| 1. |
- Graham, Jinko, et al.
(författare)
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Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset
- 1999
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Ingår i: European Journal of Immunogenetics. - : Wiley. - 0960-7420 .- 1365-2370. ; 26, s. 117-
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Tidskriftsartikel (refereegranskat)abstract
- HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype ether than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.
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| 2. |
- Hagopian, William A., et al.
(författare)
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Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children
- 1995
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 95:4, s. 1505-1511
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Tidskriftsartikel (refereegranskat)abstract
- Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA1*0501/B1*0201 (DQ2; P = 0.007) but not DQA1*0301/B1*0302 (DQ8), and IAA with DQA1*0301/B1*0302 (DQ8; P = 0.03) but not DQA1*0501/B1*0201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population.
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| 3. |
- Ivarsson, Sten-A., et al.
(författare)
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Glutamate decarboxylase antibodies in non-diabetic pregnancy precedes insulin-dependent diabetes in the mother but not necessarily in the offspring
- 1997
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Ingår i: Autoimmunity. - 0891-6934. ; 26:4, s. 261-269
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Tidskriftsartikel (refereegranskat)abstract
- We studied the risk for diabetes of glutamate decarboxylase (GAD65Ab) and islet cell (ICA) autoantibodies in non-diabetic pregnant mothers and their children. Pregnancy and cord blood sera were collected in 1970-87 from about 35,000 mothers who delivered a child in the city of Malmo, Sweden. A total of 42 mothers were identified in 1988 who, 1-18 years after their pregnancies, had developed either insulin-dependent (n = 22) or non-insulin dependent (n = 20) diabetes mellitus. First, in 123 pregnant mothers selected as controls, 0.8% had GAD65Ab and 0.8% ICA. Second, among the mothers with non-insulin dependent diabetes, 7/20 (35%) had GAD65Ab eight months to 13 years, 10 months before clinical diagnosis. Third, in mothers who later developed insulin-dependent diabetes, 12/22 (55%) had GAD65Ab and 10/22 (45%) had ICA in pregnancies preceding the clinical diagnosis by 13 months to 9 years, 4 months. In 1996, none of the children born to the 42 mothers have developed diabetes. GAD65Ab and ICA in non-diabetic pregnancies may predict insulin-dependent diabetes in the mother but not necessarily in the offspring.
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| 4. |
- Kockum, Ingrid, et al.
(författare)
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Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus
- 1996
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 28:7, s. 344-347
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Tidskriftsartikel (refereegranskat)abstract
- Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune markers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recombination frequency within the HLA region. The frequency of the DR3-DQA1 * 0501-DQB1 * 0201 haplotype and the DR3-DQA1 * 0501 DQB1 * 0201 (DQ2)/DR4-DQA1 * 0301-DQB1 * 0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30. The negatively associated haplotype, DR15-DQA1 * 0102-DQB1 * 0602 was absent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tandem repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive but not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onset and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest sensitivity (54%) was in 0-10 year old boys, while age did not affect the sensitivity in girls. In contrast, the sensitivity of IAA was highest (46%) before the age of 15 but decreased thereafter as did the sensitivity for ICA. Classification of patients who develop IDDM above 20-25 years of age was inadequate since many patients classified with NIDDM either had GAD65Ab or ICA or developed these antibodies after 1-2 years of NIDDM. We conclude that not only age but also gender affects the risk for IDDM associated with HLA, other IDDM genes as well as commonly used immunological markers for IDDM.
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| 5. |
- Kockum, Ingrid
(författare)
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Population-based analysis of the HLA associated risk for IDDM
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 6. |
- Lindberg, Bengt, et al.
(författare)
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Prevalence of β-cell and Thyroid Autoantibody Positivity in Schoolchildren during Three-Year Follow-up
- 1999
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 31:3, s. 175-185
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65Ab), insulin (IAA), islet cells (ICA), thyroid peroxidase (TPOAb) and thyroglob-ulin (TgAb), in relation to HLA-DR types, was assessed in 310 (HLA in 280) twelve-year-old children during three-year follow-up. Altogether, 26.8% (83?10) of the children were found to carry at least one autoantibody. The HLA-DR3/DR4 genotype was significantly more prevalent in the subgroup of children GAD65Ab-positive on at least one occasion than among GAD65Ab-negative children |33% (2/6) vs. 5% (12/274);? = 0.03|, as was the HLA-DR4/x genotype among children seropositive for at least one thyroid autoantibody, compared to the corresponding seronegative subgroup [52% (34/65) vs. 34% (74/215); p = 0.01]. The proportion of children seropositive in at least one of the three tests was 1.9% (6?10) for GAD65Ab, 2.6% (8?10) for IAA, 5.2% (16?10) for ICA, 11.3% (35?10) for TPOAb and 19.4% (60?10) for TgAb. All autoantibodies except GAD65Ab tended to disappear during follow-up, and at the three-year follow-up IAA had disappeared in 50% (2/4) of cases, ICA in 67% (6/9), TPOAb in 30% (6/20) and TgAb in 38% (18/47) of cases. The turnover of seropositive subjects and the large proportion of children seropositive for at least one islet or thyroid autoantibody during a three-year follow-up suggest transient autoantibodies to be more common than is discernible in cross-sectional investigations
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