Methods of Predicting Osteoarthritis
The present invention relates generally to methods for predicting progression, initiation and susceptibility of osteoarthritis in human subjects using their genotype test results.
1 . A method for predicting progression of osteoarthritis in a patient, comprising the steps of:
a. taking a biological sample from said patient;
b. genotyping said biological sample for (i) at least one of the genetic markers selected from the group consisting of BMP2 (rs1049007), CLEC3B (rs13963), IL1RN (rs1374281), IL1RN (rs1794066), IL1RN (rs2637988), IL1RN (rs315943), IL1RN (rs315952), IL1RN (rs380092), IL1RN (rs4251961), IL1R1 (rs2287047), IL1R1 (rs315949), VDR (rs10735810), SLC17A3 (rs1165205), OPG (rs2073618), Cilp (rs2073711) and IL1RN (rs4251961) and (ii) optionally one or more genetic markers selected from the group consisting of IL1RN (RS3181052), IL1RN (RS1794066), IL1RN (RS419598), IL1RN (RS9005), and IL1RN (RS315943);
c. comparing the genotyping results of step b with a reference;
d. predicting progress of osteoarthritis of said patient based on the patient's genotype.
2 . The method of claim 1 , wherein the biological sample is genotyped for (i) at least one of the genetic markers selected from the group consisting of BMP2 (rs1049007), CLEC3B (rs13963), IL1RN (rs1374281), IL1RN (rs1794066), IL1RN (rs2637988), IL1RN (rs315943), IL1RN (rs315952), IL1RN (rs380092), IL1RN (rs4251961), IL1R1 (rs2287047), IL1R1 (rs315949), VDR (rs10735810), SLC17A3 (rs1165205), OPG (rs2073618), Cilp (rs2073711) and IL1RN (rs4251961) and (ii) IL1RN (rs419598) and IL1RN (rs9005).
3 . The method of claim 2 , wherein the biological sample is genotyped for IL1RN (rs315952), IL1RN (rs419598), and IL1RN (rs9005); wherein a haplotype of rs419598/rs315952/rs9005 (TTA or TCG) indicates that said patient has low risk of osteoarthritis progression; wherein a haplotype of rs419598/rs315952/rs9005 (TTG) indicates that said patient has high risk of osteoarthritis progression.
4 . The method of claim 2 , wherein the biological sample is genotyped for IL1RN (rs419598), IL1RN (rs9005), and IL1RN (rs315943); wherein a haplotype of rs419598/rs9005/rs315943 (AGT or AAT) indicates that said patient has low risk of osteoarthritis progression; wherein a haplotype of rs419598/rs315952/rs9005 (AGC) indicates that said patient has high risk of osteoarthritis progression.
5 . The method of claim 1 wherein said biological sample is genotyped for at least two of the genetic markers selected from the group consisting of BMP2 (rs1049007), CLEC3B (rs13963), IL1RN (rs1374281), IL1RN (rs1794066), IL1RN (rs2637988), IL1RN (rs315943), IL1RN (rs315952), IL1RN (rs380092), IL1RN (rs4251961), IL1R1 (rs2287047), IL1R1 (rs315949), VDR (rs10735810), SLC17A3 (rs1165205), OPG (rs2073618), Cilp (rs2073711) and IL1RN (rs4251961).
6 . The method of claim 4 , wherein said biological sample is genotyped for IL1RN (rs3181052), IL1RN (rs 419598), IL1RN (rs9005), and IL1RN (rs315943) wherein a haplotype of RS3181052|RS419598|RS90051RS315943 (GAAT or AAGT) indicates that said patient has low risk of osteoarthritis progression; wherein a haplotype RS3181052|RS419598|RS90051RS315943 (GAGC) indicates that said patient has high risk of osteoarthritis progression.
7 . The method of claim 1 wherein said biological sample is genotyped for at least three of the genetic markers selected from the group consisting of BMP2 (rs1049007), CLEC3B (rs13963), IL1RN (rs1374281), IL1RN (rs1794066), IL1RN (rs2637988), IL1RN (rs315943), IL1RN (rs315952), IL1RN (rs380092), IL1RN (rs4251961), IL1R1 (rs2287047), IL1R1 (rs315949), VDR (rs10735810), SLC17A3 (rs1165205), OPG (rs2073618), Cilp (rs2073711) and IL (rs4251961).
8 . The method of claim 6 , wherein said biological sample is genotyped for IL1RN (rs4251961), IL1RN (rs419598), IL1RN (rs315952), and IL1RN (rs9005); wherein a haplotype of rs4251961/rs419598/rs315952/rs9005 (TTCG) indicates that said patient has low risk of osteoarthritis progression; wherein a haplotype of rs4251961/rs419598/rs315952/rs9005 (CTTG) indicates that said patient has high risk of osteoarthritis progression.
9 . The method of claim 6 , wherein said biological sample is genotyped for IL1RN RS3181052|RS1794066|RS4195981RS90051 RS315943 wherein a haplotype GTAGT or GTAAT (RS3181052|RS1794066|RS419598|RS90051 RS315943) indicates that said patient has low risk of osteoarthritis progression; wherein a haplotype GTAGC (RS3181052|RS1794066|RS419598|RS90051RS315943) indicates that said patient has high risk of osteoarthritis progression.
10 . The method of claim 1 wherein said biological sample is genotyped for (i) at least six genetic markers selected from the group consisting of BMP2 (rs1049007), CLEC3B (rs13963), IL1RN (rs1374281), IL1RN (rs1794066), IL1RN (rs2637988), IL1RN (rs315943), IL1RN (rs315952), IL1RN (rs380092), IL1RN (rs4251961), IL1R1 (rs2287047), IL1R1 (rs315949), VDR (rs10735810), SLC17A3 (rs1165205), OPG (rs2073618), Cilp (rs2073711) and IL1RN (rs4251961); and (ii) at least four of the genetic markers selected from the group consisting of IL1RN (rs419598), IL1RN (rs315931), IL1RN (rs3181052), IL1RN (rs579543) and IL1RN (rs9005).
11 . The method of claim 1 , further comprising the identification of an IL1RN haplotype which comprises at least seven markers selected from the group consisting of IL1RN(rs315931), IL1RN(rs4251961), IL1RN(rs2637988), IL1RN(rs3181052), IL1RN(rs1794066), IL1RN(rs419598), IL1RN(rs380092), IL1RN(rs579543), IL1RN(rs315952), IL1RN(rs9005), IL1RN(rs315949), IL1RN(rs315943) and IL1RN(rs1374281); wherein said IL1RN haplotype with at least seven markers can be used to predict whether said patient is at high risk, neutral or low risk from OA progression.
12 . The method of claim 10 , wherein said IL1RN haplotype comprises at least seven markers selected from the group consisting of IL1RN(rs315931), IL1RN(rs4251961), IL1RN(rs2637988), IL1RN(rs3181052), IL1RN(rs1794066), IL1RN(rs419598), IL1RN(rs380092), IL1RN(rs579543), IL1RN(rs315952), IL1RN(rs9005), IL1RN(rs315949), IL1RN(rs315943), and IL1RN(rs1374281).
13 . The method of claim 10 , wherein said IL1RN haplotype comprises at least ten markers selected from the group consisting of IL1RN(rs315931), IL1RN(rs4251961), IL1RN(rs2637988), IL1RN(rs3181052), IL1RN(rs1794066), IL1RN(rs419598), ILIRN(rs380092), IL1RN(rs579543), IL1RN(rs315952), IL1RN(rs9005), IL1RN(rs315949), IL1RN(rs315943), and IL1RN(rs1374281).
14 . The method of claim 10 , wherein said IL1RN haplotype comprises at least ten markers selected from the group consisting of IL1RN(rs315931), IL1RN(rs4251961), IL1RN(rs2637988), IL1RN(rs3181052), IL1RN(rs1794066), IL1RN(rs419598), IL1RN(rs380092), IL1RN(rs579543), IL1RN(rs315952), IL1RN(rs9005), IL1RN(rs315949), IL1RN(rs315943), and IL1RN(rs1374281).
15 . The method of claim 13 , wherein a haplotype of TCAGTAACTGCG (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs3159 52/rs9005/rs315943/rs1374281) indicate that said human subject is at risk of osteoarthritis progression; a haplotype of GTGGCGATTATC (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs3159 52/rs9005/rs315943/rs1374281) indicates that said human subject is neutral to osteoarthritis progression; and a haplotype of TTAGTATCCGTC (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs3159 52/rs9005/rs315943/rs1374281) indicates that said human subject is at low risk of osteoarthritis progression.
16 . The method of claim 10 , wherein said IL1RN haplotype comprises IL1RN(rs315931), IL1RN(rs4251961), IL1RN(rs2637988), IL1RN(rs3181052), IL1RN(rs1794066), IL1RN(rs419598), IL1RN(rs380092), IL1RN(rs579543), IL1RN(rs315952), IL1RN(rs9005), IL1RN(rs315949), IL1RN(rs315943), IL1RN(rs1374281).
17 . A method of predicting progression of osteoarthritis comprising the steps of claim 1 and further comprising the step of calculating a gene score of said patient to predict severity of osteoarthritis progression.
18 . The method of claim 17 , wherein a gene score of 2 or less indicates that such patient is at very low risk; wherein a gene score of 3-4 indicates that the patient is at low risk of osteoarthristis progression; wherein a gene score of 5-6 indicates that the patient is at risk of osteoarthristis progression; wherein a gene score of 7 or above indicates that the patient is at high risk of osteoarthristis progression.
19 . The method of claim 1 , wherein said biological sample is saliva, buccal cells, blood, tissue samples or urine.
20 . A method for predicting initiation of osteoarthritis in a patient, comprising the steps of:
a. taking a biological sample from said patient;
b. genotyping said biological sample for at least one of the genetic markers selected from the group consisting of ADAM12 (rs3740199), BMP2 (rs1049007), CLEC3B (rs13963), HFE (rs1799945), IL1RN (rs315931), IL1RN (rs419598), IL1RN (rs579543), IL1RN (rs9005), IL1B(rs1143623), ADAM12(rs1871054), OPG(rs2073618), IL1RN(rs315943), IL1RN(rs315949), IL1RN(rs4251961), CDC42BPB(rs751837) and IL1RN(rs315952).
c. comparing the genotyping results of step b with a reference;
d. predicting said patient's risk of osteoarthritis initiation based on said patient's genotype.
21 . The method of claim 20 , wherein said biological sample is genotyped for at least two of the genetic markers selected from the group consisting of ADAM12 (rs3740199), BMP2 (rs1049007), CLEC3B (rs13963), HFE (rs1799945), IL1RN (rs315931), IL1RN (rs419598), IL1RN (rs579543), IL1RN (rs9005), IL1B(rs1143623), ADAM12(rs1871054), OPG(rs2073618), IL1RN(rs315943), IL1RN(rs315949), IL1RN(rs4251961), CDC42BPB(rs751837) and IL1RN(rs315952).