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- Lindell, Nina, 1984-
(author)
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Perinatal risk factors for type 1 diabetes in children and adolescents
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Background Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive loss of the insulin producing pancreatic β-cells. The disease process starts years before the clinical diagnosis. The cause of T1D is unknown, but it is believed to be a combination of genetic and environmental factors. Around 50% of the genetic risk is attributed to the human leucocyte antigen (HLA) genes and the strongest associations are with the HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes. The highest risk genotype is the heterozygote form of the two, the HLA-DQ2/8 genotype. It may be that certain environmental factors pose a risk to individuals with a particular genetic susceptibility but not to others. In the last few decades T1D incidence has risen very quickly and due to the rate of the increase, it is believed to depend on environmental factors rather than genetic. In parallel with this increase, the incidence of several environmental factors has also risen i.e., the incidence of cesarean section (CS), overweight/obesity in the general population and birthweight. These environmental factors have been implicated as risk factors for T1D, but studies have had conflicting results.Objective The overall aim of this thesis was to increase knowledge regarding factors during pregnancy and the perinatal period that could increase or decrease the risk of T1D among children and adolescents. The environmental risk factors studied were mode of childbirth (study I), maternal BMI and gestational weight gain (GWG) (study II) and the child’s size for gestational age and birthweight (study III). In the last study the environmental risk factors were compared between children with different genetic risks of T1D.Material and methods The studies included in this thesis are population-based register studies, three case-control studies and one cohort study, using prospectively collected material from the Swedish medical birth registry (MBR) and the Swedish pediatric diabetes quality registry (SWEDIABKIDS), as well as information from the Swedish national cohort study Better Diabetes Diagnosis (BDD). The study population consists of children and adolescents (0–18/19 years) diagnosed with T1D Jan 2000-Oct 2012 and registered in SWEDIABKIDS (n=9,376). All children with T1D were matched with four control children from the MBR with the same year and day of birth, same sex, and born in the same region of Sweden (n=37,504). In study I, the entire study population was used but in study III twins were excluded (n=552). In study II, children for whom data on their mother’s BMI in early pregnancy and GWG were available were included (3,231 children with T1D and 12,948 control children). In study IV, children with T1D who also participated in the BDD study were included (4,533 children).Results and conclusions Maternal overweight and obesity were associated with an increased risk of T1D in the offspring but were not more common among children with high or low genetic risk. Maternal BMI was also inversely associated with the age at onset of T1D in children with HLADQ8/ X and/or HLA-DQ2/X. Neither GWG nor mode of childbirth had any obvious impact on the risk of developing T1D. Being born large for gestational age or with a birthweight ≥4000 g (macrosomia) was associated with an increased risk of T1D and being born small for gestational age or with a low birthweight (<2500 g) was associated with a decreased risk of T1D, irrespective of maternal BMI and diabetes. Comparing children with T1D and different HLA genotypes revealed a slight difference in birthweight between the genotype groups. Children with HLA-DQ2/8 were more often born with macrosomia compared to children with HLA-DQ8/X. Children without either HLA-DQ2 or HLADQ8 (HLA-DQX/X) were more often born with a low birthweight compared to those with HLADQ2/ 8 and HLA-DQ8/X. Size for gestational age did not differ between the genotype groups, and the effect of size for gestational age and birthweight on age at onset of T1D was ambiguous.The effects of the environmental risk factors identified in this thesis are generally weak and no clear conclusion on whether they are causative can be drawn. Yet since overweight/obesity and a high birthweight are common in the population, even a small increase in risk can result in many cases of T1D. Overweight/obesity and a high birthweight are also associated with other adverse health outcomes and they are, at least partly, modifiable. This motivates additional research regarding their involvement in T1D etiology as well as preventive actions against overweight and obesity in the population.
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| 2. |
- Berhan, Yonas, 1970-
(author)
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Epidemiological studies of childhood diabetes and important health complications to the disease
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Background and aims: The overall aim of this thesis was to increase knowledge regarding the occurrence of childhood onset T1D and T2D in Sweden and in relation to that describe and elucidate important aspects on two grave complications to diabetes; end-stage renal disease (ESRD) and mortality. The two first studies included in this thesis aimed to describe and analyze the cumulative incidence of childhood onset T1D in Sweden and to assess the occurrence of undetected T2D in Swedish children. The aim with the third study was to describe the cumulative incidence of ESRD, and to analyze how ESRD risk differs with age at-onset and sex. The aim of the fourth study was to show how parental socioeconomic status (SES) affects all cause mortality in Swedish patients with childhood onset T1D.Study populations: The foundation for the studies on T1D was data from the Swedish Childhood Diabetes Registry (SCDR). When studying ESRD we also included adult onset T1D cases from the Diabetes Incidence Study in Sweden (DISS). The study on T2D was a population-based screening study where BMI was measured in 5528 school-children and hemoglobin A1c was measured in children with overweight according to international age and sex specific BMI cut-offs. To study ESRD and mortality, we linked the SCDR to various nationwide registers containing individual information on SES, mortality and ESRD.Results: The incidence rates of childhood onset T1D has continued to increase in Sweden 1977–2007. Age- and sex-specific incidence rates varied from 21.6 (95% CI 19.4–23.9) during 1978–1980 to 43.9 (95% CI 40.7– 47.3) during 2005–2007. Cumulative incidence by birth-cohorts has shifted to a younger age at-onset over the first 22 years of incidence registration. From the year 2000 there was a significant reverse in this trend (p<0.01). In contrast to the increase of T1D, we found no evidence of undetected T2D among Swedish school children. Despite a relatively high incidence in T1D in Sweden there is low cumulative incidence of ESRD, 3.3% at maximum 30 years of duration. We found difference between the sexes regarding long-term risk of developing ESRD that was dependent on the age at onset of T1D. When analyzing how socioeconomic status affects mortality in different age at death groups, we found that having parents that received income support increased mortality up to three times in those who died after 18 years of age.Conclusion: The incidence of childhood onset T1D continued to increase in Sweden 1978-2007. Between the years 1978-1999 there was a shift to a younger age at-onset, but from the year 2000 there is a change in this shift indicating a possible trend break. The prevalence of T2D among Swedish children up to 12 years of age is probably very low. There is still a low cumulative incidence of T1D associated ESRD in Sweden. The risk of developing ESRD depends on age at-onset of T1D, and there is a clear difference in risk between men and woman. Excess mortality among subjects with childhood onset T1D still exists, and low parental socioeconomic status additionally increased mortality in this group.
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| 3. |
- Wernroth, Mona-Lisa
(author)
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Type l diabetes in childhood and adolescence, environmental exposures and gut microbiota
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Environmental factors leading to disturbances in the gut microbiota might play an important role as triggers for, and/or contributing factors in, the development of type 1 diabetes (T1D). The overall aim of the research underlying this thesis was to study the influence of environmental factor exposure on the risk of T1D in childhood and adolescence, and gut microbiota composition in early childhood.In this project, national registers provided information about T1D onset and exposure to animals, antibiotics, caesarean section and severe stress, defined as death of a first degree relative. In the first study (1,999 T1D events), no evidence supported an association between early exposure to dog or farm animals and T1D in childhood. In the second study (1,297 T1D events), dispensed prescriptions of antibiotics in the first year of life was found to be associated with T1D during childhood. Sibling analysis did not indicate confounding from familial factors. Furthermore, the effect estimate for the association between antibiotics and T1D was largest in children delivered by caesarean section. In the third study (10,789 T1D events), death of a close relative was associated with an increased risk for T1D within the first years following the loss, and when the loss occurred during the teenage years. The fourth study was a longitudinal study using 16S rRNA sequencing to analyse faecal samples from 83 children to study the gut microbiota development from birth to 2 years of age. Having a furry pet in the household was associated with a lower abundance of a bacterial species belonging to the genus Bifidobacterium. The overall gut microbiota composition was associated with prenatal exposure to antibiotics and caesarean section. Finally, caesarean section was associated with a lower abundance of Bacteroidetes and a higher abundance of Firmicutes.In conclusion, no evidence was found in the present study to support the association of exposure to animals to lowered risk of T1D in the general population. Although exposure to antibiotics was associated with T1D, it is likely to only make a small contribution to the overall risk of T1D. Our findings support the hypothesis that severe stress might accelerate T1D onset during certain time periods. Furthermore, our findings add to the body of research showing that exposure to animals, prenatal antibiotics and caesarean section account for some of the inter-individual variation in early childhood microbiota development.
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