WO2015091524A1 - Polymorphismes pour le diagnostic de la polyarthrite rhumatoïde - Google Patents

Polymorphismes pour le diagnostic de la polyarthrite rhumatoïde Download PDF

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WO2015091524A1
WO2015091524A1 PCT/EP2014/078028 EP2014078028W WO2015091524A1 WO 2015091524 A1 WO2015091524 A1 WO 2015091524A1 EP 2014078028 W EP2014078028 W EP 2014078028W WO 2015091524 A1 WO2015091524 A1 WO 2015091524A1
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rsl
risk
allele
rheumatoid arthritis
spp1
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Philippe DIEUDE
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Diderot - Paris 7
Assistance Publique-Hôpitaux De Paris (Aphp)
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    • C—CHEMISTRY; METALLURGY
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    • 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

  • the invention is in the field of Rheumatoid arthritis (RA) diagnosis.
  • the invention relates to specific combination of allelic variant in single nucleotide polymorphisms (SNPs) in the human genome and their association with Rheumatoid arthritis (RA).
  • SNPs single nucleotide polymorphisms
  • Rheumatoid arthritis is a common, complex disease affecting 0.5% to 1% of the population. It is an autoimmune disease characterized by persistent synovitis, destruction of synovial joints, systemic inflammation and expression of autoantibodies. It can be subdivided clinically by the presence or absence of autoantibodies directed against the Fc portion of immunoglobulins (rheumatoid factor [RF]) and against citrullinated peptides (anti- citrullinated peptide antibodies [ACPAs]) [1].
  • RF immunoglobulins
  • ACPAs anti- citrullinated peptide antibodies
  • ACP5 which encodes tartrate-resistant acid phosphatase (TRAP)
  • OMIM 271550 rare disease spondyloenchondrodysplasia
  • SLE systemic lupus erythematosus
  • a major substrate of TRAP is osteopontin (OPN), an extracellular matrix glycosylated phosphoprotein with multiple functions including bone formation and remodeling [17], T- and B-cell activation [18] and type I IFN production [19].
  • OPN also known as early T-lymphocyte activation 1 (Eta-1)
  • Eta-1 early T-lymphocyte activation 1
  • s-OPN secreted protein
  • i-OPN intracellular form
  • s-OPN is classified as a Thl cytokine because it promotes interleukin 12 (IL-12) production and suppresses IL-10 production [20]
  • IL-12 interleukin 12
  • i-OPN is required for the production of type I IFN by plasmacytoid dentritic cells in response to Tolllike receptor 9 or 7 stimulation [19].
  • Elevated plasma level of s-OPN were found in RA [21] and at sites of bone erosion in a murine experimental model of collagen- induced arthritis [22].
  • SPP1 secreted phosphoprotein 1
  • SPP1 secreted phosphoprotein 1
  • DALD autoimmune lymphoproliferative syndrome
  • inter-individual differences in OPN expression may be influenced by variations in the promoter region: a G insertion at position -156 generates a runt-related transcription factor 2 (RUNX-2) binding site, which was found to increase OPN transcriptional activity [31] and contribute to several autoimmune conditions [23,26,28].
  • SPP1 rsl 1439060-rs9138 haplotypes were found to confer susceptibility to SLE, systemic sclerosis and Crohn's disease [23,28,32] and to modulate the progression of multiple sclerosis [33].
  • RA-associated gene Screening for this gene should improve the clinical outcome for ACPA negative patient by allowing early detection and appropriate clinical management of RA from its earliest stages.
  • a first object of the invention is a method of identifying a subject having or at risk of having or developing a rheumatoid arthritis (RA), comprising determining, in a sample obtained from said subject, the presence or absence of a combination of allelic variant of single nucleotide polymorphisms (SNPs) located at the SPP1 nucleic sequence.
  • RA rheumatoid arthritis
  • the SNP are selected from the group consisting of rsl 1439060 and rs9138 wherein :
  • the SNP is selected from the group consisting of rsl 1439060 and rs9138 wherein :
  • a second object of the invention is a kit for identifying whether a subject has or is at risk of having or developing a rheumatoid arthritis, comprising:
  • At least a means for detecting the SNP selected from the group consisting of rsl 1439060, rs9138 and
  • SPP1 also known as "secreted phosphoprotein 1” (OMIM 166490) means the gene coding for the osteopontin (OPN also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric)), protein (NM 000582 NP 000573) which is a extracellular matrix glycosylated phosphoprotein with multiple functions including bone formation and remodeling [17], T- and B-cell activation [18] and type I IFN production [19].
  • the whole sequence of human SPP1 gene is referenced as Gene ID: 6696.
  • SPPl nucleic acid means the SPP1 gene and all nucleic sequences which regulate transcription of the gene (cis-regulatory element in the promoter region or even further upstream, in an intron, or downstream of the gene's coding sequence, either in the translated or untranscribed region, ...)
  • “Risk” in the context of the present invention relates to the probability that an event will occur over a specific time period, as in the conversion to rheumatoid arthritis, and can mean a subject's "absolute” risk or “relative” risk.
  • Absolute risk can be measured with reference to either actual observation post-measurement for the relevant time cohort, or with reference to index values developed from statistically valid historical cohorts that have been followed for the relevant time period.
  • Relative risk refers to the ratio of absolute risks of a subject compared either to the absolute risks of low risk cohorts or an average population risk, which can vary by how clinical risk factors are assessed.
  • Odds ratios the proportion of positive events to negative events for a given test result, are also commonly used (odds are according to the formula p/(l-p) where p is the probability of event and (1- p) is the probability of no event) to no conversion.
  • Alternative continuous measures which may be assessed in the context of the present invention include time to RA conversion and therapeutic Rheumatoid arthritis conversion risk reduction ratios.
  • Risk evaluation in the context of the present invention encompasses making a prediction of the probability, odds, or likelihood that an event or disease state may occur, the rate of occurrence of the event or conversion from one disease state to another, i.e., from a normal condition to a RA condition or to one at risk of developing a rheumatoid arthritis.
  • Risk evaluation can also comprise prediction of future clinical parameters, traditional laboratory risk factor values, or other indices of rheumatoid arthritis, such as dopamine level detection, cellular population determination in peripheral tissues, in serum or other fluid (i.e. cerebrospinal fluid), either in absolute or relative terms in reference to a previously measured population.
  • the methods of the present invention may be used to make continuous or categorical measurements of the risk of conversion to RA, thus diagnosing and defining the risk spectrum of a category of subjects defined as being at risk for a RA.
  • the invention can be used to discriminate between normal and other subject cohorts at higher risk for RA.
  • the present invention may be used so as to help to discriminate those having rheumatoid arthritis from normal.
  • “Clinical parameters or indicia” encompasses all non-sample or non-analyte biomarkers of subject health status or other characteristics, such as, without limitation, age (Age), geographical origin (Origin), gender (Sex), family history (FamHX), height (HT), weight (WT), waist (Waist) and body-mass index (BMI), as well as others such as clinical cardinal signs of rheumatoid arthritis (like the joint destruction, synovitis/arthritis).
  • sample in the context of the present invention is a biological sample isolated from a subject and can include, by way of example and not limitation, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a subject. Tissue extracts are obtained routinely from tissue biopsy and autopsy material. Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof. In a preferred embodiment, the sample to be tested is saliva or blood. As used herein "blood” includes whole blood, plasma, serum, circulating epithelial cells, constituents, or any derivative of blood. In a preferred embodiment the sample is a blood sample
  • SPP1 polymorphism is a genomic polymorphism and is detected by using any type of body cell.
  • the cell is a blood cell.
  • the sample comprises SPP1 nucleic acid, wherein SPP1 nucleic acid is genomic DNA.
  • a "subject” in the context of the present invention is preferably a human.
  • Allele has the meaning which is commonly known in the art, that is, an alternative form of a gene (one member of a pair) that is located at a specific position on a specific chromosome which, when translated results in functional or dysfunctional (including non-existent) gene products.
  • allelic variant means a common sequence variation of a gene. Allelic variants can be found in the exons, introns, untranslated regulatory regions of the gene, or in the sequences that control expression of the gene. Complete gene sequencing often identifies numerous allelic variants (sometimes hundreds) for a given gene. The significance of allelic variants is often unclear until further study of the genotype and corresponding phenotype occurs in a sufficiently large population.
  • SNP Single nucleotide polymorphism
  • haplotype refers to a set of alleles of closely linked loci on a chromosome that tend to be inherited together (means a 5' to 3' sequence of nucleotides found at a set of one or more polymorphic sites in a locus on a single chromosome from a single individual).
  • the SNPs pertaining to the invention are known per se and sequences of them are publicly available from the data base htt ://www.ncbi.n!m.nih. gov 'SN ' or http ://hapmap .ncbi.nlm.nih. gov/.
  • the rsl 1439060 frequent (or common) allele is allele "del” and the rsl 1439060 rare allele is allele "G"
  • the rs9138 frequent (or common) allele is allele “A” and the rs9138 rare allele is allele “C”.
  • CCP-negative patient and “CCP-negative subject”
  • ACPA-negative and "Anti-Citrullinated Peptide Antibodies-negative” and are used herein interchangeably. They refer to a subject whose serum contains no antibodies (or at least no detectable antibodies) directed against citrullinated proteins.
  • the present inventors have assayed for a statistical association between specific polymorphisms located at SPPl nucleic acid and rheumatoid arthritis (RA) using a cohort of patients and controls. More precisely, the present inventors have assayed for a statistical association between specific polymorphisms contained in chromosome 4q22.1 locus of RA patients and controls.
  • the inventors demonstrate, in a recessive model of allelic heterogeneity, a significant contribution of the combination of SPPl rsl 1439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association greater in patients negative for ACPA.
  • a first object of the invention is a method of identifying a subject having or at risk of having or developing a rheumatoid arthritis, comprising determining, in a sample obtained from said subject, the presence or absence of combination of allelic variant of single nucleotide polymorphisms (SNPs) located at the SPPl nucleic acid.
  • SNPs single nucleotide polymorphisms
  • the SNP are selected from the group consisting of rsl 1439060 and rs9138 wherein :
  • the rsl 1439060 frequent (or common) allele is allele "del” and the rsl 1439060 rare allele is allele "G"
  • the rs9138 frequent (or common) allele is allele "A” and the rs9138 rare allele is allele "C”.
  • the presence of a combination of at least two rsl 1439060 and rs9138 rare allele indicates a lower risk of having or developing a rheumatoid arthritis.
  • the presence of a combination of at least two rsl 1439060 and rs9138 rare allele significantly decreases the risk of RA compared with controls.
  • the SNPs are selected from the group consisting of rsl 1439060 and rs9138, wherein:
  • the subject to be tested is ACPA-negative or the biological sample to be tested is obtained from a ACPA-negative subject.
  • the presence of the allele (del) of SNP rsl 1439060 and the presence of the allele (A) of SNP rs9138 indicates an increased risk of having or developing a rheumatoid arthritis.
  • Haplotype Del/A significantly increases the risk of RA compared with controls.
  • the presence of the allele (G) of SNP rsl 1439060 and the presence of the allele (A) of SNP rs9138 indicates a lower risk of having or developing a rheumatoid arthritis. As shown in the examples (see table 2), Haplotype G/A significantly decreases the risk of RA compared with controls.
  • the method of identifying a subject having or at risk of having or developing a rheumatoid arthritis comprising determining the presence or absence of a combination of allelic variant in single nucleotide polymorphisms (SNPs) located at SPP1 nucleic acid (in 4q22.1 locus) in a blood sample obtained from said subject.
  • SNPs single nucleotide polymorphisms located at SPP1 nucleic acid (in 4q22.1 locus) in a blood sample obtained from said subject.
  • the subject having or at risk of having or developing a rheumatoid arthritis may be a substantially healthy subject, which means that the subject has not been previously diagnosed or identified as having or suffering from a rheumatoid arthritis, or that has not developed a rheumatoid arthritis.
  • said subject may also be one that is asymptomatic for the rheumatoid arthritis.
  • an "asymptomatic" subject refers to a subject that does not exhibit RA symptoms, which are diagnosed, according to internationally validated criteria (ACR 1987 ref : Arnett, FC. Arthritis Rheum 1988).
  • said subject may be one that is at risk of having or developing a rheumatoid arthritis, as defined by clinical indicia such as for example: age, gender, clinical marker (like the joint destruction or arthritis/synovitis), family history of rheumatoid arthritis.
  • clinical indicia such as for example: age, gender, clinical marker (like the joint destruction or arthritis/synovitis), family history of rheumatoid arthritis.
  • the determination of the presence or absence of said SNPs may be determined by DNA sequencing, PCR analysis or any genotyping method known in the art.
  • methods include, but are not limited to, chemical assays such as allele specific hybridation, primer extension, allele specific oligonucleotide ligation, sequencing, enzymatic cleavage, flap endonuclease discrimination; and detection methods such as fluorescence, chemiluminescence, and mass spectrometry.
  • the presence or absence of said polymorphisms may be detected in a DNA sample, preferably after amplification.
  • the isolated DNA may be subjected to amplification by polymerase chain reaction (PCR), using specific oligonucleotide primers that are specific for the polymorphism or that enable amplification of a region containing the polymorphism.
  • PCR polymerase chain reaction
  • conditions for primer annealing may be chosen to ensure specific amplification; so that the appearance of an amplification product be a diagnostic of the presence of the polymorphism according to the invention.
  • DNA may be amplified, after which a mutated site may be detected in the amplified sequence by hybridization with a suitable probe or by direct sequencing, or any other appropriate method known in the art.
  • nucleic acid molecule may be tested for the presence or absence of a restriction site.
  • a base polymorphism creates or abolishes the recognition site of a restriction enzyme, this allows a simple direct PCR genotype of the polymorphism.
  • RNA sequencing includes, but are not limited to, direct sequencing, restriction fragment length polymorphism (RFLP) analysis; hybridization with allele-specific oligonucleotides (ASO) that are short synthetic probes which hybridize only to a perfectly matched sequence under suitably stringent hybridization conditions; allele-specific PCR; PCR using mutagenic primers; ligase-PCR, HOT cleavage; denaturing gradient gel electrophoresis (DGGE), temperature denaturing gradient gel electrophoresis (TGGE), single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (Kuklin et al, 1997).
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature denaturing gradient gel electrophoresis
  • SSCP single-stranded conformational polymorphism
  • Direct sequencing may be accomplished by any method, including without limitation chemical sequencing, using the Maxam-Gilbert method ; by enzymatic sequencing, using the Sanger method ; mass spectrometry sequencing ; sequencing using a chip-based technology; and real-time quantitative PCR.
  • DNA from a subject is first subjected to amplification by polymerase chain reaction (PCR) using specific amplification primers.
  • PCR polymerase chain reaction
  • RCA rolling circle amplification
  • InvaderTMassay or oligonucleotide ligation assay (OLA).
  • OLA may be used for revealing base polymorphisms.
  • two oligonucleotides are constructed that hybridize to adjacent sequences in the target nucleic acid, with the join sited at the position of the polymorphism.
  • DNA ligase will covalently join the two oligonucleotides only if they are perfectly hybridized to one of the allele.
  • short DNA sequences in particular oligonucleotide probes or primers, according to the present invention include those which specifically hybridize the one of the allele of the polymorphism.
  • Oligonucleotide probes or primers may contain at least 10, 15, 20 or 30 nucleotides. Their length may be shorter than 400, 300, 200 or 100 nucleotides.
  • RA rheumatoid arthritis
  • said method comprising determining, in a sample obtained from said subject, the presence or absence of a combination of allelic variant of single nucleotide polymorphisms (SNPs) located at SPP1 nucleic acid, said SNPs are selected from the group consisting of rsl 1439060 and rs9138, wherein:
  • the presence of a combination of at least two SPP1 rsl 1439060 and rs9138 rare allele is indicative of a protective effect regarding rheumatoid arthritis.
  • the rsl 1439060 frequent (or common) allele is allele "del” and the rsl 1439060 rare allele is allele "G"
  • the rs9138 frequent (or common) allele is allele "A” and the rs9138 rare allele is allele "C”.
  • RA rheumatoid arthritis
  • said method comprising determining, in a sample obtained from said subject, the presence or absence of a combination of allelic variant of single nucleotide polymorphisms (SNPs) located at SPP1 nucleic acid, said SNPs are selected from the group consisting of rsl 1439060 and rs9138, wherein
  • the "diagnosis” means the identification of the condition or the assessment of the severity of the disease.
  • prognosis means the assessment of the outcome of the disease, i.e. to determine the evolution of the condition, and the risk of worsening.
  • Kits of the inventions A second object of the invention is a kit for identifying whether a subject has or is at risk of having or developing a rheumatoid arthritis, comprising:
  • the kit for identifying whether a subject has or is at risk of having or developing a rheumatoid arthritis comprising:
  • the primer or probe may be labelled with a suitable marker. In another embodiment of the invention, the primer or probe may be coated on an array.
  • nucleo-acid base may be substituted by other nucleo- acid base and still result in a nucleic acid sequence (i.e. primers) with similar activity, i.e. amplification of DNA target like SNPs.
  • nucleic acid sequences are "substantially homologous” or “substantially similar” when greater than 90 % of the nucleic acid are identical, or preferably greater than 95 %, are similar (with similar activity) over the whole length of the shorter sequence
  • the similar or homologous sequences are identified by alignment using, for example, the GCG (Genetics Computer Group, Program Manual for the GCG Package, Version 7, Madison, Wisconsin) pileup program, or any of sequence comparison algorithms such as BLAST, FASTA, etc.
  • GCG Genetics Computer Group, Program Manual for the GCG Package, Version 7, Madison, Wisconsin
  • sequence comparison algorithms such as BLAST, FASTA, etc.
  • kit of the present invention will also include instructions for using the kit components to conduct the appropriate methods.
  • FIGURES
  • A Anti-citrullinated protein antibody (ACPA)-negative RA
  • B ACPA-positive RA
  • C overall RA.
  • Data are proportion of SPP1 risk allele combination, odds ratios (ORs), 95% confidence intervals (95% CIs) and P-values.
  • Forest plot shows ORs with symbol size proportional to case sample size. Results for several samples are shown in bold, with diamond widths indicating 95% CIs
  • Top box plot shows results of SPP1 ILMN 1651354 probe in macrophages.
  • Bottom box plot shows results of SPP1 ILMN 2374449 probe in macrophages.
  • P-values are the probability of having the SPP1 allelic risk combination.
  • SLE systemic lupus erythematosus
  • OPN serum level in RA patients stratified by presence of the SPP1 allelic risk combination: in red, 20 RA patients without the risk allele combination; in green, 40 RA patients carrying the risk combination. Each dot represents the OPN serum level for one patient. Lines and outer bars are mean ⁇ SD. P-values were calculated by non-parametric Mann- Whitney U test.
  • the line is the best-fit regression line.
  • This case-control association study consisted of 1 1,715 RA cases and 26,493 controls and included a replication step.
  • the discovery sample included 1,584 RA patients and 1,21 1 controls of European Caucasian ancestry from the French network and the ESPOIR cohort [53].
  • Our replication sample consisted of 8 independent samples from 6 countries (Spain, Sweden, United Kingdom, Canada, United States and Japan), for 10,131 RA cases and 25,282 controls (Table 1). All patients fulfilled the American College of Rheumatology 1987 revised criteria for RA [54]. All subjects provided informed written consent as approved by the recruiting site review board at each of the affiliate institutions.
  • the French, Spanish, Swedish and Japanese samples were genotyped for the SPP1 rsl 1439060 and rs9138 polymorphisms by use of a competitive allele-specific PCR system (Kaspar genotyping, Kbio science, Hoddeston, UK) and TaqMan 5' discrimination assay (Applied Biosystem, Foster City, CA).
  • Kaspar genotyping Kbio science, Hoddeston, UK
  • TaqMan 5' discrimination assay Applied Biosystem, Foster City, CA.
  • the success of genotyping was > 95%, and randomly selected samples were genotyped twice to verify the genotyping accuracy. In all, 99% of the genotypes were identical.
  • genotypes were imputed from data from Stahl et al. [2] with IMPUTE [55].
  • the genotypes, coded as number of rare alleles, were fixed at 0, 1 and 2 if the allele dosage from imputation was ⁇ 0.25, 0.75 to 1.25, and > 1.75, respectively.
  • EIRA Epidemiological Investigation of Rheumatoid arthritis
  • the expected frequency of haplotype del- A was calculated as fdel-A*fG-C/(fdel-A*fG-C+fdel-C*fG-A), with fdel-A, fG-C, fdel-C and fG-A the estimated frequencies of the haplotypes del-A, G-C, del-C and G-A, respectively.
  • the G-C haplotype had very low frequency in the Caucasian samples, as did the G-A haplotype in the Japanese sample, which allowed for unambiguous phasing.
  • the Bonferroni correction was used for "generating a hypothesis step" in comparing RA subgroups and controls (2 phenotypic subsets, i.e., ACPA-positive and -negative RA). P- values remaining significant after this adjustment for multiple testing are indicated in the tables and termed Padj in the text. In case of a defined hypothesis for any particular ACPA RA status, we tested it in the relevant RA samples without correction for multiple testing.
  • Allele dosage outcomes from IMPUTE which take into account the uncertainty of imputed genotypes, were used to test the single marker association of rsl 1439060 and rs9138.
  • the probability of having the SPP1 rsl 1439060 and rs9138 allelic risk combination was computed for the 599 subjects with the following formula: Pdel/del*PA/A+Pdel/del*PA/C+Pdel/G*PA/A, where Pdel/del, Pdel/G, PA/A and PA/C are the probabilities calculated from IMPUTE of having the genotypes del/del, del/G, A/A and A/C for rsl 1439060 or rs9138.
  • the adjusted expression was analyzed by linear regression for corresponding P-values.
  • Non-parametric Mann- Whitney U or Kruskal-Wallis test was used to compare serum OPN level in 2 allelic combination subgroups (i.e., presence or absence of the SPP1 risk allele combination) or rsl 1439060 and rs9138 genotype distribution, respectively.
  • Pearson linear regression analysis with GraphPad Prism v6.0 http://www.graphpad.com/scientific- software/prism/) was used for correlation analysis of OPN and anti-CCP2 serum levels
  • AIC Akaike information criterion
  • carriage of rsl 1439060 was not associated with OPN serum level, whereas that of rs9138 slightly modulated OPN serum level.
  • rs9138 which is located in the 3' UTR, was found significantly associated with OPN serum level in controls [28,44] and males with SLE [30].
  • a direct re-sequencing of the SPP1 exons would be necessary to definitely exclude a rare coding-region variant.
  • a recent large genetic association study of 25 genes from 20 GWAS-identified risk loci showing overlap among 6 common autoimmune disorders found little support for a significant impact of rare coding-region variants in known risk genes for the autoimmune phenotypes investigated, which provides little support for exome sequencing [45].
  • rsl 1439060 might have a synergistic effect in regulating OPN production: by regulating SSP1 expression, rsl 1439060, located in the promoter, may cooperate with rs9138, located in the 3' UTR, to regulate OPN serum level by its altering mRNA polyadenylation or stability.
  • rsl 1439060 located in the promoter
  • rs9138 located in the 3' UTR
  • OPN has multiple contributions to the humoral immune response: in T-cells, OPN potentiates proliferation, IFN- ⁇ production and CD40L expression, which in turn favors B-cell proliferation and antibody production [46]. In plasmacytoid dentritic cells, i-OPN promotes type I IFN production, which may also enhance antibody responses [47]. In several RA samples, the presence of a type I IFN signature in peripheral blood mononuclear cells was associated with the presence and titer of autoantibodies, which is similar to findings in other autoantibody-associated diseases [14,48- 50].
  • the type I IFN signature was also identified in a subset of arthralgia patients positive for autoantibodies in whom RA later developed [51].
  • several lines of evidence support the hypothesis of a pivotal role of OPN in autoantibody production: rsl 1730582, a SPP1 promoter variant in high LD with rsl 1439060, was found associated with autoantibody-mediated cytopenia in SLE [52], and serum OPN level was associated with IgG serum level in DALD patients [26].
  • rs9138 which modulates OPN serum level, was also reported to affect IFN-a serum activity in SLE [30].
  • RA cases were from 9 samples with available genotypes for both rsl 1439060 and rs9138 markers. Markers were genotyped in France, Spain, Sweden and Japan samples. Markers in other samples were imputed. RA cases were classified as anti-citrullinated protein antibody (ACPA)-positive (ACPA+) or - negative (ACPA-).
  • ACPA anti-citrullinated protein antibody
  • FRAGC French Rheumatoid arthritis Genetic Consortium
  • EIRA Epidemiological Investigation of Rheumatoid Arthritis
  • WTCCC Epidemiological Investigation of Rheumatoid Arthritis
  • BRASS Brigham and Women's Hospital Rheumatoid arthritis Sequential Study
  • NARAC North American Rheumatoid arthritis Consortium.
  • Table 2 SPPl rsll439060-rs9138 haplotype association with rheumatoid arthritis (RA) in discovery sample (France).
  • Model 1 Model 2 Model 3 Wei 4 Model 5 Model 6 Model ? Model s
  • Model 3 both mart ers with an interaction
  • Model 4 -A haplotype
  • Model 7 an iddifce model based on the number of rsl 1439060 and rs9138 rare aletes (from 0-4), lode! 8 : a recessive model with allelic heterogeneity (i.e. at least 2 rsl 1439060 anil rs9138 rare alleles).
  • Bilgic H Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC, et al. (2009)
  • Genomes Project C Abecasis GR, Altshuler D, Auton A, Brooks LD, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061- 1073.
  • Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes 58: 125-133.

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Abstract

L'invention concerne un procédé d'identification d'un sujet ayant ou pouvant présenter ou développer la polyarthrite rhumatoïde, ce procédé comprenant la détermination, dans un échantillon pris sur le sujet, de la présence ou de l'absence d'une combinaison de variants alléliques dans des polymorphismes d'un seul nucléotide (SNP) situés au niveau de la séquence nucléique SPP1.
PCT/EP2014/078028 2013-12-16 2014-12-16 Polymorphismes pour le diagnostic de la polyarthrite rhumatoïde WO2015091524A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018149186A1 (fr) * 2017-02-15 2018-08-23 中国医学科学院北京协和医院 Marqueur de diagnostic de ra acpa-négatif et application associée
CN110331195A (zh) * 2019-06-17 2019-10-15 右江民族医学院附属医院 一种系统性红斑狼疮骨桥蛋白基因标志物及其筛选方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018149186A1 (fr) * 2017-02-15 2018-08-23 中国医学科学院北京协和医院 Marqueur de diagnostic de ra acpa-négatif et application associée
CN110331195A (zh) * 2019-06-17 2019-10-15 右江民族医学院附属医院 一种系统性红斑狼疮骨桥蛋白基因标志物及其筛选方法

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