Population-based analysis of the HLA associated risk for IDDM
Author: Kockum, Ingrid
Date: 1995-11-24
Location: Föreläsningssalen vid Radiumhemmet plan 1
Time: 10.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
Abstract
Insulin dependent diabetes (IDDM) is one of the most common chronic illnesses among children and young adults in Sweden. The disease has a complex pattern of inheritance and environmental factors are important. The strongest linkage to IDDM is found on chromosome 6p21 in the Major Histocompatibility Complex (MHC) region. A strong linkage disequilibrium in the MHC have made identification of the alleles responsible for the primary association difficult. The aim of this project was to Identify the primary association of Human leukocyte antigens (HLA) to IDDM in Swedish population-based case-control studies and to analyse the interaction of these factors age, gender and islet cell autoantibody levels. In addition the transmission of IDDM associated HLA haplotypes were investigated in patient and control families.
Patients and controls from three population-based case-control studies were HLA typed for DQA1, DQB1 and DRB. A comparison of allele frequencies between patients and controls showed that two haplotypes DR3-DQA1*0501-DQB1*0201 and DR4-DQA1*0301-DQBl-0302, were positively associated with IDDM. The genotype associated with the highest risk for IDDM was DR3-DQA1*0501-DQB1*0201/DR4-DQAl*0301-DQB1*0302. All other positively associated genotypes contained either the DR3-DQA1*0501-DQB1*0201 or DR4-DQA1*0301-DQB1*0302 haplotype. A total of 6 haplotypes showed a negative association: DR15-DQA1-0102-D9B1*0602,DR4-DQA 1*0301 -DQB1*0301, DR13-DQA1*0103-DQB1*0603, DR11-DQA1*0501-DQB1*0301, DR14-DQA1*0101-DQB1*0503 and DR7-DQA1*0201-DQB1*0303. The relative predisposing allele test, employed to asses if all negatively associated haplotypes were protective for IDDM, showed that only DR15-DQA1*0102-DQB1*0602 was protective in this analysis. This was further conflrmed bythe observation that all genotypes with a negative association contained DR15-DQA1*0102-DQB1*0602 or alleles on this haplotype. The 95% confidence intervals of the OR estimates of alleles occurring on the same haplotype overlapped extensively and could therefore not be used to distinguish which allele was responsilble for the association. Stratification analysis and the predisposing allele test revealed that DQB1*0302 on the DR4-DQA1*0301-DQB1*0302, DR3 on the DR3-DQA1*0501-DQB1*0201 and DQBl*0602 on the DR15-DQAl*0102-DQBl*0602 haplotype showed the strongest association toIDDM. Additional risk to that associated with DQB1*0302, was conferred by DRB1*0401 on theDR4-DQA1*0301-DQB1*0302 haplotype. The highest absolute risk (1/54) was observed for the combination of DR3 and DQBl*0302.
Kendalls rank order correlation demonstrated a correlation between the rank of OR associated with different genotypes and age at onset. This correlation remained after correcting for the correlation between age and islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GAD65Ab). The DR3-DQA1*0501-DQB1*0201 haplotype and the DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302 genotype showed a significantly lower frequency among patients diagnosed before the age of 7 compared with those diagnosed after 28. DR15-DQA1*0102-DQB1*0602 was not found among patients diagnosed before the age of 8 but showed a significant trend in association with age. DR15-DQA1*0102-DQBl*0602 was more common among male than female patients. Logistic regression modelling showed an interaction between DR3 and gender, DQB1*0602 and age and DQB1*0302 and season at onset while GAD65Ab showed an interaction with season and age at onset. Hence not only age but also season at onset as well as gender affect the risk for IDDM conferred by HLA.
Offspring to diabetic fathers have a higher risk for developing IDDM than offspring to diabetic mothers. This has been suggested to be due to an increased transmission of IDDM risk HLA haplotypes from fathers to their offspring compared with mothers. Transmission rates were analysed in both IDDM and control families. In the control families there was no deviation from expected transmission rates. In IDDM families, DR4 haplotypes show an increased and DR2 haplotypes a decreased transmission to patients. No significant differences in transmission rates from mothers and fathers were detected. The haplotype that the mother do not transmit to her offspring, the non-inherited maternal haplotype (NIMH) showed a decrease in positively associated haplotypes, while the non-inherited paternal haplotype (NIPH), did not differ compared with control haplotypes. Hence development of tolerance to antigens coded for on the NIMH may affect the risk of developing IDDM later in life.
Swedish population-based case-control studies have identified HLA high-risk haplotypes and uncovered significant effects of age and gender. Studies of the 0-35 year olds show that the protective effect of DQB1*0602 decreases with Increasing age at onset.
Patients and controls from three population-based case-control studies were HLA typed for DQA1, DQB1 and DRB. A comparison of allele frequencies between patients and controls showed that two haplotypes DR3-DQA1*0501-DQB1*0201 and DR4-DQA1*0301-DQBl-0302, were positively associated with IDDM. The genotype associated with the highest risk for IDDM was DR3-DQA1*0501-DQB1*0201/DR4-DQAl*0301-DQB1*0302. All other positively associated genotypes contained either the DR3-DQA1*0501-DQB1*0201 or DR4-DQA1*0301-DQB1*0302 haplotype. A total of 6 haplotypes showed a negative association: DR15-DQA1-0102-D9B1*0602,DR4-DQA 1*0301 -DQB1*0301, DR13-DQA1*0103-DQB1*0603, DR11-DQA1*0501-DQB1*0301, DR14-DQA1*0101-DQB1*0503 and DR7-DQA1*0201-DQB1*0303. The relative predisposing allele test, employed to asses if all negatively associated haplotypes were protective for IDDM, showed that only DR15-DQA1*0102-DQB1*0602 was protective in this analysis. This was further conflrmed bythe observation that all genotypes with a negative association contained DR15-DQA1*0102-DQB1*0602 or alleles on this haplotype. The 95% confidence intervals of the OR estimates of alleles occurring on the same haplotype overlapped extensively and could therefore not be used to distinguish which allele was responsilble for the association. Stratification analysis and the predisposing allele test revealed that DQB1*0302 on the DR4-DQA1*0301-DQB1*0302, DR3 on the DR3-DQA1*0501-DQB1*0201 and DQBl*0602 on the DR15-DQAl*0102-DQBl*0602 haplotype showed the strongest association toIDDM. Additional risk to that associated with DQB1*0302, was conferred by DRB1*0401 on theDR4-DQA1*0301-DQB1*0302 haplotype. The highest absolute risk (1/54) was observed for the combination of DR3 and DQBl*0302.
Kendalls rank order correlation demonstrated a correlation between the rank of OR associated with different genotypes and age at onset. This correlation remained after correcting for the correlation between age and islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GAD65Ab). The DR3-DQA1*0501-DQB1*0201 haplotype and the DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302 genotype showed a significantly lower frequency among patients diagnosed before the age of 7 compared with those diagnosed after 28. DR15-DQA1*0102-DQB1*0602 was not found among patients diagnosed before the age of 8 but showed a significant trend in association with age. DR15-DQA1*0102-DQBl*0602 was more common among male than female patients. Logistic regression modelling showed an interaction between DR3 and gender, DQB1*0602 and age and DQB1*0302 and season at onset while GAD65Ab showed an interaction with season and age at onset. Hence not only age but also season at onset as well as gender affect the risk for IDDM conferred by HLA.
Offspring to diabetic fathers have a higher risk for developing IDDM than offspring to diabetic mothers. This has been suggested to be due to an increased transmission of IDDM risk HLA haplotypes from fathers to their offspring compared with mothers. Transmission rates were analysed in both IDDM and control families. In the control families there was no deviation from expected transmission rates. In IDDM families, DR4 haplotypes show an increased and DR2 haplotypes a decreased transmission to patients. No significant differences in transmission rates from mothers and fathers were detected. The haplotype that the mother do not transmit to her offspring, the non-inherited maternal haplotype (NIMH) showed a decrease in positively associated haplotypes, while the non-inherited paternal haplotype (NIPH), did not differ compared with control haplotypes. Hence development of tolerance to antigens coded for on the NIMH may affect the risk of developing IDDM later in life.
Swedish population-based case-control studies have identified HLA high-risk haplotypes and uncovered significant effects of age and gender. Studies of the 0-35 year olds show that the protective effect of DQB1*0602 decreases with Increasing age at onset.
Issue date: 1995-11-03
Publication year: 1995
ISBN: 91-628-1803-1
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