ref | NM_006367.2 | NM 006367 222 812 00800_528_M21 gi | 24234719 | ref | NM_005494.2 | NM 005494 223 813 00800_529_F03 gi | 113428394 | ref | XM_001129992.1 | XM 001129992 224 814 00800_529_I14 gi | 66346647 | ref | NM_147780.2 | NM 147780 225 815 00800_529_J10 gi | 24308369 | ref | NM_152395.1 | NM 152395 226 816 00800_529_M18 gi | 21361946 | ref | NM_030795.2 | NM 030795 227 817 00800_529_P23 gi | 6912539 | ref | NM_012225.1 | NM 012225 228 818 00800_532_119 gi | 42794610 | ref | NM_012088.2 | NM 012088 229 819 00800_533_B08 gi | 4507284 | ref | NM_003765.1 | NM 003765 230 820 00800_533_J24 ref | | NT_007592.14 | Hs6_7749 gi | 51465675 NT 007592 231 821 00800_536_F02 gi | 33598947 | ref | NM_002660.2 | NM 002660 232 822 00800_537_D14 233 823 00800_537_N15 gi | 56676308 | ref | NM_006221.2 | NM 006221 234 824 00800_538_N11 235 825 00800_540_H17 236 826 00800_540_P11 gi | 22219473 | ref | NM_003824.2 | NM 003824 237 827 00800_541_E17 238 828 00800_541_M17 gi | 4503580 | ref | NM_001978.1 | NM 001978 239 829 00800_544_D23 240 830 00800_546_A20 gi | 42794610 | ref | NM_012088.2 | NM 012088 241 831 00800_546_O05 gi | 49640010 | ref | NM_001001894.1 | NM 001001894 242 832 00800_548_A24 gi | 67906194 | ref | NM_173551.3 | NM 173551 243 833 00800_549_K24 244 834 00800_549_M24 245 835 00800_550_C21 ref | | NM_005474.4 | gi | 62750346 NM 005474 246 836 00800_552_K06 247 837 00800_556_H09 248 838 00800_562_A13 gi | 113428396 | ref | XM_939572.2 | XM 939572 249 839 00800_562_M15 ref | | NT_007933.14 | Hs7_8090 gi | 51493052 NT 007933 250 840 00800_563_J13 gi | 42794610 | ref | NM_012088.2 | NM 012088 251 841 00800_565_H12 gi | 89059057 | ref | NT_019197.5 | Hs22_19353 NT 019197 252 842 00800_566_E12 ref | | NM_032019.4 | gi | 41393569 NM 032019 253 843 00800_566_K12 ref | NM_004192.1 || gi | 4757793 NM 004192 254 844 00800_566_K23 gi | 93141017 | ref | NM_138610.2 | NM 138610 255 845 00800_568_A22 gi | 83721968 | ref | NM_001024678.2 | NM 001024678 256 846 00800_568_O18 257 847 00800_570_E19 gi | 29801560 | ref | NT_011295.10 | Hs19_11452 NT 011295 258 848 00800_570_M06 gi | 51470970 | ref | NT_009237.17 | Hs1 1_9394 NT 009237 259 849 00800_572_P18 gi | 29789113 | ref | NM_020773.1 | NM 020773 260 850 00800_573_F24 gi | 92859661 | ref | NM_005090.2 | NM 005090 261 851 00800_573_I17 262 852 00800_574_D01 gi | 21361946 | ref | NM_030795.2 | NM 030795 263 853 00800_577_C12 gi | 22027621 | ref | NM_004295.2 | NM 004295 264 854 00800_577_I10 gi | 31543652 | ref | NM_003134.2 | NM 003134 265 855 00800_577_L03 gi | 113428394 | ref | XM_001129992.1 | XM 001129992 266 856 00800_577_M06 gi | 4503816 | ref | NM_002035.1 | NM 002035 267 857 00800_578_J08 268 858 00800_579_A06 269 859 00800_579_L22 gi | 23510452 | ref | NM_021149.2 | NM 021149 270 860 00800_581_K11 gi | 42476152 | ref | NM_002825.5 | NM 002825 271 861 00800_581_L04 gi | 32880228 | ref | NM_031454.1 | NM 031454 272 862 00800_582_C24 gi | 51464299 | ref | NT_022778.15 | Hs4_22934 NT 022778 273 863 00800_582_M05 274 864 00800_584_D05 gi | 31343485 | ref | NM_178841.2 | NM 178841 275 865 00800_586_C17 gi | 83656775 | ref | NM_001961.3 | NM 001961 276 866 00800_586_C23 277 867 00800_587_P09 gi | 90903236 | ref | NM_002085.3 | NM 002085 278 868 00800_589_C07 gi | 22219473 | ref | NM_003824.2 | NM 003824 279 869 00800_589_N14 gi | 47519746 | ref | NM_002751.5 | NM 002751 280 870 00800_590_K13 gi | 6912539 | ref | NM_012225.1 | NM 012225 281 871 00800_590_L02 gi | 23238257 | ref | NM_152247.1 | NM 152247 282 872 00800_591_F21 gi | 113426244 | ref | XM_926195.2 | XM 926195 283 873 00800_592_M14 gi | 4505904 | ref | NM_002676.1 | NM 002676 284 874 00800_594_G16 gi | 113423859 | ref | XM_944677.2 | XM 944677 285 875 00800_594_P22 gi | 40807483 | ref | NM_030815.2 | NM 30815 286 876 00800_595_H19 gi | 56549124 | ref | NM_001005362.1 | NM 001005362 287 877 00800_595_L06 gi | 89041118 | ref | NW_926561.1 | HsCraAAD602_569 NW 926561 288 878 00800_596_C04 gi | 14670374 | ref | NM_015894.2 | NM 015894 289 879 00800_596_D22 gi | 89060463 | ref | NT_011726.13 | HsX_11883 NT 011726 290 880 00800_596_J07 gi | 72534659 | ref | NM_001031684.1 | NM 001031684 291 881 00800_596_M11 gi | 27501067 | ref | NT_011387.8 | Hs20_11544 NT 011387 292 882 00800_597_A10 gi | 39725675 | ref | NM_005851.3 | NM 005851 293 883 00800_597_K23 gi | 113428756 | ref | XM_001128735.1 | XM 001128735 294 884 00800_597_L02 gi | 50234883 | ref | NM_018083.3 | NM 018083 295 885 00800_598_I01 gi | 40807483 | ref | NM_030815.2 | NM 030815 296 886 00800_598_M18 gi | 33591068 | ref | NM_000386.2 | NM 000386 297 887 00800_599_I11 gi | 47933378 | ref | NM_003827.2 | NM 003827 298 888 00800_599_K21 299 889 00800_600_C22 gi | 51473128 | ref | NT_010542.15 | Hs16_10699 NT 010542 300 890 00800_601_N15 gi | 50592995 | ref | NM_006086.2 | NM 006086 301 891 00800_603_N12 gi | 89028628 | ref | NW_923907.1 | HsCraAAD602_330 NW 923907 302 1082 00800_505_B21 gi | 57165374 | ref | NM_001009184.1 | NM 001009184 303 1083 00800_505_H09 304 1084 00800_506_A09 305 1085 00800_509_N24 ref | | NM_004099.4 | gi | 38016910 NM 004099 306 1086 00800_510_B13 307 1087 00800_510_P22 gi | 89059606 | ref | NT_079573.3 | HsX_79638 NT 079573 308 1088 00800_511_J11 gi | 67189547 | ref | NM_000970.3 | NM 000970 309 1089 00800_515_G12 gi | 23111053 | ref | NM_015976.2 | NM 015976 310 1090 00800_517_F13 gi | 27436942 | ref | NM_021976.3 | NM 021976 311 1091 00800_523_H14 gi | 7705806 | ref | NM_016035.1 | NM 016035 312 1092 00800_523_L07 313 1093 00800_523_P23 gi | 83921601 | ref | NM_001037984.1 | NM 001037984 314 1094 00800_525_D02 gi | 38788318 | ref | NM_005275.2 | NM 005275 315 1095 00800_526_D14 ref | | NT_006713.14 | Hs5_6870 gi | 51465008 NT 006713 316 1096 00800_526_D09 gi | 42544158 | ref | NM_006644.2 | NM 006644 317 1097 00800_526_O19 gi | 30026033 | ref | NM_178148.1 | NM 178148 318 1098 00800_528_J11 319 1099 00800_528_N06 gi | 38524584 | ref | NM_024407.3 | NM 024407 320 1100 00800_528_P11 gi | 38257138 | ref | NM_002735.1 | NM 002735 321 1101 00800_530_H15 322 1102 00800_532_H21 323 1103 00800_533_F23 gi | 45359857 | ref | NM_002086.3 | NM 002086 324 1104 00800_538_I10 325 1105 00800_538_O16 326 1106 00800_540_L07 gi | 71773207 | ref | NM_000683.3 | NM 000683 327 1107 00800_541_P01 gi | 7705806 | ref | NM_016035.1 | NM 016035 328 1108 00800_541_P08 gi | 19743568 | ref | NM_004180.2 | NM 004180 329 1109 00800_545_I22 ref | NM_020166.2 || gi | 13518227 NM 020166 330 1110 00800_545_O21 331 1111 00800_547_J22 gi | 88944472 | ref | NW_921350.1 | HsCraAADB02_1 NW 921350 332 1112 00800_548_B04 gi | 7705806 | ref | NM_016035.1 | NM 016035 333 1113 00800_549_G07 gi | 113427446 | ref | XM_941435.2 | XM 941435 334 1114 00800_550_B21 ref | | NM_005474.4 | gi | 62750346 NM 005474 335 1115 00800_551_A12 gi | 15718669 | ref | NM_000681.2 | NM 000681 336 1116 00800_551_B22 gi | 4503816 | ref | NM_002035.1 | NM 002035 337 1117 00800_551_D04 338 1118 00800_556_J21 gi | 7705964 | ref | NM_016372.1 | NM 016372 339 1119 00800_557_I16 gi | 22538469 | ref | NM_005442.2 | NM 005442 340 1120 00800_558_L22 341 1121 00800_561_L03 ref | | NT_009237.17 | Hs11_9394 gi | 51470970 NT 009237 342 1122 00800_564_O09 343 1123 00800_566_K09 ref | NM_152600.1 || gi | 22749232 NM 152600 344 1124 00800_569_A13 gi | 113427260 | ref | XM_941783.2 | XM 941783 345 1125 00800_569_105 ref | NM_006058.2 || gi | 21361267 NM 006058 346 1126 00800_570_H05 ref | | NT_035014.4 | Hs9_35176 gi | 51467290 NT 035014 347 1127 00800_571_L02 ref | NM_006034.2 || gi | 33695116 NM 006034 348 1128 00800_574_D19 gi | 20302149 | ref | NM_007260.2 | NM 007260 349 1129 00800_577_A10 gi | 7705964 | ref | NM_016372.1 | NM 016372 350 1130 00800_577_P22 ref | | NM_001780.4 | gi | 91199544 NM 001780 351 1131 00800_578_L03 ref | NM_000182.3 || gi | 37059733 NM 000182 352 1132 00800_579_A01 gi | 12597634 | ref | NM_022898.1 | NM 022898 353 1133 00800_581_A14 gi | 6857798 | ref | NM_006667.2 | NM 006667 354 1134 00800_581_D11 355 1135 00800_581_J21 356 1136 00800_582_B01 357 1137 00800_582_H11 gi | 22748870 | ref | NM_152411.1 | NM 152411 358 1138 00800_582_K06 gi | 17981697 | ref | NM_001262.2 | NM 001262 359 1139 00800_583_B14 gi | 21389314 | ref | NM_005984.1 | NM 005984 360 1140 00800_583_D15 361 1141 00800_583_D23 gi | 39725935 | ref | NM_016930.2 | NM 016930 362 1142 00800_583_H16 363 1143 00800_583_K19 gi | 34222326 | ref | NM_015980.3 | NM 015980 364 1144 00800_584_J19 ref | | NT_007933.14 | Hs7_8090 gi | 51493052 NT 007933 365 1145 00800_584_N22 gi | 11034854 | ref | NM_020644.1 | NM 020644 366 1146 00800_585_E05 gi | 21265103 | ref | NM_004615.2 | NM 004615 367 1147 00800_585_K18 gi | 88977422 | ref | NT_016354.18 | Hs4_16510 NT 016354 368 1148 00800_586_O14 gi | 49574506 | ref | NM_016645.2 | NM 016645 369 1149 00800_588_K07 370 1150 00800_592_E20 371 1151 00800_592_F21 gi | 14149778 | ref | NM_032125.1 | NM 032125 372 1152 00800_592_K11 gi | 20336240 | ref | NM_013271.2 | NM 013271 373 1153 00800_592_K06 gi | 68299771 | ref | NM_001069.2 | NM 001069 374 1154 00800_593_C06 gi | 4506970 | ref | NM_003049.1 | NM 003049 375 1155 00800_595_L13 376 1156 00800_597_B24 gi | 40804743 | ref | NM_017789.3 | NM 017789 377 1157 00800_597_N16 gi | 51475307 | ref | NT_011515.11 | Hs21_11672 NT 011515 378 1158 00800_599_M06 gi | 46430498 | ref | NM_021975.2 | NM 021975 379 1159 00800_599_P10 ref | NM_015125.2 || gi | 16507207 NM 015125 380 1160 00800_600_C16 gi | 41872442 | ref | NM_199368.1 | NM 199368 381 1161 00800_600_D09 gi | 21359925 | ref | NM_018200.2 | NM 018200 382 1162 00800_600_J18 gi | 34222374 | Ref | NM_182563.2 | NM 182563 383 1163 00800_600_O12 gi | 16306547 | ref | NM_006513.2 | NM 006513 384 1164 00800_601_H17 gi | 22094134 | ref | NM_032482.1 | NM 032482 385 1165 00800_602_B09 ref | NM_004559.2 || gi | 34098945 NM 004559 386 1166 00800_602_I05 ref | NM_004559.2 || gi | 34098945 NM 004559 387 1167 00800_602_J21 gi | 4504752 | ref | NM_002206.1 | NM 002206 388 1168 00800_602_K08 gi | 40807499 | ref | NM_014458.3 | NM 014458 389 1169 00800_602_L12 390 1170 00800_602_L21 ref | NM_138493.1 || gi | 63003893 NM 138493 391 1171 00800_603_O13

It follows Sequence listing according to WIPO St. 25. This can of the official publication platform of the DPMA become.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 99/57311 [0004, 0036, 0042]
• WO 99/57312 [0004, 0036, 0042]

Cited non-patent literature

• Heyman, JA, Cornthwaite, J., Foncerrada, L., Gilmore, JR, Gontang, E., Hartman, KJ, Hernandez, CL, Hood, R., Hull, HM, Lee, WY, Marcil, R. Marsh, EJ, Mudd, KM, Patino, MJ, Purcell, TJ, Rowland, JJ, Sindici, ML and Hoeffler, JP (1999) Genome-scale cloning and expression of individual open reading frames using topoisomerase I-mediated ligation. Genome Res, 9, 383-392; Kersten, B., Feilner, T., Kramer, A., Wehrmeyer, S., Possling, A., Witt, I., Zanor, MI, Stracke, R., Lueking, A., Kreutzberger, J., Lehrach , H. and Cahill, DJ (2003) Generation of Arabidopsis Protein Chip for Antibody and Serum Screening. Plant Molecular Biology, 52, 999-1010; Reboul, J., Vaglio, P., Rual, JF, Lamesch, P., Martinez, M., Armstrong, CM, Li, S., Jacotot, L., Bertin, N., Janky, R., Moore, T., Hudson, JR, Jr., Hartley, JL, Brasch, MA, Vandenhaute, J., Boulton, S., Endress, GA, Jenna, S., Chevet, E., Papasotiropoulos, V., Tolias, PP , Ptacek, J., Snyder, M., Huang, R., Chance, MR, Lee, H., Doucette strain, L., Hill, DE and Vidal, M. (2003) C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression. Nat Genet, 34, 35-41; Walhout, AJ, Temple, GF, Brasch, MA, Hartley, JL, Lorson, MA, van den Heuvel, S. and Vidal, M. (2000) GATEWAY recombinational cloning: application to the cloning of large numbers of open reading frames ORFeomes. Methods Enzymol, 328, 575-592 [0003]
• Büssow, K., Cahill, D., Nietfeld, W., Bancroft, D., Scherzinger, E., Lehrach, H. and Walter, G. (1998) A method for global protein expression and antibody screening at high density filters of an arrayed cDNA library. Nucleic Acids Research, 26, 5007-5008; Büssow, K., Nordhoff, E., Lübbert, C., Lehrach, H. and Walter, G. (2000) A human cDNA library for high-throughput protein expression screening. Genomics, 65, 1-8; Holz, C., Lueking, A., Bovekamp, L., Gutjahr, C., Bolotina, N., Lehrach, H. and Cahill, DJ (2001) A human cDNA expression library in yeast enriched for open reading frames. Genome Res, 11, 1730-1735; Lueking, A., Holz, C., Gotthold, C., Lehrach, H. and Cahill, D. (2000) A system for dual protein expression in Pichia pastoris and Escherichia coli, Protein Expr. Purif., 20, 372- 378 [0003]
• Brown P., Hu, Y., Shen, B., Halleck, A., Koundinya, M., Harlow, E. and LaBaer, J. (2002) Proteome-scale purification of human protein from bacteria. Proc Natl Acad Sci USA, 99, 2654-2659; Büssow (2000) supra; Lueking, A., Horn, M., Eickhoff, H., Büssow, K., Lehrach, H. and Walter, G. (1999) Protein microarrays for gene expression and antibody screening. Analytical Biochemistry, 270, 103-111 [0004]
• Lal et al (2002) Antibody arrays: An embryonic but growing technology, DDT, 7, 143-149; Kuznetsov et al. (2003), Antibody microarrays: An evaluation of production parameters, Proteomics, 3, 254-264 [0005]
• - "rheumatoid arthritis" [0012]
• - Pschyrembel, de Gruyter, 261st edition (2007), Berlin [0012]
• - z. As commonly defined in J. Sambrook, EF Fritsch, T. Maniatis (1989), Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Habor Laboratory Press, Cold Spring Habor, USA or Ausubel, "Current Protocols in Molecular Biology Green Publishing Associates and Wiley Interscience, NY (1989) [0027]
• - http://www.ncbi.nlm.nih.gov/ [0031]
• - Büssow et al. 1998 (supra) [0040]
• - Terpe T Appl Microbiol Biotechnol. 2003 Jan; 60 (5): 523-33 [0040]
• Sambrook et al, "Molecular Cloning, A laboratory handbook, 2nd edition (1989), CSH press, Cold Spring Harbor, New York [0041]

Claims (17)

Use of the marker sequences for the diagnosis of rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-391 or in each case one protein coding for this or one each Partial sequence or fragment thereof on a patient to be examined is determined. Use of the marker sequences for the diagnosis of rheumatoid Arthritis according to claim 1, characterized in that at least 2 to 5 or 10, preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences on a patient to be examined is determined. Use of the marker sequences for the diagnosis of rheumatoid Arthritis according to claim 1 or 2, characterized in that the Determination by means of in-vitro diagnosis. Use of a marker sequence of a cDNA, respectively selected from the group SEQ 1-391 or respectively a protein coding for it or in each case a partial sequence or fragment thereof as a diagnostic. Use of the marker sequences for the diagnosis of rheumatoid Arthritis according to one of the preceding claims, characterized characterized in that the marker sequences are on a solid support be applied, in particular a filter, a membrane, a magnetic or fluorophore-labeled bead, a Silicon wafer, glass, metal, plastic, a chip, a mass spectrometric Target or a matrix. Method for the diagnosis of rheumatoid arthritis, in which a.) at least one marker sequence of a cDNA selected from the group SEQ 1-391 or in each case one coding for it Protein or in each case a partial sequence or fragment thereof on a solid support is applied and b.) with body fluid or tissue extract of a patient is brought into contact and c.) the proof of an interaction of the body fluid or tissue extract with the marker sequences from a.). Method for stratifying, in particular for risk stratification, or for therapy control of a patient with rheumatoid arthritis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-391 or one each for it coding protein or in each case a partial sequence or fragment thereof is determined on a patient to be examined. The method of claim 7, wherein the stratifying or the therapy control decisions for treatment and therapy of the patient, in particular hospitalization of the patient, use, Action and / or dosage of one or more drugs, one therapeutic measure or the monitoring of a Disease course and therapy course, etiology or Classification of a disease including prognosis includes. Arrangement of marker sequences containing at least a marker sequence of a cDNA selected from the group SEQ 1-391 or each protein coding for it. Arrangement according to claim 9, characterized that at least 2 to 5 or 10, preferably 30 to 50 marker sequences or 50 to 100 or more marker sequences are included. Arrangement according to claim 9, characterized that the marker sequences are present as clones. Assay, protein biochip consisting of an assembly according to claim 9, characterized in that the marker sequences are applied to a solid support. Use of an arrangement according to one of the claims 9 to 11 or an assay according to claim 12 for identifying and Characterizing a substance for rheumatoid arthritis containing means for detecting a binding success, characterized that an assembly or assay with a.) at least one to be examined Substance is brought into contact and b.) A binding success is detected. Use of an arrangement according to one of the claims 9 to 11 or an assay according to claim 12 for the screening of drugs for rheumatoid arthritis. Diagnostics for the diagnosis of rheumatoid arthritis each selected from the group SEQ 1-391 or in each case one protein coding for this or one each Partial sequence or fragment thereof. Target for the treatment and therapy of rheumatoid Arthritis in each case selected from the group SEQ 1-391 or in each case a protein coding for it or in each case a partial sequence or fragment thereof. Use of a marker sequence of a cDNA selected from the group SEQ 1-391 or one each for it coding protein or in each case a partial sequence or fragment thereof as an affinity material for carrying out an apheresis or blood wash for patients with rheumatoid arthritis.