Biomedical subjects
Publications and source records attributed to I Kockum.
A study of 109 Swedish patients and 85 healthy Swedish controls with Crohn's disease (CD) by HLA class II RFLP genotyping was carried out. There was no significant association for any single DR or DQ specificity or phenotypic combination of DR and/or DQ specificities among our study group of Caucasian extraction.
The association between HLA-DR and -DQ and insulin-dependent diabetes mellitus (IDDM) in a defined high-incidence area was analyzed in a total of 58 population-based patients, representing 77% of IDDM patients with age at onset below 16 years, and in 92 unrelated parents in control families without IDDM. HLA haplotypes were confirmed by analyzing first-degree relatives in both groups. Seven different methods were used to analyze risk: (1) odds ratio, (2) absolute risk, (3) haplotype relative risk, (4) transcomplementation relative risk, (5) relative predisposing effects, (6) stratification analysis, and (7) test of predisposing allele on haplotype. DQB1*0302 indicated somewhat higher risk than did DR4, while DR3 had a higher risk than DQB1*0201; however, the 95% confidence intervals of the risk estimates overlapped. The positive association between IDDM and the DQB1*0201-DQA1*0501-DR3 haplotype seems to be due to DR3 or to an unknown linked gene. More important, DQA1*0301 was present among 93% of the patients, and this allele in various transcomplementation combinations with DQB1 alleles showed closer association to IDDM than did any other alleles. The strong negative association of the DQB1*0602 allele also in the presence of either DR4 or DQB1*0302 or both suggests that, in a high-risk population for IDDM, HLA-DQ primarily confers protection, perhaps by induction of tolerance. Consistent with known functions, HLA-DR may primarily confer susceptibility, perhaps by induction of autoreactive T lymphocytes.
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Atopic dermatitis is a multifactorial disorder probably caused by environmental factors in combination with susceptibility genes. The clinical similarity between atopic dermatitis and the eczema manifestation in patients with Wiskott-Aldrich syndrome made the previously identified WAS gene in chromosome sub-band Xpl 1.23 an interesting candidate gene for atopic dermatitis. We studied linkage and association to the WAS gene region using four polymorphic microsatellite markers in 406 Swedish families with at least two siblings affected with atopic dermatitis (in total 1514 individuals). In the analyses, we studied two qualitative traits: atopic dermatitis and elevated allergen-specific serum IgE antibodies, and one quantitative trait, a severity score of atopic dermatitis. We found that the marker MAOB gave positive linkage with a maximum lod score of 1.68 (p<0.05) to the severity score of atopic dermatitis. Association could not be seen to atopic dermatitis nor to elevated allergen-specific serum IgE antibodies in this region using the transmission disequilibrium test. Our results indicate that either the WAS gene or another gene in the area contributes to the severity of atopic dermatitis.
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 other 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.
The aetiology of atopic dermatitis is unknown, but is probably multifactorial, with interactions between several genetic and environmental factors. Twin studies indicate a strong genetic factor, but the susceptibility genes are unknown. This paper, describing the phenotypes of family material, forms part of a large genetic study seeking to identify susceptibility genes for atopic dermatitis by linkage analysis. We selected families with at least 2 siblings affected with atopic dermatitis (1,097 affected siblings who together form 650 affected sib pairs and 49 affected half-sib pairs). We established a phenotype database of information about the affected siblings and their relatives, in total 5,830 individuals. All siblings were diagnosed with atopic dermatitis and participated in a standardized interview covering aspects of atopy and atopic dermatitis. Of the affected siblings, 72% suffered or had suffered from asthma and/or allergic rhinoconjunctivitis and 74% had raised total and/or allergen-specific IgE serum levels. Seventeen percent of the siblings had been hospitalized for atopic dermatitis. Sixty-nine percent had 1 or both parents with atopic dermatitis. Among siblings with 1 parent with atopic dermatitis, 37% had a father with atopic dermatitis and 63% had a mother with atopic dermatitis, indicating maternal preponderance. Analysis of the occurrence of atopic dermatitis in relation to the birth order in the sibship shows an increased risk of atopic dermatitis in persons born early in a sibship. Although the families were selected for genetic sib-pair linkage analysis, we believe that this material is representative of atopic dermatitis families managed at hospitals in Stockholm.