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PMID: 2881947 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Molecular cloning of a polymorphic DNA endonuclease fragment associates insulin-dependent diabetes mellitus with HLA-DQ.

The Journal of clinical investigation ·Vol. 79 ·No. 4 ·1987-04-00 ·Pages 1144-52

Michelsen B, Lernmark A

Abstract

A BamHI 3.7-kilobase (kb) fragment detected by an HLA-DQ beta-chain complementary DNA (cDNA) probe and negatively associated with insulin-dependent diabetes mellitus (IDDM) was cloned and sequenced to localize the polymorphism to BamHI sites in intervening sequences of an HLA-DQ beta-chain gene. A probe of the first intervening sequence (IVS 1) showed the BamHI 3.7-kb fragment in 6 of 17 HLA-DR3/4 controls but in 0 of 13 DR-identical IDDM patients. All IDDM patients (13 of 13) had BamHI fragments of 12 and 4 kb, detected in 9 of 17 controls (P less than 0.02). The simple restriction fragment length polymorphism pattern of the IVS 1 probe was exploited by comparing 113 IDDM patients with 177 healthy controls to show increased prevalences in IDDM of the 12-kb (P less than 0.0001) and 4-kb (P less than 0.0001) fragments. In IDDM patients younger than 20 yr at onset, 98% were 12- and/or 4-kb positive, compared with 63% of controls (P less than 0.0001), giving a relative risk of 91.8 for individuals with both fragments. The 12-kb fragment was linked to HLA-DR4, and the 4-kb fragment to HLA-DR3. Both serologic markers were split and a non-DR3/non-DR4 IDDM patient was 4-kb positive. HLA-DQ seems therefore closer, than HLA-DR, to an IDDM susceptibility gene.

MeSH Terms
Amino Acid Sequence Base Sequence Cloning, Molecular DNA/analysis DNA Restriction Enzymes/metabolism Deoxyribonuclease BamHI Deoxyribonuclease I/metabolism Diabetes Mellitus, Type 1/genetics,immunology Diabetes Mellitus, Type 2/genetics,immunology HLA-D Antigens/genetics HLA-DQ Antigens/genetics HLA-DR Antigens/genetics Humans Nucleic Acid Hybridization Polymorphism, Genetic Polymorphism, Restriction Fragment Length
Chemicals
HLA-D Antigens HLA-DQ Antigens HLA-DR Antigens DNA DNA Restriction Enzymes Deoxyribonuclease BamHI Deoxyribonuclease I
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Michelsen B
Lernmark A
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43 references, click to expand
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI112931
Published
1987-04-00
Pages
1144-52
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC424296
Subset
IM
Databases
GENBANK
M15809
External Links
PubMed source DOI: 10.1172/JCI112931 PMC Full Text View journal details
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