-
[show abstract]
[hide abstract]
ABSTRACT: Addison's disease is an organ-specific autoimmune disorder with a polygenic background. The aim of the study was to identify non-class II human leukocyte antigen (HLA) susceptibility genes for Addison's disease.
Addison's disease patients from three European populations were analysed for selected HLA-DR-DQ alleles and for 11 microsatellite markers covering approximately 4 Mb over the HLA region. Subjects were 69 patients with Addison's disease from Estonia (24), Finland (14) and Russia (31). Consecutively recruited healthy newborns from the same geographical regions were used as controls (269 Estonian, 1000 Finnish and 413 Russian). Association measures for HLA-DRB1, DQB1, DQA1 and 11 microsatellites between D6S273 and D6S2223 were taken. A low-resolution full-house typing was used for HLA class II genes, while microsatellite markers were studied using fluorescence-based DNA fragment sizing technology.
We confirmed that the HLA-DR3-DQ2 and the DQB1*0302-DRB1*0404 haplotypes confer disease susceptibility. In Russian patients, we also found an increase of DRB1*0403 allele, combined with DQB1*0305 allele in three out of six cases (P<0.0001). Analysis of 11 microsatellite markers including STR MICA confirmed the strong linkage in DR3-DQ2 haplotypes but DRB1*0404-DQB1*0302 haplotypes were diverse. MICA5.1 allele was found in 22 out of 24 Estonian patients, but results from Finnish and Russian patients did not support its independent role in disease susceptibility.
HLA-DRB1*0403 was identified as a novel susceptibility allele for Addison's disease. Additionally, we found no evidence of a non-class II HLA disease susceptibility locus; however, the HLA-DR3-DQ2 haplotype appeared more conserved in patient groups with high DR-DQ2 frequencies.
European Journal of Endocrinology 12/2007; 157(6):757-61. · 3.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We determined the distribution of DR4 subtypes in 309 DQB1*0302-positive haplotypes found in insulin-dependent diabetes mellitus (IDDM) patients and 70 control haplotypes present only in healthy family members. An increased frequency of DRB1*0401 allele (74.4% vs. 55.7%, P = 0.003) and a decrease of DRB1*0404 allele (23.6% vs. 40.0%, P = 0.0064) was revealed. A further analysis of extended haplotypes demonstrated strong linkages between various B alleles and DRB1*04 subtypes. HLA-B39 was more frequent in DRB1*0404–DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA-DRB1 in the susceptibility to IDDM.
European Journal of Immunogenetics 10/2003; 24(5):357 - 363.
-
Diabetologia 08/2002; 45(7):1041-2. · 6.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To further characterize the HLA gene products that play an important role in the pathogenesis of rheumatoid arthritis (RA).
One hundred thirty-four haplotypes from 67 Finnish RA patients and 77 control haplotypes were analyzed for HLA-DRB1 loci, associated alleles of the HLA-DQB1 locus, alleles of the type 2 transporter-associated antigen processing (TAP2) genes, and HLA-B27. In addition, a panel of microsatellite markers within the HLA class I and class III regions was studied.
The frequency of HLA-DRB1*04 in the haplotypes of RA patients was found to be 34% (45 of 134) compared with 14% (10 of 72) in control haplotypes (P = 0.004). The frequency of HLA-DRB1*13 was decreased in RA haplotypes (4%, or 5 of 134) in contrast to control haplotypes (24%, or 17 of 72) (P = 0.000031). The decrease in DRB1*13 was not secondary to the increase in DRB1*04, since it was also found among DRB1*04-negative haplotypes (P < 0.001). The DRB1*13-associated DQB1*0604 allele was similarly decreased in RA haplotypes (P = 0.025). The TAP2I allele of I/J dimorphism was increased in RA patients (85%, or 114 of 134) as compared with controls (69%, or 49 of 71) (P = 0.011). Of the tumor necrosis factor (TNF) microsatellite alleles, TNFa6 and TNFb5 were found to be increased in RA haplotypes (for a6 27% versus 5% in controls [P = 0.00043], and for b5 43% versus 26% in controls [P = 0.037]).
Both protection-associated and susceptibility-associated alleles can be found among HLA class II genes, and the results suggest that loci outside DR/DQ may contribute to the pathogenesis of RA.
Arthritis & Rheumatism 03/2001; 44(2):315-22. · 7.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)- and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association.
Diabetes 01/2001; 49(12):2217-21. · 8.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The intercellular adhesion molecule-1 (ICAM-1) has an important role in the process of lymphocyte migration and activation, and is supposed to be involved in the pathogenesis of type 1 diabetes. We studied A/G (K469E) polymorphism of the ICAM-1 gene in 218 type 1 diabetes patients and 212 controls from Finland and found no association. We then studied transmission of the ICAM-1 alleles in 102 Finnish families using a transmission disequilibrium test (TDT). Alleles A and G were transmitted to the affected offspring in 50% each. Stratification by the HLA-DQB1-DQA1 genotypes, sex and age at onset did not reveal association. Our data demonstrate that in the Finnish population K469E polymorphism of the ICAM-1 gene is not associated with type 1 diabetes.
Tissue Antigens 07/2000; 55(6):568-70. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To improve sensitivity and specificity of the diabetes risk assessment of the population-based genetic screening used in the Finnish Diabetes Prediction and Prevention (DIPP) trial.
One thousand consecutive newborns enrolled in the DIPP were compared with 316 samples from children with Type 1 diabetes mellitus. A modification of the previously described technique based on hybridization of relevant PCR products with five lanthanide-labelled probes detected by time-resolved fluorometry (TRF) was used. A new probe was designed and allowed discrimination between DQB1*0602 and 0603 alleles, in addition to DQB1*02, *0301 or *0302, each of which required specific probes. A new, added screening strategy was developed for individuals carrying low-risk genotypes through specific typing of DQA1 *05 and *0201 alleles in DQB1*02 positive, and DRB1 typing for DR4 subtypes in DQB1*0302 positive subjects, with a new specifically designed high-resolution TRF-based DR4 subtyping technique.
This two-step screening approach enhanced the sensitivity of the detection of genetic risk for Type 1 diabetes mellitus in this cohort up to 85.4%. In the general population cohort, 24.4% were identified for prospective follow-up, 2.6% of these are expected to develop Type 1 diabetes mellitus before the age of 15 years. Exclusive typing for HLA-DQB1 locus as an alternative screening strategy had sensitivities of 26.3-77.2% with general population cohorts of 2.3-23.1% identified for follow-up.
The described strategy for genetic prediction of Type 1 diabetes mellitus relies on the convenient genotyping procedure and could be applied in large scale screening projects such as DIPP.
Diabetic Medicine 01/2000; 16(12):985-92. · 2.90 Impact Factor
-
S Nejentsev,
S Koskinen,
M Sjöroos,
H Reijonen,
E I Schwartz,
L Kovalchuk,
A Sochnev,
B Adojaan,
T Podar,
M Knip,
O Simell,
M Koskenvuo,
H K Akerblom,
J Ilonen
[show abstract]
[hide abstract]
ABSTRACT: The high incidence of insulin-dependent diabetes mellitus (IDDM) in Finland contrasts strikingly with the low rates in the neighbouring populations of countries in the Eastern Baltic region: Estonia, Latvia and Russia. To evaluate the possible contribution of genetic factors to these differences, the frequencies of HLA-DQB1 alleles and relevant DQB1-DQA1 or DQB1-DRB1 haplotypes associated with IDDM risk or protection were analysed among IDDM patients and control subjects from these four populations. An increased frequency of HLA-DQB1*0302, DQB1*02-DQA1*05 and DQB1*0302-DRB1*0401 was observed in subjects with IDDM in all studied populations, whereas the prevalence of DQB1*0301 and DQB1*0602 and/or *0603 was decreased among patients. The degree of IDDM risk associated with HLA alleles analysed here did not differ significantly between the populations. Comparisons of the distribution of IDDM-related HLA alleles and haplotypes in the background populations revealed its consonance with IDDM incidence. The combined frequency of high risk genotypes was significantly higher among Finns than in other populations studied. Our data support the hypothesis that variance in the dispersion of HLA alleles is the genetic basis of variation of IDDM incidence observed in the Eastern Baltic region.
Tissue Antigens 12/1998; 52(5):473-7. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We determined the distribution of DR4 subtypes in 309 DQB1*0302-positive haplotypes found in insulin-dependent diabetes mellitus (IDDM) patients and 70 control haplotypes present only in healthy family members. An increased frequency of DRB1*0401 allele (74.4% vs. 55.7%, P = 0.003) and a decrease of DRB1*0404 allele (23.6% vs. 40.0%, P = 0.0064) was revealed. A further analysis of extended haplotypes demonstrated strong linkages between various B alleles and DRB1*04 subtypes. HLA-B39 was more frequent in DRB1*0404-DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA-DRB1 in the susceptibility to IDDM.
European Journal of Immunogenetics 11/1997; 24(5):357-63.
-
[show abstract]
[hide abstract]
ABSTRACT: The genes encoding the HLA-DQ heterodimer molecules, DQB1 and DQA1, have been found to have the strongest association with IDDM risk, although there is cumulative evidence for the effect of other gene loci within the major histocompatibility complex gene region. After the HLA-DQ locus, the HLA-DR locus has been suggested most often as contributing to the disease susceptibility. In this study we analyzed at the population level the effect of DR4 subtypes and class I, HLA-B alleles, on IDDM risk when the influence of the DQ locus was stratified. In all three populations studied (Estonian, Latvian, and Russian), DQB1*0302 haplotypes most frequently carried DRB1*0401 or DRB1*0404. DRB1*0401 was the most prevalent subtype in IDDM patients, whereas DRB1*0404 was decreased in frequency. DRB1*0402 was also prevalent among Russian haplotypes, but was not associated with IDDM risk. When HLA-B alleles were analyzed, strong associations between the presence of specific B alleles and DRB1*04 subtypes were detected. The HLA-B39 allele was found significantly more often in DRB1*0404-DQB1*0302-positive patients than in healthy control subjects positive for this haplotype: 27 of 54 (50%) vs. 4 of 49 (8.2%) (P < 0.0001). The results demonstrate that DQ and DR genes cannot explain all of the HLA-linked susceptibility to IDDM, and that the existence of a susceptibility locus telomeric to DR is probable.
Diabetes 11/1997; 46(11):1888-92. · 8.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The rare HLA-DQB1*0304 allele was found increased among IDDM patients in the populations of the eastern Baltic region. Its frequency among IDDM patients was 4.5% (20/443) compared to 1.1% (9/853) in healthy controls in the combined series of Estonian, Latvian and St. Petersburg Russian populations (P=0.0001). HLA-DQB1*0304 in these populations was associated with DRB1*0408, and the haplotype was further characterized by a B35 allele and a typical combination of microsatellite markers from the TNF gene region. The result is compatible with the significance of the 57th amino acid in the DQ beta-chain but also emphasizes the importance of alleles in other HLA loci adjacent to DQ in the determination of IDDM susceptibility.
Tissue Antigens 06/1997; 49(5):532-4. · 2.59 Impact Factor
