Hans K. Åkerblom

Cohort Profile: The Cardiovascular Risk in Young Finns Study

In Finland, coronary heart disease (CHD) incidence was very high in the 1960s and 1970s. In line with this high incidence, the Seven Countries Study showed that the level of serum cholesterol in Finns was also the highest among the investigated countries in the 1960s. Because several studies indicated that the atherosclerotic process starts early in life, and in accord with the World Health Organization Recommendation of 1978 which stated that studies assessing atherosclerosis precursors in children should be initiated, a program was launched in Finland in the late 1970s to study cardiovascular risk in the youth. The Cardiovascular Risk in Young Finns Study was designed as a collaborative effort between five university departments of medical schools (i.e. in Helsinki, Kuopio, Oulu, Tampere and Turku) and several other institutions in Finland. The aim was to study the levels of CHD risk factors and their determinants in children and adolescents of various ages in different parts of the country. Two pilot studies were carried out in 1978 (N1⁄4 264, age 8 years) and in 1979 (N1⁄4 634, aged 3, 12 and 17 years). The first main cross-sectional (baseline) study was performed in 1980. The baseline study included 3596 children and adolescents aged 3, 6, 9, 12, 15 and 18 years. Between 1980 and 1992, these cohorts were followed up at 3-year intervals. The latest examination of the Cardiovascular Risk in Young Finns Study was performed in 2001, when the participants were young adults, aged 24–39 years. At the time of writing, the 27-year (i.e. 27 years since the start of the study when the participants are aged 30–45 years) follow-up field studies are being conducted, and will be completed in the beginning of 2008.

A Prospective Study of the Role of Coxsackie B and Other Enterovirus Infections in the Pathogenesis of IDDM

Coxsackievirus B infections have been associated with clinical manifestation of insulin-dependent diabetes mellitus (IDDM) in several studies, but their initiating role in the slowly progressing β-cell damage is not known. This is the first prospective study designed to assess the role of coxsackie B and other enterovirus infections in the induction and acceleration of this process. Three separate series were studied: 1) an intrauterine exposure series comprising 96 pregnant mothers whose children subsequently manifested IDDM and 96 control mothers whose children remained nondiabetic; 2) a cohort of 22 initially unaffected siblings of diabetic children who were followed until they developed clinical IDDM (mean observation time, 29 months) and 110 control siblings who remained nondiabetic; 3) a case-control series comprising 90 children with newly diagnosed IDDM and 90 control subjects. Enterovirus infections were identified on the basis of significant increases in serum IgG, IgM, or IgA class antibodies against a panel of enterovirus antigens (capture radioimmunoassay). Enterovirus antibodies were significantly elevated in pregnant mothers whose children subsequently manifested IDDM, particularly in cases in which IDDM appeared at a very young age, before the age of 3 years (P < 0.005). Serologically verified enterovirus infections were almost two times more frequent in siblings who developed clinical IDDM than in siblings who remained nondiabetic (mean, 1.0 vs. 0.6 infections/follow-up year; P < 0.001). This difference was seen both close to the diagnosis of IDDM and several years before diagnosis. Up to 19% (10 of 52) of the infections in prediabetic siblings were associated with increases in islet cell antibody (ICA) levels, and 83% (10 of 12) of ICAs increase with enterovirus infections. The corresponding figures in control siblings were 3% (5 of 185, P < 0.001) and 38% (5 of 13, Ns). IgM class enterovirus antibodies were slightly elevated in young children (<3 years old)with newly diagnosed IDDM (P < 0.05), but not in older patients. These observations suggest that exposures to enterovirus infections, both in utero and in childhood, are able to induce β-cell damage and lead to clinical IDDM after a varying subclinical period.

Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group.

An unselected population of 755 siblings of children with insulin-dependent diabetes mellitus (IDDM) was studied to evaluate the predictive characteristics of islet cell antibodies (ICA), antibodies to the IA-2 protein (IA-2A), antibodies to the 65-kD isoform of glutamic acid decarboxylase (GADA), insulin autoantibodies (IAA), and combinations of these markers. We also evaluated whether the histochemical ICA test could be replaced by the combined detection of other markers. 32 siblings progressed to IDDM within 7.7 yr of the initial sample taken at or close to the diagnosis of the index case (median follow-up, 9.1 yr). The positive predictive values of ICA, IA-2A, GADA, and IAA were 43, 55, 42, and 29%, and their sensitivities 81, 69, 69, and 25%, respectively. In contrast to the other three antibody specificities, GADA levels were not related to the risk for IDDM. The risk for IDDM in siblings with four, three, two, one, or no antibodies was 40, 70, 25, 2, and 0.8%, respectively. Combined screening for IA-2A and GADA identified 70% of all ICA-positive siblings, and all of the ICA-positive progressors were also positive for at least one of the three other markers. The sensitivity of the combined analysis of IA-2A and GADA was 81%, and the positive predictive value was 41%. In conclusion, combined screening for IA-2A and GADA may replace the ICA assay, giving comparable sensitivity, specificity, and positive predictive value. Accurate assessment of the risk for IDDM in siblings is complicated, as not even all those with four antibody specificities contract the disease, and some with only one or no antibodies initially will progress to IDDM.

Tracking of Serum Lipid Levels, Blood Pressure, and Body Mass Index from Childhood to Adulthood: The Cardiovascular Risk in Young Finns Study.

OBJECTIVES To examine tracking and predictiveness of childhood lipid levels, blood pressure, and body mass index for risk profile in adulthood and the best age to measure the childhood risk factor levels. STUDY DESIGN Study subjects were participants of the longitudinal Cardiovascular Risk in Young Finns Study, started in 1980 (age 3, 6, 9, 12, 15, and 18 years). A total of 2204 subjects participated to the 27-year follow-up in 2007 (age, 30 to 45 years). RESULTS In both sex groups and in all age groups, childhood risk factors were significantly correlated with levels in adulthood. The correlation coefficients for cholesterol levels and body mass index were 0.43 to 0.56 (P < .0001), and for blood pressure and triglyceride levels, they were 0.21 to 0.32 (P < .0001). To recognize children with abnormal adult levels, the National Cholesterol Education Program and the National High Blood Pressure Education Program cutoff points for lipid and blood pressure values and international cutoff points for overweight and obesity were used. Age seemed to affect associations. The best sensitivity and specificity rates were observed in 12- to 18-year-old subjects. CONCLUSIONS Childhood blood pressure, serum lipid levels, and body mass index correlate strongly with values measured in middle age. These associations seemed to be stronger with increased age at measurements.

Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

BACKGROUND Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children. METHODS In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cows-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age. RESULTS The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups. CONCLUSIONS Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity--markers that may reflect an autoimmune process leading to type 1 diabetes. (ClinicalTrials.gov number, NCT00570102.).

Atherosclerosis precursors in Finnish children and adolescents. I. General description of the cross-sectional study of 1980, and an account of the children's and families' state of health.

ABSTRACT. The paper describes the general outline of a multicentre study on the risk factors of coronary heart disease (CHD) and their determinants in children of various ages in different parts of Finland. The study was a cross‐sectional one, and was carried out in 1980 in five university cities of Finland with medical schools and in 12 rural communities in their vicinity. The randomized sample included an equal number of boys and girls, aged 3, 6, 9, 12, 15, and 18 years, and an equal number of urban and rural population in each area. The total sample size was 4,320 subjects, and of these 3,596 participated (83.1 %). The families received before the medical examination of the child, questionnaires on the Socioeconomic background, the childs general health and development, the parents’and grandparents’health status, and the childs food and exercise habits. At the physical examination also a fasting blood sample (lipids, insulin, trace elements) was taken, a bundle of hair was cut for trace element analysis, and a 48‐hour recall on food intake was obtained from every second subject.

Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes—indication of an increased environmental pressure?

Aims/hypothesisThe incidence of Type 1 diabetes has increased 2.5 times during the time period from 1966 to 2000 in Finland—a general trend seen in almost all developed countries that can only be explained by environmental factors. The aim of this study was to test the possible effect of a changing environment on distribution of genotypes associated with disease susceptibility.MethodsHLA DRB1-DQA1-DQB1 genes and two diabetes-associated polymorphisms at IDDM2 and IDDM12 were analyzed. The frequencies of genotypes were compared between cases diagnosed with childhood-onset Type 1 diabetes during the period of 1939–1965 (n=367) and those diagnosed between 1990 and 2001 (n=736). Chi-square statistics or the Fishers Exact test were used for the comparison of frequencies of analyzed haplotypes and genotypes in the two groups.ResultsThe frequencies of (DR3)-DQA1*05-DQB1*02 and (DR4)-DQB1*0302 risk haplotypes and the high risk (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 genotype were higher while proportion of patients carrying protective haplotypes—(DR15)-DQB1*0602 and (DR1301)-DQB1*0603—or protective genotypes was lower in patients diagnosed before 1965 as compared to those who developed disease after 1990. No temporal variation was found in the frequencies of genotypes at IDDM2 and IDDM12.Conclusion/interpretationOur data suggest that the need for genetic susceptibility to develop Type 1 diabetes has decreased over time due to an increasing environmental pressure and this results in a higher disease progression rate especially in subjects with protective HLA genotypes.

Putative environmental factors in Type 1 diabetes.

Various environmental triggers, e.g. certain viruses and dietary factors, are thought to initiate the autoimmune process, leading to the destruction of pancreatic beta-cells and consequent Type 1 diabetes. A genetic predisposition is another prerequisite allowing the autoimmune process to progress. Twin studies, major geographical variations in incidence rates, temporal trends in the incidence and findings in migrant studies indicate that environmental factors play a crucial role in the development of Type 1 diabetes. In the present review the major focus is on dietary factors, and among them particularly the possible role of cows milk proteins. The cows milk and Type 1 diabetes hypothesis was developed more than 10 years ago, and the issue is still not settled. Among viral infections, enteroviruses are today the most interesting group of viruses in this respect, as recent prospective studies indicate that these viruses may trigger and potentiate existing beta-cell autoimmunity. Among toxins, particularly N-nitroso compounds are of potential interest, as they are probably involved in the aetiology of some cases. Finally, psychosocial factors and the interaction between genetic predisposition and environmental factors are briefly discussed.

Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries.

There are marked geographic differences in the incidence of insulin-dependent diabetes mellitus (IDDM); for example, children in countries such as Finland are over 35 times more likely to develop IDDM than children in Japan. An understanding of the reasons for the geographic differences is likely to be important for understanding and, hopefully, preventing IDDM. There are problems, however, because of the lack of registries with adequate standardization. The major needs for the future studies include (1) to clarify the definition of IDDM for epidemiologic study, (2) to establish a standardized approach for IDDM registries, (3) to use registries to evaluate viral, immunologic, and genetic differences in order to explain differential risks across populations, and (4) to encourage the development of new population-based registries worldwide.

Epidemiology of childhood diabetes mellitus in Finland-background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus

SummaryA 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%).