The combination of several polymorphic amino acid residues in the DQalpha and DQbeta chains forms a domain structure pattern and is associated with insulin-dependent diabetes mellitus.
IDDM is positively associated with HLA-DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) and negatively associated with DQA1*0102-DQB1*0602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQalpha and DQbeta, in addition to residue 52 DQalpha and residue 57 DQbeta, with regard to susceptibility or resistance in new-onset 0- to 15-year-old Swedish children with IDDM (n = 425) and matched controls (n = 367). HLA genotyping identified several polymorphic residues of the DQalpha and DQbeta to be either positively or negatively associated with IDDM, including Arg 52 DQalpha and Asp 57 DQbeta. Leu 69 DQalpha was positively (OR 7.02, P < 0.0001), Ala 69 DQalpha was negatively (OR 0.22, P < 0.0001), Gln 47 DQalpha was positively (OR 5.8, P < 0.0001), Cys 47 DQalpha was positively (OR 2.2, P < 0.0001), Lys 47 DQalpha was negatively (OR 0.47, P < 0.005), and Arg 47 DQalpha was negatively (OR 0.22, P < 0.005) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQbeta, Leu 53 DQbeta was positively (OR 11.01, P < 0.0001), Gln 53 DQbeta was negatively (OR 0.22, P < 0.0005), Arg 70 DQbeta was positively (OR 11.01, P < 0.0001), and Gly 70 DQbeta was negatively (OR 0.19, P < 0.0001) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQbeta with IDDM. Certain domains in the DQalpha, RFTIL (at DQalpha positions 52, 61, 64, 66, and 69), were present in 95% of patients compared to 69% of controls (OR 9.01, P(c) < 0.0001), and DQbeta domain GR (at DQbeta positions 45 and 70) was present in 95% of patients and 68% of controls (OR 8.68, P < 0.0001), which correlated better than the individual amino acid residues with IDDM. A combination of the DQalpha and DQbeta chain domains was present in 94% of patients compared to 60% of controls (OR 10.6, P < 0.001). In conclusion, domains in the DQalpha, DQbeta, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.
Sanjeevi
C B
CB
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden. sanjeevi.carani@molmed.ki.se
Landin-Olsson
M
M
Kockum
I
I
Dahlquist
G
G
Lernmark
A
A
D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013548:Sweden
D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C057615:HLA-DQbeta antigen; D006684:HLA-DR Antigens