Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility.
Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)
Khalil
I
I
Institut National de la Sante et de la Recherche Medicale (INSERM) U93, Saint Louis Hospital, Paris, France.
Deschamps
I
I
Lepage
V
V
al-Daccak
R
R
Degos
L
L
Hors
J
J
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004198:Disease Susceptibility; D005787:Gene Frequency; D005838:Genotype; D006681:HLA-D Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics*; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D012307:Risk Factors
D006681:HLA-D Antigens; D006683:HLA-DQ Antigens; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D015345:Oligonucleotide Probes; D004247:DNA