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  • 1
    Electronic Resource
    Electronic Resource
    HLA haplotypes in Type 1 (insulin-dependent) diabetes mellitus: molecular analysis of the HLA-DQ locus (1992)
    Springer
    Diabetologia 35 (1992), S. 254-260 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; HLA haplotypes ; HLA-DQ ; restriction fragment length polymorphism ; genetics ; disease susceptibility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In Caucasians the predisposition to Type 1 (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQβ chain. In Finland the haplotype-specific absolute risk for developing Type 1 diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQα and DQβ restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type 1 diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,Cw4,Bw35,DR4 A3,Cw3,Bw62,DR4, A24,Cw7,Bw39,DR4, A2,Cw3,Bw62, DR4, and A2,Cw1,Bw56,DR4 was 35/100,000, 130/100,000, 166/100,000, 196/100,000, and 218/100,000, respectively. The absolute risks for DR3,DQw2 positive haplotypes A1, Cw7,B8,DR3 and A2,Cw7,B8,DR3 were 68/100,000 and 103/100,000, respectively. These results provide further evidence that not only the polymorphism at the DQ locus but also other genes of the haplotypes contribute to susceptibility to Type 1 diabetes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400926
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  • 2
    Electronic Resource
    Electronic Resource
    Epidemiology of childhood diabetes mellitus in Finland — background of a nationwide study of Type 1 (insulin-dependent) diabetes mellitus (1992)
    Springer
    Diabetologia 35 (1992), S. 70-76 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; epidemiology ; genetic-environmental interaction ; incidence ; familial occurrence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A nationwide study of childhood Type 1 (insulin-dependent) diabetes mellitus was established in 1986 in Finland, the country with the highest incidence of this disease worldwide. The aim of the project called “Childhood Diabetes in Finland” is to evaluate the role of genetic, environmental and immunological factors and particularly the interaction between genetic and environmental factors in the development of Type 1 diabetes. From September 1986 to April 1989, 801 families with a newly-diagnosed child aged 14 years or younger at the time of diagnosis were invited to participate in this study. The vast majority of the families agreed to participate in the comprehensive investigations of the study. HLA genotypes and haplotypes were determined in 757 families (95%). Our study also incorporates a prospective family study among non-diabetic siblings aged 3–19 years, and two case-control studies among the youngonset cases of Type 1 diabetes. During 1987–1989, the overall incidence of Type 1 diabetes was about 35.2 per 100,000 per year. It was higher in boys (38.4) than in girls (32.2). There was no clear geographic variation in incidence among the 12 provinces of Finland. Of the 1,014 cases during these 3 years only six cases were diagnosed before their first birthday. The incidence was high already in the age group 1–4-years old: 33.2 in boys and 29.5 in girls. Of the 801 families 90 (11.2%) were multiple case families, of which 66 had a parent with Type 1 diabetes at the time of diagnosis of the proband. The prevalence of Type 1 diabetes in the parents of these newly-diagnosed diabetic children was higher in fathers (5.7%) than in mothers (2.6%).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400854
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  • 3
    Electronic Resource
    Electronic Resource
    Decline of mumps antibodies in Type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of Type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland (1993)
    Springer
    Diabetologia 36 (1993), S. 1303-1308 
    Details
    ISSN: 1432-0428
    Keywords: Mumps ; mumps antibodies ; mumps-measlesrubella vaccination ; Type 1 (insulin-dependent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A nationwide mumps-measles-rubella vaccination was introduced in 1982 in Finland to children aged 1.5 to 6 years and since then mumps has virtually disappeared in the country. We investigated whether this rapid epidemiological change had any impact on antibody activity against mumps virus in Type 1 (insulin-dependent) diabetic children or on the incidence of Type 1 diabetes in Finland. Two case-control series were collected before (series I and II) and three series after (series III–V) the introduction of the vaccination. IgA class mumps antibody levels were significantly higher in Type 1 diabetic children than in matched control children in the first two but not in the three later series. IgG class antibody levels were similar in patients and control subjects in the first two series but significantly lower in patients than in control subjects in the three later series. The overall incidence of Type 1 diabetes in 0–14-year-old children increased until 1987 but remained about the same during 1988–1990. In 5–9-year-old children no further increase in Type 1 diabetes was seen since 1985, whereas in 0–4-year-old children the incidence continued to rise until 1990. The results suggest that the elimination of natural mumps by mumps-measles-rubella vaccination may have decreased the risk for Type 1 diabetes in Finland; a possible causal relationship is substantiated by the observed concomitant decrease in mumps antibody levels in diabetic children. However, further studies are required to determine if the vaccine virus, like natural mumps, could trigger the clinical onset of Type 1 diabetes in young children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400810
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  • 4
    Electronic Resource
    Electronic Resource
    A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population (1994)
    Springer
    Diabetologia 37 (1994), S. 937-944 
    Details
    ISSN: 1432-0428
    Keywords: Key words Genetics ; haplotype ; HLA-A ; HLA-DQ ; HLA-DR ; tumour necrosis factor ; diabetes mellitus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In Finland the haplotype A2, Cw1, B56, DR4, DQ8 is the third most common haplotype in insulin-dependent diabetic (IDDM) patients and has the highest haplotype-specific absolute risk for IDDM. Cw1, B56, DR4, DQ8 haplotypes containing HLA-A alleles other than A2 are infrequent in the population and are not associated with IDDM. Comparison of the A2 and non-A2 haplotypes at the DNA level showed that they were identical at HLA-B, -DR, and -DQ loci. Evidence that class I alleles confer susceptibility to IDDM was obtained from the two HLA-C, -B, -DR and -DQ haplotypes most frequently found in IDDM patients in Finland. A24, A3 and A2 on the Cw3, B62, DR4, DQ8 haplotype, and A28, A2 and A1 on the Cw7, B8, DR3, DQ2 were all found to be associated with IDDM. In Finland these seven haplotypes, including A2, Cw1, B56, DR4, DQ8, account for 33 % of diabetic haplotypes and 10.3 % of non-diabetic haplotypes (p 〈 0.00001). The contribution of the class I region to IDDM susceptibility was also apparent in those IDDM patients lacking the disease-predisposing class II alleles. Significantly more non-DR3/non-DR4 IDDM patients (47 of 55) possessed two of the IDDM-associated HLA-A alleles compared to non-DR3/non-DR4 control subjects (40 of 58; p = 0.038). Moreover, IDDM patients confirmed by oligotyping as unable to form a ’diabetes-susceptibility' DQ heterodimer, tended to possess two diabetes-associated HLA-A alleles (12 of 13) compared to control subjects (12 of 20; p = 0.056). [Diabetologia (1994) 37: 937–944]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400951
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  • 5
    Electronic Resource
    Electronic Resource
    In Finland insulin gene region encoded susceptibility to IDDM exerts maximum effect when there is low HLA-DR associated risk (1995)
    Springer
    Diabetologia 38 (1995), S. 1223-1229 
    Details
    ISSN: 1432-0428
    Keywords: Insulin gene ; HLA ; haplotype ; genetic susceptibility ; insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An association between insulin-dependent diabetes mellitus (IDDM) and polymorphisms of the insulin gene on chromosome 11p15 (INS) is a consistent finding in Europid populations. While one study suggested that the INS association is restricted to HLA-DR4-positive individuals, studies in other Europid populations have shown the disease-associated INS genotype to confer susceptibility independently of HLA-DR. We have investigated the role of INS in susceptibility to IDDM in Finland, which has the highest incidence of diabetes mellitus in the world, at two polymorphic restriction sites, 5′ and 3′ to the insulin gene. From the DiMe (Childhood Diabetes in Finland) Study we studied 154 diabetic children without regard to HLA-DR type; 108 DR4 positive/non-DR3 diabetic children; 39 DR3 positive/non-DR4 diabetic children; 30 DR4/DR3 positive diabetic children; 31 non-DR4/non-DR3 diabetic children; 96 matched DiMe control subjects and 86 other healthy, non-diabetic Finnish control subjects. We found an overall association between IDDM and INS in the high-risk Finnish population only with the 5′ polymorphism and identified an INS haplotype negatively associated with IDDM in Finland. However, among diabetic subjects with a reduced HLA-associated susceptibility (non-DR4/non-DR3) both 3′ and 5′ INS loci showed an association with IDDM (p values 0.02 and 0.0002, respectively). Thus, in the Finnish population insulin gene-encoded susceptibility to IDDM exerts a maximum effect in those with reduced HLA-associated risk.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00422373
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  • 6
    Electronic Resource
    Electronic Resource
    Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children (1994)
    Springer
    Diabetologia 37 (1994), S. 381-387 
    Details
    ISSN: 1432-0428
    Keywords: Infant feeding ; dairy products ; cow's milk protein antibodies ; IDDM ; childhood ; islet cell antibodies ; insulin autoantibodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date-and sex-matched population-based control children in the nationwide “Childhood Diabetes in Finland” study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabeticpopulation-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408475
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  • 7
    Electronic Resource
    Electronic Resource
    Natural history of preclinical IDDM in high risk siblings (1994)
    Springer
    Diabetologia 37 (1994), S. 388-393 
    Details
    ISSN: 1432-0428
    Keywords: Preclinical IDDM ; islet cell antibodies ; early insulin response ; glucose elimination rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To learn more about the preclinical phase of IDDM we observed for a median period of 46.5 months (range 0.5–69 months) a group of 57 siblings positive for ICA and/or IAA when first screened within 6 months of the diagnosis of the proband. Sequential blood samples and IVGTTs were obtained at intervals of 6–12 months. Seventeen siblings (29.8%) presented with IDDM during the observation period. The duration of the known preclinical period ranged from 0.5 to 51 months (median 29 months). The converters were younger than the other siblings (P〈0.05) and had higher initial ICA levels (P〈0.01). In addition they had a lower FPIR in the first IVGTT (P〈0.001). On all subsequent tests the converters had higher ICA levels and a lower FPIR (P〈0.05 or less), a lower glucose elimination rate from the third test onwards (P〈0.01 or less) and higher IAA levels at 3 years (P〈0.05). Some variation could be observed in the FPIR in the converters with an initial increase and subsequent decrease (P〈0.05 for both). Their levels of complement-fixing ICA increased up to 18 months (P〈0.05) and IAA levels up to 3 years (P〈0.01). Those high risk siblings who progress to clinical IDDM are characterized by young age, strong and increasing signs of islet-cell specific autoimmunity, reduced insulin secreting capacity and emerging glucose intolerance. The present observations seem to be incompatible with the hypothesis of beta-cell destruction occurring at a constant, predictable rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408476
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  • 8
    Electronic Resource
    Electronic Resource
    Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease (1995)
    Springer
    Diabetologia 38 (1995), S. 481-486 
    Details
    ISSN: 1432-0428
    Keywords: Insulin receptor substrate-1 ; gene mutations ; non-insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p=0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00410287
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  • 9
    Electronic Resource
    Electronic Resource
    Evidence for importance of gender and birth cohort for risk of IDDM in offspring of IDDM parents (1995)
    Springer
    Diabetologia 38 (1995), S. 975-982 
    Details
    ISSN: 1432-0428
    Keywords: Insulin-dependent diabetes mellitus ; epidemiology ; cumulative risk ; sex differential ; family history
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The risk of developing diabetes is higher in offspring of fathers than of mothers with insulin-dependent diabetes mellitus (IDDM). The reasons for this sex differential are unclear, as early studies were often selected and relatively small. We conducted a prospective study on the risk of IDDM in a cohort of 9,453 offspring from 5,255 Finnish parents with diabetes diagnosed before age 30 years. Age of first admission to the hospital was considered to be the age of diagnosis of IDDM in the offspring; IDDM occurred in 248 offspring. The risk of IDDM tended to be lower in the offspring of the same gender as the diabetic parent (adjusted risk ratio (RR) 0.78; p=0.50). When offspring were of same gender as the diabetic parent, male offspring had a higher risk of IDDM than female offspring (RR 2.28; 95% confidence interval 1.53–3.38), whereas if the gender of the diabetic parent and the offspring were different, the risk in male offspring was lower (RR 0.43; 95% confidence interval 0.31–0.62). For the offspring of diabetic fathers, the cumulative risk by the age of 20 was higher (7.6%) than for those with diabetic mothers (3.5%) (p〈0.0001). In a multivariate analysis statistically significant predictors of IDDM in the offspring were the sex of the parent, the year of birth and the birth order of the offspring. The risk of IDDM in the offspring increased by 9% per year of birth cohort. By age 20, the cumulative risk of developing IDDM in the offspring of diabetic parents was 5.3%, 10 times higher than in the background population. It is likely that genetic factors seem to have played a major role in the continuous increase of IDDM incidence in Finnish children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400588
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  • 10
    Electronic Resource
    Electronic Resource
    Evidence for importance of gender and birth cohort for risk of IDDM in offspring of IDDM parents (1995)
    Springer
    Diabetologia 38 (1995), S. 975-982 
    Details
    ISSN: 1432-0428
    Keywords: Key words Insulin-dependent diabetes mellitus ; epidemiology ; cumulative risk ; sex differential ; family history.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The risk of developing diabetes is higher in offspring of fathers than of mothers with insulin-dependent diabetes mellitus (IDDM). The reasons for this sex differential are unclear, as early studies were often selected and relatively small. We conducted a prospective study on the risk of IDDM in a cohort of 9,453 offspring from 5,255 Finnish parents with diabetes diagnosed before age 30 years. Age of first admission to the hospital was considered to be the age of diagnosis of IDDM in the offspring; IDDM occurred in 248 offspring. The risk of IDDM tended to be lower in the offspring of the same gender as the diabetic parent (adjusted risk ratio (RR) 0.78; p = 0.50). When offspring were of same gender as the diabetic parent, male offspring had a higher risk of IDDM than female offspring (RR 2.28; 95 % confidence interval 1.53–3.38), whereas if the gender of the diabetic parent and the offspring were different, the risk in male offspring was lower (RR 0.43; 95 % confidence interval 0.31–0.62). For the offspring of diabetic fathers, the cumulative risk by the age of 20 was higher (7.6 %) than for those with diabetic mothers (3.5 %) (p 〈 0.0001). In a multivariate analysis statistically significant predictors of IDDM in the offspring were the sex of the parent, the year of birth and the birth order of the offspring. The risk of IDDM in the offspring increased by 9 % per year of birth cohort. By age 20, the cumulative risk of developing IDDM in the offspring of diabetic parents was 5.3 %, 10 times higher than in the background population. It is likely that genetic factors seem to have played a major role in the continuous increase of IDDM incidence in Finnish children. [Diabetologia (1995) 38: 975–982]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400588
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