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Genetic and environmental factors in relation to childhood type 1 diabetes mellitus aetiology and clinical presentation in Sweden and Lithuania
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2004. , 142 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 835
Keyword [en]
Type 1 diabetes mellitus, children, environmental factors, aetiology
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-22011Local ID: 1032ISBN: 91-7373-806-9 (print)OAI: oai:DiVA.org:liu-22011DiVA: diva2:242313
Public defence
2004-02-27, Victoriasalen, University Hospital, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-26Bibliographically approved
List of papers
1. Severity at onset of childhood type 1 diabetes in countries with high and low incidence of the condition
Open this publication in new window or tab >>Severity at onset of childhood type 1 diabetes in countries with high and low incidence of the condition
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2002 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 55, no 3, 247-254 p.Article in journal (Refereed) Published
Abstract [en]

Severity of Type 1 diabetes mellitus (DM) at presentation was compared between south-east Sweden and Lithuania where incidence of childhood Type 1 diabetes is three times lower than in Sweden. New cases of diabetes at age 0–15 years from August 1995 to March 1999 in south-east Sweden and from August 1996 to August 2000 in Lithuania were included. Symptoms and clinical characteristics at diagnosis were recorded. Data about the close environment were collected using questionnaires. Lithuanian children were diagnosed in a more severe condition, mean pH 7.30 and HbA1c 11.5% compared with mean pH 7.36 and HbA1c 9.7% in Swedish children (P<0.0001). More Lithuanian than Swedish children were diagnosed in ketoacidosis (pH≤7.2, hyperglycaemia and ketonuria), 21.3 versus 7.3% (P<0.0001). Only 4.6% of Swedish children and 1.0% of Lithuanian children had no symptoms (P=0.007). Children in families with at least one first degree relative with diabetes (12.2% in Sweden and 8.4% in Lithuania, NS) had laboratory values at diagnosis closer to normal than sporadic cases in either country. Factors predicting ketoacidosis in Sweden were an unemployed mother and absence of infections in the 6 months before diagnosis. In Lithuania it was younger age and mother with less education. Additional educational activities for doctors are needed in countries with low incidence to reduce prevalence of ketoacidosis at onset.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26525 (URN)10.1016/S0168-8227(01)00328-X (DOI)11085 (Local ID)11085 (Archive number)11085 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. Inheritance of MHC class II genes in lithuanian families with type 1 diabetes
Open this publication in new window or tab >>Inheritance of MHC class II genes in lithuanian families with type 1 diabetes
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2003 (English)In: IMMUNOLOGY OF DIABETES II: PATHOGENESIS FROM MOUSE TO MAN, New York Academy of Sciences, 2003, Vol. 1005, 295-300 p.Conference paper, Published paper (Refereed)
Abstract [en]

Type 1 diabetes mellitus (DM) is caused by genetic and environmental factors. Twice as many fathers as mothers of children with type 1 DM have the disease. The reason for the differences remains unclear. We looked at the transmission rates of diabetes-related alleles from parents to children with diabetes. All children with newly diagnosed type 1 DM from August 1, 1996 to August 1, 2000, aged 0 to 15 years, in Lithuania were invited to participate. Blood samples for full genetic analysis were available from 125 families. HLA DQA1, DQB1, and DRB1 typing was done on DNA extracted from peripheral blood, by polymerase chain reaction amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide probe 3′-end labeling with 32P-dCTP, and hybridization, followed by stringency washes, autoradiography, and allele calling. Frequency of diabetes risk-related alleles DQB1*0302, DQA1*0201, DR4, and DR3 was less prevalent among Lithuanian than among Swedish children with type 1 DM. Transmission rates of DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501 haplotypes from parents were higher than expected: χ2 (TDT) 30.56, p < 0.0001, and χ2 (TDT) 11.26, p= 0.0008, respectively. DQB1*0302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently only from mothers. Any of these alleles had similar frequencies among female and male offspring. We conclude that, besides DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501, there are other inherited alleles that determine risk for type 1 DM among children in Lithuania. Fathers might transfer other alleles of disease susceptibility in higher frequency or mothers might provide a protective environment during pregnancy, which results in higher risk to offspring of fathers than mothers to develop diabetes.

Place, publisher, year, edition, pages
New York Academy of Sciences, 2003
Series
Annals of the New York Academy of sciences, ISSN 0077-8923, (Print) 1749-6632 (E-ISSN) ; 1005
Keyword
type 1 diabetes mellitus; MHC; genes; transmission; Lithuania
National Category
Endocrinology and Diabetes Genetics
Identifiers
urn:nbn:se:liu:diva-26532 (URN)10.1196/annals.1288.046 (DOI)000187496100045 ()11092 (Local ID)1-57331-460-9 (ISBN)11092 (Archive number)11092 (OAI)
Conference
6th International Congress of the Immunology-of-Diabetes-Society and American-Diabetes-Association Research Symposium, Copper, MT, Colorado, USA, October 3-6 2002
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2014-11-19Bibliographically approved
3. DR3 is associated with type 1 diabetes and blood group ABO incompatibility
Open this publication in new window or tab >>DR3 is associated with type 1 diabetes and blood group ABO incompatibility
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2002 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 958, 345-348 p.Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes is associated with autoimmunity against pancreatic β cells. ABO incompatibility is associated with ABO immunization during pregnancy. Type 1 diabetes is associated with certain HLA DR and DQ haplotypes. The mechanism by which blood group incompatibility is associated with the risk of type 1 diabetes is not known. We propose that certain HLA alleles contribute to the development of both type 1 diabetes and ABO blood group incompatibility. We studied 57 children with ABO blood group incompatibility, 118 children with type 1 diabetes, and 98 age- and sex-matched unrelated healthy controls from Linköping. Typing of HLA DQA1, DQB1, and DRB1 was done on DNA extracted from peripheral blood, by PCR amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide (SSO) probe 3′ end-labeling with 32P-dCTP, and hybridization followed by stringency washes and autoradiography. We observed that DR3 allele was more frequent in patients with ABO incompatibility when compared to healthy controls (OR = 2.7, Pc < 0.05). Patients with type 1 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 ABO blood group incompatibility and type 1 diabetes patients. We conclude that DR3 is associated with both the development of type 1 diabetes and ABO incompatibility.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26535 (URN)10.1111/j.1749-6632.2002.tb03002.x (DOI)11096 (Local ID)11096 (Archive number)11096 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Stress and social factors in relation to risk for type 1 diabetes
Open this publication in new window or tab >>Stress and social factors in relation to risk for type 1 diabetes
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background. Previous studies have shown controversial results regmding conelation between social status and risk for Type 1 diabetes mellitus (DM). Stress and infections have been shown to increase risk for Type 1 DM. We looked upon these factors in relation to risk for Type 1 DM in two countries, where incidence of the disease is very different.

Methods. Data from 0-15 years old 517 children (268 boys and 249 girls) in South-East of Sweden and 286 children (133 boys and 153 girls) in Lithuania with newly diagnosed type 1 diabetes mellitus were included into analysis. Three age and sex matched healthy controls were randomly selected. Response rate in control families in Sweden was 72.9% and in Lithuania 94.8%. Information was collected via questionnaires.

Results. Psychosocial stress and infections were risk factors for developing Type 1 DM in both countries (in Sweden OR 1.34, CI 1.01-1.79 and 1.99, CI 1.61-2.46 respectively, and in Lithuania 2.29, CI 1.59-3.32 and 1.82, CI 1.36-2.43, respectively). High social mixing of the mothers was also increasing risk for diabetes for the children in both countries (OR 1.32, CI 1.03-1.70 in Sweden and 1.45, CI 1.03-2.04 in Lithuania). Mother's age over 30 years at birth was a protective factor in Sweden (OR 0.66, CI 0.53-0.84), whereas in Lithuania it was a risk factor (OR 1.53, CI 1.14-2.06).

Conclusious. Psychosocial stress and infections are uniform risk factors, despite the various rate of incidence in the country. Other factors have more complex influence on the risk for diabetes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84916 (URN)
Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2012-10-26Bibliographically approved
5. Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood
Open this publication in new window or tab >>Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood
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2004 (English)In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 20, no 2, 150-157 p.Article in journal (Refereed) Published
Abstract [en]

Background

Early weaning diet, early introduction of breast milk substitution and cow's milk have been shown to increase the risk of type 1 diabetes later in life. It is also shown that older maternal age, maternal education, preeclampsia, prematurity, neonatal illness and neonatal icterus caused by blood group incompatibility, infections and stress might be risk factors for type 1 diabetes. We aimed to determine whether early nutrition is an independent risk factor for diabetes despite other life events.

Methods

Data from 517 children (268 boys and 249 girls) in south-east of Sweden and 286 children (133 boys and 153 girls) in Lithuania in the age group of 0 to 15 years with newly diagnosed type 1 diabetes mellitus were included into analysis. Three age- and sex-matched healthy controls were randomly selected. Response rate in control families in Sweden was 72.9% and in Lithuania 94.8%. Information was collected via questionnaires.

Results

Exclusive breastfeeding longer than five months (odds ratio 0.54, 95% confidence interval 0.36–0.81) and total breastfeeding longer than 7 (0.56, 0.38–0.84) or 9 months (0.61, 0.38–0.84), breastfeeding substitution that started later than the third month (0.57, 0.33–0.98) among Swedish children 5 to 9 years old and later than the seventh month (0.24, 0.07–0.84) among all Swedish children is protective against diabetes when adjusted for all other above-listed risk factors. In Lithuania, exclusive breastfeeding longer than two months in the age group of 5 to 9 years is protective (0.58, 0.34–0.99) when adjusted for other factors.

Conclusions

Longer exclusive and total breastfeeding appears as an independent protective factor against type 1 diabetes.

Keyword
type 1 (insulin-dependent) diabetes mellitus, environment, breastfeeding, cow's milk, Sweden, Lithuania
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22072 (URN)10.1002/dmrr.425 (DOI)1151 (Local ID)1151 (Archive number)1151 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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