TY - JOUR
T1 - Linkage disequilibrium between TAP2 variants and HLA class II alleles; no primary association between TAP2 variants and insulin‐dependent diabetes mellitus
AU - Rønningen, Kjersti S.
AU - Undlien, Dag E.
AU - Ploski, Rafal
AU - Maouni, Nicki
AU - Konrad, Robert J.
AU - Jensen, Elisabeth
AU - Hornes, Erik
AU - Reijonen, Helena
AU - Colonna, Marco
AU - Monos, Dimitri S.
AU - Strominger, Jack L.
AU - Thorsby, Erik
PY - 1993/5
Y1 - 1993/5
N2 - The TAP1 and TAP2 genes, located in the HLA class II region, encode subunits of a peptide transporter. Both genes display limited genetic variability; four different nucleotide substitutions have been found in theTAP2 gene. Here studies on linkage disequilibrium between TAP2 variants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin‐dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of homozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) and glut amine at 687 (687 Gin) paralleled by an increase in homozygosity for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a stop codon at 687 (687 Stop), was found in both Finnish and Norwegian IDDM patients compared to random controls. However, a strong linkage disequilibrium between these TAP2 polymorphisms and given HLA‐DR and ‐DQ genes was observed among healthy controls. The frequent 665 Thr and 687 Stop variants were in linkage disequilibrium both with the DR4‐DQ8 and the DR3‐DQ2 haplotypes, haplotypes which are strongly associated with IDDM. In contrast, the DR1‐DQ5 and DR13‐DQ6 (e.g. DQB1*0603) haplotypes, which are decreased among IDDM patients, were associated with the 665 Ala and 687 Gin variants. Thus, when DR‐ and DQ‐matched patients and controls were compared, associations of the investigated TAP2 variants and IDDM were no longer detectable. These data, therefore, indicate that the associations previously found between certain TAP2 variants and IDDM are secondary to a primary association between this disease and particular DQαβ heterodimers.
AB - The TAP1 and TAP2 genes, located in the HLA class II region, encode subunits of a peptide transporter. Both genes display limited genetic variability; four different nucleotide substitutions have been found in theTAP2 gene. Here studies on linkage disequilibrium between TAP2 variants and HLA class II alleles are reported, in an attempt to evaluate whether TAP2 variants are associated with insulin‐dependent diabetes mellitus (IDDM). As reported previously, a significant decrease of homozygosity for TAP2 alleles encoding alanine at residue 665 (665 Ala) and glut amine at 687 (687 Gin) paralleled by an increase in homozygosity for TAP2 alleles encoding threonine at residue 665 (665 Thr) and a stop codon at 687 (687 Stop), was found in both Finnish and Norwegian IDDM patients compared to random controls. However, a strong linkage disequilibrium between these TAP2 polymorphisms and given HLA‐DR and ‐DQ genes was observed among healthy controls. The frequent 665 Thr and 687 Stop variants were in linkage disequilibrium both with the DR4‐DQ8 and the DR3‐DQ2 haplotypes, haplotypes which are strongly associated with IDDM. In contrast, the DR1‐DQ5 and DR13‐DQ6 (e.g. DQB1*0603) haplotypes, which are decreased among IDDM patients, were associated with the 665 Ala and 687 Gin variants. Thus, when DR‐ and DQ‐matched patients and controls were compared, associations of the investigated TAP2 variants and IDDM were no longer detectable. These data, therefore, indicate that the associations previously found between certain TAP2 variants and IDDM are secondary to a primary association between this disease and particular DQαβ heterodimers.
KW - HLA class II
KW - Insulin‐dependent diabetes mellitus
KW - Linkage disequilibrium
KW - Peptide transporter (TAP2)
UR - http://www.scopus.com/inward/record.url?scp=0027413516&partnerID=8YFLogxK
U2 - 10.1002/eji.1830230511
DO - 10.1002/eji.1830230511
M3 - Article
C2 - 8477801
AN - SCOPUS:0027413516
SN - 0014-2980
VL - 23
SP - 1050
EP - 1056
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -