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WO2001036675A2 - Polymorphismes cd36 - Google Patents

Polymorphismes cd36 Download PDF

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Publication number
WO2001036675A2
WO2001036675A2 PCT/GB2000/004384 GB0004384W WO0136675A2 WO 2001036675 A2 WO2001036675 A2 WO 2001036675A2 GB 0004384 W GB0004384 W GB 0004384W WO 0136675 A2 WO0136675 A2 WO 0136675A2
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Prior art keywords
exon
variant
genome
human
human subject
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PCT/GB2000/004384
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English (en)
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WO2001036675A3 (fr
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David John Roberts
Arnab Pain
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Isis Innovation Limited
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Priority to AU14049/01A priority Critical patent/AU1404901A/en
Publication of WO2001036675A2 publication Critical patent/WO2001036675A2/fr
Publication of WO2001036675A3 publication Critical patent/WO2001036675A3/fr

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    • 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
    • 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

Definitions

  • the present invention is concerned with a. series of novel single nucleotide polymorphisms (SNPs ) in the human CD36 gene which provide a genetic basis for the SNPs.
  • CD36 negative phenotype observed in people of African descent .
  • CD36 deficiency is associated with hypertension and abnormalities of fatty acid metabolism and glucose metabolism (Aitman et.aj., 1999) . Furthermore, CD36 deficiency in human populations of Japanese origin may result in hypertension, myocardial fatty acid metabolism and abnormal glucose uptake (Fukuchi et.al., 1999) .
  • the present inventors have now identified a series of novel CD36 polymorphisms in a population of African descent which give rise to a CD36 deficient phenotype. It is postulated that these polymorphisms which underlie CD36 deficiency may predispose to hypertension and abnormalities of fatty acid and glucose metabolism in those of African descent . Furthermore, among those with hypertension, CD36 deficiency may define a subset with particular pathophysiology, clinical characteristics and susceptibility or resistance to different treatments.
  • the invention provides a genetic method of identifying human subjects who have a CD36 deficient phenotype, which method comprises screening for the presence or absence in the genome of the human subject of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G, wherein subjects who are homozygous for one of the variant alleles or compound heterozygous for two different variant alleles are scored as having a CD36 deficient phenotype.
  • the method of the invention involves screening for the presence or absence of all four of the variant alleles listed above in the genome of a single human subject.
  • the novel SNPs in the CD36 gene were identified by sequencing genomic DNA from individuals of Afro- American origin lacking CD36 protein on their platelets. Sequence analysis of fragments of the CD36 gene from two individuals shown to be phenotypically CD36 negative in FACS analysis of their platelets revealed the following genotypes:
  • novel SNPs are more fully defined as follows:
  • nucleotide change T to G in exon 10 of the CD36 gene nucleotide position base number 188 of the sequence shown under GenBank accession number Z32760 (see Figure 2(A)), resulting in stop codon (TAT-TAG) in exon 10.
  • This polymorphism may be referred to herein as the CD36 exon 10 188 T-G polymorphism; the wild type allele may be referred to herein as CD36 exon 10 188 T; the variant or mutant allele may be referred to herein as CD36 exon 10 188 G or as mutation 1.
  • This polymorphism may be referred to herein as the CD36 exon 7 124 T-C polymorphism; the wild type allele may be referred to herein as CD36 exon 7 124 T; the variant or mutant allele may be referred to herein as CD36 exon 1 124 C or as mutation 3.
  • nucleotide (G) deletion in exon 10 of the human CD36 gene (4) a nucleotide (G) deletion in exon 10 of the human CD36 gene, nucleotide position base number 68 of the sequence shown under GenBank accession number Z32760 (see Figure 2(A)), resulting in a frame shift and premature termination at a stop codon in exon 10.
  • This polymorphism may be referred to herein as the CD36 exon 10 68 G/ ⁇ G polymorphism; the wild type allele may be referred to herein as CD36 exon 10 68 G; the variant or mutant allele may be referred to herein as CD36 exon 10 68 ⁇ G or as mutation 4.
  • All four of the variant CD36 alleles either incorporate a splice-site mutation or incorporate a premature stop codon because of the single nucleotide substitution or deletion.
  • the altered open reading frame codes for an aberrant or truncated form of CD36 which is incapable of being translocated and/or incorporated into the membrane.
  • Individuals who are homozygous for one of the variant alleles listed above or are compound heterozygotes possessing two different variant alleles selected from the group listed above would therefore have a CD36 deficient phenotype because of a failure to express functional CD36 protein in the correct sub- cellular location.
  • the invention also provides a method of screening human subjects for susceptibility to hypertension, abnormalities in fatty acid metabolism or abnormalities of glucose metabolism, which method comprises screening for the presence or absence in the genome of the human subject of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G, wherein the presence of at least one variant CD36 allele in the genome of said human subject is taken as an indication of susceptibility to hypertension, abnormalities in fatty acid metabolism or abnormalities of glucose metabolism.
  • CD36 deficiency causes disturbances in carbohydrate and lipid metabolism both in spontaneously hypertensive rats (SHR) and in humans. Such disturbances in fatty carbohydrate and lipid metabolism are the common cause for coronary heart disease, hypertension, non-insulin dependant diabetes and obesity in rats and in humans.
  • a genetic screen for the novel SNPs that determine the phenotype of CD36 deficiency could therefore be used to identify individuals with increased risk of hypertension or coronary heart diseases. To date these disease conditions are the major causes of ill health in developed nations and there are few suitable genetic markers available that are useful in assessing the genetic risks for hypertension, coronary heart diseases and obesity among populations of African descent.
  • the novel CD36 SNPs identified by the present inventors may also be important risk factors for autoimmune diseases.
  • the applicant's co-pending UK patent application, serial No. 9915311.6 describes how CD36 binding may modulate the response of the immune system. It follows, therefore, that individuals with CD36 deficiency may suffer from immune dysregulation and as a result be at risk of developing autoimmune diseases such as, for example, Systemic Lupus Erythmatosis (SLE) or Juvenile Onset Diabetes.
  • SLE Systemic Lupus Erythmatosis
  • Juvenile Onset Diabetes Juvenile Onset Diabetes.
  • the invention also provides a method of screening human subjects for susceptibility to autoimmune disease, which method comprises screening for the presence or absence in the genome of the human subject of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G, wherein the presence of at least one variant CD36 allele in the genome of said human subject is taken as an indication of susceptibility to autoimmune disease.
  • individuals with one variant CD36 allele are also scored as being susceptible, as well as individuals who are homozygous for a variant allele or compound heterozygous for two different variant alleles.
  • Results presented in the Examples included herein suggest that the presence of one variant CD36 allele may be a protective genetic factor against severe malaria.
  • heterozygous individuals may also be susceptible, or partly susceptible, to disease conditions associated with CD36 deficiency.
  • the invention also provides a method of identifying human subjects who are likely to develop anti-platelet antibodies after receiving a blood or platelet transfusion, which method comprises screening for the presence or absence in the genome of the human subject of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G .
  • the invention provides a method of establishing the or any genetic basis for CD36 deficiency in a human subject, which method comprises screening the genome of said subject for the presence of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G.
  • the invention further provides a method of establishing the or any genetic basis for hypertension, abnormalities of glucose metabolism or abnormalities of fatty acid metabolism in a human subject, which method comprises screening the genome of said subject for the presence of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G.
  • This method of the invention may be useful in defining clinical or therapeutic subsets of hypertension, with particular pathophysiology , clinical characteristics and susceptibility or resistance to different treatments.
  • the invention provides a method of establishing the or any genetic basis for autoimmune disease in a human subject, which method comprises screening the genome of said subject for the presence of one or more variant CD36 alleles selected from the group consisting of CD36 exon 10 188 G, CD36 exon 5 180 C, CD36 exon 7 124 C and CD36 exon 10 68 ⁇ G.
  • this method of the invention may be useful in defining clinical or therapeutic subsets of autoimmune diseases, such as SLE and Juvenile Onset Diabetes, which may be susceptible/resistant to different regimes of treatment.
  • the above methods of the invention all preferably involve screening for the presence or absence of all four of the variant alleles listed as (1) to (4) above in the genome of a single human subject who has previously been identified as having a CD36 deficient phenotype or as suffering from a condition known or suspected to involve CD36 deficiency (e.g. hypertension, abnormalities of glucose metabolism, abnormalities of fatty acid metabolism, SLE or juvenile onset diabetes) or as having developed anti- platelet antibodies following a blood or platelet transfusion .
  • CD36 deficiency e.g. hypertension, abnormalities of glucose metabolism, abnormalities of fatty acid metabolism, SLE or juvenile onset diabetes
  • genome level screening for CD36 deficiency could be used in any of the following applications, although it is to be understood that the invention is in no way limited to these particular applications : - i) Screening in people of African origin to identify individuals at risk for hypertension and thus allow appropriate preventative action to be taken; ii) Identification of individuals at risk of particular complications or syndromes of hypertension or requiring specific treatments for hypertension; iii) Screening to identify individuals at risk of developing autoimmune diseases such as SLE or diabetes and thus allow appropriate preventative action to be taken; iv) Identification of individuals at risk of particular complications or syndromes of auto-immune diseases or requiring specific treatments for autoimmune diseases; v) Identification of individuals who are at risk of developing anti-CD36 antibodies after blood or platelet transfusion; vi) Screening of individuals who have developed anti- platelet antibodies (after blood or platelet transfusion) to identify those who are CD36 deficient.
  • the actual step of determining the presence or absence of a given variant CD36 allele may be carried out according to any technique known in the art and it is to be understood that the invention is in no way limited by the precise technique used to perform genotyping at the specific CD36 polymorphic loci.
  • Known techniques for the scoring of single nucleotide polymorphisms include mass spectrometry, particularly matrix-assisted laser desorption/ionization time-of- flight mass spectrometry (MALDI-TOF-MS, se Roskey, M. T. et.al., 1996, PNAS USA, 93: 4724-4729), single nucleotide primer extension (Shumaker, J. M. et.al.,
  • SNPs are commonly scored using PCR-based techniques, such as PCR-SSP using allele-specific primers (described by Bunce, 1995) . If the SNP results in the abolition or creation of a restriction site then genotyping can be carrying out by performing PCR using non-allele specific primers spanning the polymorphic site and digesting the resultant PCR product using the appropriate restriction enzyme (also known as PCR- RFLP, see Example 1).
  • the known techniques for scoring polymorphisms are of general applicability and it would therefore be readily apparent to persons skilled in the art that the known techniques could be adapted for the scoring of single nucleotide polymorphisms in the human CD36 gene.
  • the primer pair Stop-F2 5' -CTATGCTGTATTTGAATCCGACGTT-3' and 36-6R 5' -TGGACTGTGCTACTGAGGTTATTTACTC-3' may be used to generate the initial PCR product.
  • genotyping is generally carried out on genomic D A prepared from a suitable tissue sample obtained from the subject under test. Most commonly, genomic D ⁇ A is prepared from a sample of whole blood, according to standard procedures which are well known in the art.
  • the present invention further provides oligonucleotide molecules of at least 10 contiguous nucleotides in length spanning each of the novel polymorphic variants of the CD36 gene identified herein. Accordingly, the invention provides an oligonucleotide molecule comprising a sequence of at least 10 contiguous nucleotides of the sequence illustrated in Figure 2 (B) including nucleotide number 188, or the reverse complement thereof, an oligonucleotide molecule comprising a sequence of at least 10 contiguous nucleotides of the sequence illustrated in Figure 3 (B) including nucleotide number 180, or the reverse complement thereof and an oligonucleotide molecule comprising a sequence of at least 10 contiguous nucleotides of the sequence illustrated in Figure 4 (B) including nucleotide number 124, or the reverse complement thereof.
  • the oligonucleotide molecules of the invention are preferably from 10 to 50 nucleotides in length, even more preferably from 20-30 nucleotides in length, and may be DNA, RNA or a synthetic nucleic acid, and may be chemically or biochemically modified or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those skilled in the art. Possible modifications include, for example, the addition of isotopic or non-isotopic labels, substitution of one or more of the naturally occurring nucleotide bases with an analog, internucleot ide modifications such as uncharged linkages (e.g. methyl phosphonates, phosphoamidates , carbamates, etc.) or charged linkages (e.g.
  • oligonucleotide molecule may be produced according to techniques well known in the art, such as by chemical synthesis or recombinant means .
  • the oligonucleotide molecules of the invention may be double stranded or single stranded but are preferably single stranded, in which case they may correspond to the sense strand or the antisense strand of the CD36 gene.
  • the oligonucleotides may advantageously be used as probes or as primers to initiate DNA synthesis/DNA amplification. They may also be used in diagnostic kits or the like for detecting the presence of one or more variant CD36 alleles. These tests generally comprise contacting the probe with a sample of test nucleic acid (usually genomic DNA) under hybridising conditions and detecting for the presence of any duplex or triplex formation between the probe and complementary nucleic acid in the sample.
  • the probes may be anchored to a solid support to facilitate their use in the detection of variant CD36 alleles. Preferably, they are present on an array so that multiple probes can simultaneously hybridize to a single sample of target nucleic acid.
  • the probes can be spotted onto the array or synthesised in si tu on the array. (See Lockhart et al . , Nature Biotechnology, vol. 14, December 1996 "Expression monitoring by hybridisation to high density oligonucleotide arrays".
  • a single array can contain more than 100, 500 or even 1,000 different probes in discrete locations.
  • Figure 1 illustrates typical results of genotyping for the CD36 exon 10 188 T-G polymorphism. Genomic DNA was amplified by PCR using the primer pair Stop-F2 and 36-6R to amplify a fragment spanning the polymorphic locus. The resultant PCR products were digested with Ndel and the fragments separated on 5%
  • MetaPhorTM agarose ⁇ T' alleles generate two restriction fragments of 147bp and 65bp, whilst a single fragment of 212bp is seen with variant ⁇ G' alleles.
  • the three possible genotypes can therefore be distinguished: M-G/G homozygote, H-T/G heterozygote, -T/T homozygote.
  • Figure 2 shows the nucleotide sequence of exon 10 of the human CD36 gene (GenBank accession number Z32760); (B) shows the nucleotide sequence of a CD36 exon 10 having the exon 10 188 G variant.
  • Figure 3 shows the nucleotide sequence of exon 5 of the human CD36 gene (GenBank accession number Z32755); (B) shows the nucleotide sequence of a CD36 exon 5 having the exon 5 180 C variant.
  • Figure 4 shows the nucleotide sequence of exon 7 of the human CD36 gene (GenBank accession number Z32757); (B) shows the nucleotide sequence of a CD36 exon 7 having the exon 7 124 C variant.
  • Example 1- Identification of human platelets of African/Afro-American origin expressing reduced or no glycoprotein IV.
  • CD36 Glycoprotein IV
  • Mutation 1 In exon 10 of the CD36 gene a T-G transition was detected (by PCR with the pair of primers 36-6F and 36-6R) in both of the individuals.
  • Mutation 2 At the splice site junction near the 3 'end of exon 5 of the CD36 gene, a T-C transition was detected (by PCR with the pair of primers 36-4F and 36-4R) in one of the individuals.
  • Mutation 3 At the splice site junction near the 3' end of exon 7 of the CD36 gene, a T-C transition was detected (by PCR with the pair of primers 36-5F and 36-5R)in one of the individuals.
  • Mutation 4 A single nucleotide (G) deletion in exon 10 of the human CD36 gene was detected (by PCR with the pair of primers 36-6F and 36-6R) in one of the individuals .
  • a new polymorphism has been identified in exon 10 of the human CD36 gene that could be the main contributing genetic factor for CD36 deficiency among African and Afro-American individuals.
  • This new mutation involves a single nucleotide change from T to G at base number 188 (T-G) in the nucleotide sequence of CD36 exon 10 (GenBank accession number Z32760) resulting in the creation of a premature stop codon (TAT-TAG) .
  • T-TAG premature stop codon
  • the resultant variant /mutant allele of CD36 could code for a truncated form of the CD36 protein lacking 148 a ino acids at the C-terminus, including the C-terminal transmembrane domain .
  • This truncated form of CD36 is expected to be non- functional, hence the variant CD36 exon 10 188 G allele is a candidate allele for CD36 deficiency.
  • Stop-F2 (5'-CTATGCTGTATTTGAATCCGACGTT-3' ) and 36-6R (5' -TGGACTGTGCTACTGAGGTTATTTACTC-3' ) were used to perform PCR on about 25-50ng genomic DNA.
  • AmplitaqTM DNA polymerase (Perkin Elmer) or BioTaqTM DNA polymerase (Bioline, UK) were used (1 unit/25 ⁇ l PCR reaction) , the PCR cycling parameters were as follows: 95°C for 4 minutes x 1 cycle
  • a new polymorphism has been identified at the splice site junction at 3' end of exon 5 of human CD36 gene that could be one of the contributing genetic factors for CD36 deficiency among African and Afro-American individuals and others of African descent.
  • This new mutation involves a single nucleotide change from T to C residue at the base number 180 (T-C) in the nucleotide sequence of CD36 exon 5 (GenBank accession number Z32755) resulting in a splice mutation.
  • the resulting mutant allele of the CD36 gene could code for aberrant CD36 mRNA molecules because of splicing defect and hence is a candidate allele for CD36 deficiency.
  • This polymorphism was detected using primer pairs 36- 4F (5'TTGTTTACTGCTGTTTCTTTAG3' ) and 36-4R (5 ⁇ ATATTGCCATTCATATTTGGTAC3' ) and PCR amplification (95°C for 4 minutes for 1 cycle, followed by 35 cycles of 95°C for 1 minute, 55°C for 1 minute, 72°C for 1 minute and finally 1 cycle of 72°C for 5 minutes) .
  • a new polymorphism has been identified at the splice site junction at the 3' end of exon 7 of human CD36 gene that could also be another potential contributing genetic factor for CD36 deficiency among African and Afro-American individuals and others of African descent.
  • This new mutation involves a single nucleotide change from T to C at base number 124 (T-C) in the nucleotide sequence of exon 7 of the CD36 gene (GenBank accession number Z32757) resulting in a splice mutation.
  • the resulting mutant allele of the CD36 gene could code for aberrant CD36 mRNA molecules because of splicing defect and hence is a candidate allele for CD36 deficiency.
  • This polymorphism was detected using primer pairs 36-5F ( 5 ' GTAACATTTTCCCATACATATATTTCAG 3') and 36-5R ( 5 ' GAGATGACCACAAAACAAATATTCTT 3') and PCR amplification (95°C for 4 minutes for 1 cycle, followed by 35 cycles of 95°C for 1 minute, 62.5°C for 1 minute, 72°C for 1 minute and finally 1 cycle of 72°C for 5 minutes) .
  • Example 6- The CD36 exon 10 68 G/ ⁇ G polymorphism.
  • a second new polymorphism has been identified in exon 10 of the human CD36 gene that could be one of the contributing genetic factors for CD36 deficiency.
  • This new mutation involves a single nucleotide deletion (G deletion) at the base position 68 in the nucleotide sequence of CD36 exon 10 (GenBank accession number Z32760) , resulting in a frame shift and premature termination at a stop codon (TAG) in exon 10 of the CD36 gene.
  • This polymorphism was detected using primer pairs 36- 6F (5'CTAATCATTTGCCACTCGATTTTTA3' ) and 36-6R (5'TGGACTGTGCTACTGAGGTTATTTACTC3' ) and PCR amplification (95°C for 4 minutes for 1 cycle, followed by 35 cycles of 95°C for 1 minutes, 63°C for 1 minute, 72°C for 1 minute and finally 1 cycle of 72°C for 5 minutes) .
  • genotyping of this polymorphism could in principle by carried out by PCR-RFLP, first performing PCR using a primer pair flanking the polymorphic locus and then digesting the PCR product with Hpyl881X.
  • Hpyl881X is not available from a commercial supplier.
  • typing of this polymorphism can be carried out using allele-specific PCR or allele-specific hybridisation.

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Abstract

L'invention concerne une série de nouveaux polymorphismes à nucléotide simple dans le gène humain CD36 offrant une base génétique pour un phénotype CD36 négatif. L'invention concerne également des méthodes de criblage génétique pour déterminer une sensibilité à l'hypertension, des anomalies du métabolisme des acides gras et des anomalies du métabolisme du glucose sur la base de l'utilisation des polymorphismes.
PCT/GB2000/004384 1999-11-19 2000-11-17 Polymorphismes cd36 WO2001036675A2 (fr)

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GBGB9927502.6A GB9927502D0 (en) 1999-11-19 1999-11-19 CD36 Polymorphisms
GB9927502.6 1999-11-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005116644A3 (fr) * 2004-05-26 2006-01-05 Aase Handberg Procede pour evaluer le risque relatif de developpement de l'atherosclerose chez des patients
US9372190B2 (en) 2004-05-26 2016-06-21 Region Nordjylland Method of evaluation of the relative risk of developing atherosclerosis in patients
CN108660198A (zh) * 2018-05-15 2018-10-16 广州血液中心 一种血小板膜蛋白cd36抗原基因分型的pcr-sbt方法及试剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506126A (en) * 1988-02-25 1996-04-09 The General Hospital Corporation Rapid immunoselection cloning method
AU2795892A (en) * 1991-10-03 1993-05-03 Center For Blood Research, The Cd36 immunoadhesins and their use in selectively killing (plasmodium falciparum) infected erythrocytes
US6322976B1 (en) * 1998-05-28 2001-11-27 Medical Research Council Compositions and methods of disease diagnosis and therapy

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005116644A3 (fr) * 2004-05-26 2006-01-05 Aase Handberg Procede pour evaluer le risque relatif de developpement de l'atherosclerose chez des patients
US9372190B2 (en) 2004-05-26 2016-06-21 Region Nordjylland Method of evaluation of the relative risk of developing atherosclerosis in patients
CN108660198A (zh) * 2018-05-15 2018-10-16 广州血液中心 一种血小板膜蛋白cd36抗原基因分型的pcr-sbt方法及试剂

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