- Sadauskaite-Kühne, Vaiva, 1970-
Genetic and environmental factors in relation to childhood type 1 diabetes mellitus aetiology and clinical presentation in Sweden and Lithuania
Doktorsavhandling (övrigt vetenskapligt)abstract
- Background. Incidence of Type I diabetes mellitus (DM) is increasing worldwide. It is affecting mostly young people, with the dramatically rising incidence among youngest children (those under age of 5 years). Most evident genetic association with Type I DM so far identified is by HLA (Human Leukocyte Antigen) region on the short arm of human chromosome 6p21.3 encoding class II genes. A higher accumulation of new cases is also seen in the families where already one member has been diagnosed with Type I DM. Still, even monozygotic twins who are HLA identical, have Type I DM concordance rates as low as 30-50 %. Therefore a role of environment as a risk factor for Type I DM is suggested Nutrition, especially early in life, environmental toxins, viruses, perinatal events, stress, social factors, seem to modify risk for the disease. It still remains unclear why the incidence of Type I DM varies so greatly, above 350-fold world wide, why countries in a close neighbourhood sharing similar latitude and climate like Sweden and Lithuania have such an extreme difference in childhood Type I OM incidence (Sweden 34.0/100 000 and Lithuania 8.9/100 000 in year 1999).A simultaneous epidemiological study in these two neighbouring countries with different type 1 DM incidence focused on clinical expression, genetic and environmental background of Type 1 DM diabetes, which could help to detect aetiological factors of the disease.Aims. Compare clinical presentation of childhood Type 1 diabetes mellitus in Sweden and Lithuania, in countries with high and low Type 1 DM incidence. Identify transmission rate of Type I DM related alleles and haplotypes in Lithuanian families with a child with diabetes. Test the hypothesis whether children with AB0 blood group incompatibility have a similar frequency of diabetes risk related HLA alleles as children with type 1 diabetes and healthy children. Identify environmental factors conferring possibly protection or risk for developing Type 1 diabetes mellitus.Material and methods. The study was designed as a case-control study. 517 0-15 years old newly diagnosed children with type I DM during 01 08 1995-01 08 2000 in South-East of Sweden (closest neighbouring part to Lithuania) and all 286 newly diagnosed children during 01 08 1996 - 01 08 2000 in Lithuania participated in the study, with control response rate 72.9% and 94.8%, respectively. Children and their parents filled in questionnaires at the time of diagnosis, as well as population-based age and sex matched randoruly selected three healthy controls. Blood samples were collected from newly diagnosed children with diabetes and their first degree relatives.Results. Swedish children were younger at the moment of diagnosis than were the Lithuanian children. In both countries the status at time of diagnosis was more severe among children without any first degree relative with diabetes. The proportion of children with ketoacidosis was three time higher in Lithuania than in Sweden. In Sweden, age, recent infections and mother's employment status were best predictors for DKA, whereas in Lithuania it was age and maternal education. Childhood type 1 diabetes mellitus presentation was more severe in Lithuania than in Sweden, especially in the young age.Together with a four times higher incidence of Type 1 in Sweden the children diagnosed in the south-east part of Sweden had also twice as often a family member with Type I diabetes. Mainly it was due to the higher prevalence of Type I DM among fathers in Sweden.Frequency of known diabetes risk related alleles was less prevalent among Lithuanian than among Swedish children with Type 1 DM. In Lithuania, DQB1*0302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently ouly from mothers. Any of these alleles had similar frequencies among female and male offspring.DR3 allele was increased in patients with AB0 incompatibility when compared to healthy controls. Patients with type I diabetes had significantly higher frequency of DR3, DQ2, DR4 and DQ8 alleles when compared to healthy controls. No significant difference was observed in frequency of DR3 between AB0 blood group incompatibility and type I diabetes patients.Psychosocial stress and infections were risk factors for developing Type 1 DM in both countries. High social mixing of the mothers was also increasing risk for diabetes for the children in both countries. Mother's age over 30 years at birth was a protective factor in Sweden, whereas in Lithuania it was a risk factor.Proportions of breast fed children were similar between cases and controls in both countries. Duration of exclusive and total breast feeding was significantly longer in Sweden than in Lithuania when diabetes status, country, age at diagnosis and sex were included as covariates. Both in Sweden and in Lithuania exclusive breast feeding was found to be protective against diabetes in certain age groups and in Sweden also the duration of total breast feeding was protective. Early introduction of breast milk substitution was a risk factor, when controlled for a group of other known risk factors.Conclusions. There are differences in clinical presentation of Type 1 DM between Sweden and Lithuania. This might be due to increased knowledge of disease in country with higher incidence. Environmental factors, such as suspended breastfeeding, infections or psychosocial stress are uniform risk factors despite the rate of incidence in the country. The way the predisposition of the innnune system is built up is complex and depends not only on differences in genetic background of the disease or different transmission rates of diabetes related risk haplotypes, but also in shared environment.