Search

US-12620489-B2 - Method for determining the risk to develop type 1 diabetes

US12620489B2US 12620489 B2US12620489 B2US 12620489B2US-12620489-B2

Abstract

The present invention relates to a method of determining whether a subject is at risk of developing type 1 diabetes by determining the genetic risk score (GRS) of a subject. The present invention also comprises a pharmaceutical composition comprising insulin and a pharmaceutical acceptable carrier for use in a method for preventing type 1 diabetes in a subject having a genetic risk score as determined by the method mentioned above. Further, it encompasses a kit for use in a method of determining whether a subject is at risk of developing type 1 diabetes by determining the genetic risk score of a subject and a type 1 diabetes antigen for use in a method of immunizing a subject against type 1 diabetes having a genetic risk score as determined by the method mentioned above.

Inventors

  • Anette-G. ZIEGLER
  • Ezio BONIFACIO
  • Christiane WINKLER
  • Jan Krumsiek
  • Fabian Theis
  • Peter Achenbach

Assignees

  • HELMHOLTZ ZENTRUM MÜNCHEN-DEUTSCHES FORSCHUNGSZENTRUM FÜR GESUNDHEIT UND UMWELT (GMBH)
  • Technische Universität Dresden

Dates

Publication Date
20260505
Application Date
20180627
Priority Date
20170628

Claims (7)

  1. 1 . A kit for determining a genetic risk score for developing type 1 diabetes, comprising: an oligonucleotide comprising SEQ ID NO: 1; an oligonucleotide comprising SEQ ID NO: 2; an oligonucleotide comprising SEQ ID NO: 3; an oligonucleotide comprising SEQ ID NO: 4; an oligonucleotide comprising SEQ ID NO: 5; an oligonucleotide comprising SEQ ID NO: 6; an oligonucleotide comprising SEQ ID NO: 7; an oligonucleotide comprising SEQ ID NO: 8; an oligonucleotide comprising SEQ ID NO: 9; an oligonucleotide comprising SEQ ID NO: 10; an oligonucleotide comprising SEQ ID NO: 11; an oligonucleotide comprising SEQ ID NO: 12; an oligonucleotide comprising SEQ ID NO: 13; an oligonucleotide comprising SEQ ID NO: 14; an oligonucleotide comprising SEQ ID NO: 15; an oligonucleotide comprising SEQ ID NO: 16; an oligonucleotide comprising SEQ ID NO: 17; an oligonucleotide comprising SEQ ID NO: 18; an oligonucleotide comprising SEQ ID NO: 19; an oligonucleotide comprising SEQ ID NO: 20; an oligonucleotide comprising SEQ ID NO: 21; an oligonucleotide comprising SEQ ID NO: 22; an oligonucleotide comprising SEQ ID NO: 23; an oligonucleotide comprising SEQ ID NO: 24; an oligonucleotide comprising SEQ ID NO: 25; an oligonucleotide comprising SEQ ID NO: 26; an oligonucleotide comprising SEQ ID NO: 27; an oligonucleotide comprising SEQ ID NO: 28; an oligonucleotide comprising SEQ ID NO: 29; an oligonucleotide comprising SEQ ID NO: 30; an oligonucleotide comprising SEQ ID NO: 31; an oligonucleotide comprising SEQ ID NO: 32; an oligonucleotide comprising SEQ ID NO: 33; an oligonucleotide comprising SEQ ID NO: 34; an oligonucleotide comprising SEQ ID NO: 35; an oligonucleotide comprising SEQ ID NO: 36; an oligonucleotide comprising SEQ ID NO: 37; an oligonucleotide comprising SEQ ID NO: 38; an oligonucleotide comprising SEQ ID NO: 39; an oligonucleotide comprising SEQ ID NO: 40; an oligonucleotide comprising SEQ ID NO: 41; and an oligonucleotide comprising SEQ ID NO: 42.
  2. 2 . A method of immunizing a subject against type 1 diabetes, comprising administering to the subject a type 1 diabetes antigen, wherein the subject is determined to be at risk of developing type 1 diabetes by a method of: (a) multiplying the corresponding score weight per risk allele of each of the 41 single nucleotide polymorphisms (SNPs), listed in the table below, with the corresponding number of risk alleles determined in a sample from the subject for each of the 41 SNPs, SNP score weight per allele rs1264813 0.43 rs2395029 0.92 rs2476601 0.76 rs2816316 0.16 rs3024505 0.22 rs1990760 0.16 rs3087243 0.16 rs10517086 0.19 rs2069763 0.11 rs6897932 0.19 rs3757247 0.19 rs9388489 0.14 rs6920220 0.15 rs1738074 0.05 rs7804356 0.15 rs4948088 0.17 rs7020673 0.23 rs12722495 0.47 rs947474 0.15 rs10509540 0.25 rs689 or rs1004446 0.65 rs4763879 0.06 rs2292239 0.36 rs3184504 0.24 rs1465788 0.13 rs17574546 0.13 rs3825932 0.15 rs12708716 0.15 rs4788084 0.20 rs7202877 0.19 rs2290400 0.25 rs7221109 0.15 rs45450798 0.09 rs763361 0.12 rs425105 0.21 rs2281808 0.07 rs3788013 0.16 rs5753037 0.15 rs229541 0.18 rs5979785 0.09 rs2664170 0.14 wherein the number of risk alleles for each SNP is 0 if a risk allele of the SNP is determined to be not present, 1 if a risk allele of the SNP is determined to be present heterozygously, or 2 if a risk allele of the SNP is determined to be present homozygously; (b) assigning a score number of 3.15 if SNP rs17426593, SNP rs2187668, and SNP rs7454108 are determined in the subject having a HLA DR4-DQ8/DR4-DQ8 genotype and a score number of 3.98 if SNP rs17426593, SNP rs2187668, and SNP rs7454108 are determined in the subject having a HLA DR3/DR4-DQ8 genotype; and (c) summing up multiplication products of step (a) and any corresponding assigned score number of step (b) determined in the subject, thereby obtaining a genetic risk score, wherein the genetic risk score equal to or greater than 13.47 is indicative that the subject is at risk of developing type 1 diabetes, wherein said type 1 diabetes antigen is administered to the subject at a dose of 50 to 100 mg, wherein said type 1 diabetes antigen is administered orally and daily, and wherein said type 1 diabetes antigen is selected from the group consisting of insulin, proinsulin, insulin analog, and peptides thereof, thereby immunizing a subject against type 1 diabetes.
  3. 3 . The method of claim 2 , wherein said type 1 diabetes antigen is administered to the subject for 60 months or less.
  4. 4 . The method of claim 2 , wherein said subject is an infant 2 to 10 months of age at the beginning of the administration.
  5. 5 . The method of claim 2 , wherein said subject is an adult, a non-adult, a newborn or an infant, and wherein said newborn or said infant is not older than 3 months.
  6. 6 . The method of claim 2 , wherein if the genetic risk score is at least 13.9, it is indicative that said newborn or said infant has an at least 10% genetic risk to develop type 1 diabetes by an age of 6 years.
  7. 7 . The method of claim 2 , wherein said sample is a blood sample or saliva sample.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. national phase application of International PCT Patent Application Serial No. PCT/EP2018/067240, filed Jun. 27, 2018, which claims priority to European Application No. 17178396.2, filed Jun. 28, 2017, and Luxembourg Application No. 100334, filed Jul. 13, 2017, which are incorporated herein by reference in their entirety. This application contains a Sequence Listing in computer readable form, which is incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION The present invention relates to a method of determining whether a subject is at risk of developing type 1 diabetes by determining the genetic risk score (GRS) of a subject. The present invention also comprises a pharmaceutical composition comprising insulin and a pharmaceutical acceptable carrier for use in a method for preventing type 1 diabetes in a patient having a genetic risk score as determined by the method mentioned above. Further, it encompasses a kit for use in a method of determining whether a subject is at risk of developing type 1 diabetes by determining the genetic risk score of a subject as determined by the method of the present invention. Additionally, a type 1 diabetes antigen for use in a method of immunizing a subject against type 1 diabetes having a genetic risk score as determined by the method of the present invention is also comprised. BACKGROUND ART Precision medicine usually relies on our ability to identify individuals with precise genetic elements, which define a disease. These elements may also be used to identify individuals who may benefit from interventions aimed at disease prevention. Most ongoing studies aimed at understanding disease etiology and clinical trials aimed at preventing childhood diseases, such as allergy, type 1 diabetes, and celiac disease, rely on identifying and enrolling infants with increased risk of the disease17. The risk is usually assessed in terms of family history1,3-7, which correctly identifies up to 10% of children who subsequently develop the disease.7,8 Genotypes in the human leukocyte antigen (HLA) DR and DQ loci are sometimes used to identify at-risk infants with or without a family history. These at-risk infants could be enrolled in studies aimed at identifying children who are likely to develop autoantibodies before the clinical manifestation of diabetes2,9,10. The risk of type 1 diabetes was predicted to be 5% in children with the HLA DR3/4-DQ8 and DR4-DQ8/DR4-DQ8 genotypes without first-degree relatives with diabetes11. Although the HLA loci are the strongest genetic risk markers for type 1 diabetes, other regions of the genome also confer susceptibility to type 1 diabetes12. Therefore, it is conceivable that risk stratification could be improved if risk is calculated according to genetic information derived from multiple genetic susceptibility regions. Some researchers have questioned the utility of combining genetic markers for predicting the development of type 1 diabetes13. However, multi-loci genetic scores were developed in two case-control cohort studies to identify cases of type 1 diabetes, or discriminates between type 1 and type 2 diabetes14,15. Yet, this approach to identify cases of type 1 diabetes from the prior art did not fully satisfy the need to perfectly establish genetic scores, which precisely predict the risk to develop type 1 diabetes. Thus, the objective of the present invention is the provision of a method to determine the degree to which type 1 diabetes genetic scores stratify the probability for developing type 1 diabetes. SUMMARY OF THE INVENTION Even though the prior art provides evidence that multi-loci genetic scores are developed suggesting an approach to identify cases of type 1 diabetes, the risk stratification strategy for developing type 1 diabetes, and particularly pre-symptomatic type 1 diabetes cited by the prior art is insufficient to establish genetic risk scores, which precisely predict the risk to develop type 1 diabetes. The solution of the present invention is a method of determining whether a subject is at risk of developing type 1 diabetes by determining the genetic risk score (GRS) of a subject by (a) multiplying the score weight of 41 SNPs, if determined in a sample from said subject with the number of risk alleles for each SNP, if determined, wherein the 41 SNPs and their corresponding score weight are selected from the following ones TABLE 1Overview of the 41 non HLA class II SNPs of themerged score.SNPscore weight per allelers12648130.43rs23950290.92rs24766010.76rs28163160.16rs30245050.22rs19907600.16rs30872430.16rs105170860.19rs20697630.11rs68979320.19rs37572470.19rs93884890.14rs69202200.15rs17380740.05rs78043560.15rs49480880.17rs70206730.23rs127224950.47rs9474740.15rs105095400.25rs689 or rs10044460.65rs47638790.06rs22922390.36rs31845040.24rs14657880.13rs175745460.13rs38259320.15rs127087160.15rs47880840.20rs72028770.19rs22904000.25rs72211090.15rs454507980.09r