A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families

Children with type 1 diabetes (T1D) susceptibility HLA genotypes are shown to have an increased birthweight. We investigated to what extent T1D-predisposing HLA haplotypes were associated with increased birthweight. A total of 1255 Finnish children comprising those with T1D and their non-diabetic siblings were investigated. A total of 342 children and their non-diabetic parents were HLA genotyped. Birthweight data were obtained from the national Medical Birth Registry. The population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 was associated with high birthweight (P=0.0280) in families with a diabetic offspring. Other T1D-predisposing HLA haplotypes showed nonsignificant tendency with high birthweight. More infants with a birthweight ⩾4000 g were born in families with a T1D offspring than in the general Finnish population (P=0.0139). The previously observed direct association between birthweight and T1D risk may be mediated through the modulating effects that T1D susceptibility HLA genes have on weight. High birthweight and subsequent weight gain may accelerate the ongoing pancreatic autoimmune process in genetically susceptible individuals. The high proportion of infants having a birthweight ⩾4000 g in families with a diabetic offspring raises a concern of potential adverse health outcomes that high birthweight can have.

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title: Type 1 diabetes: new perspectives on disease pathogenesis and treatment
abstract: As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic complexity of this disease and the challenges associated with its treatment. Many new concepts about the pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate. Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

title: Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends
abstract: Several reports on the incidence of Type I (insulin-dependent) diabetes mellitus have suggested that the incidence is increasing. The aim of this study was to find out whether the incidence is increasing globally or restricted to a selected populations only and to estimate the magnitude of the change in . During 1960 to 1996 37 studies in 27 countries were carried out. To fulfil the inclusion criteria the study periods ranged from 8–32 years. The temporal trend was fitted by linear regression, with the logarithm of the age-standardized incidence as the dependent variable and the calendar year as the independent variable. Then, the regression coefficient ( × 100 %) is approximately the average relative increase in incidence per year (as percentage).¶Results. Results from the pooled data from all 37 populations showed that the overall increase in incidence was 3.0 % per year (95 % CI 2.6; 3.3, p = 0.0001). The statistically significant increase was found in 24 of 37 populations including all high incidence ( > 14.6 per 100 000 a year) populations. The relative increase was, however, steeper in the populations with a lower incidence. The correlation between logarithm of the incidence and the increase in incidence was r = –0.56, p = 0.0004.¶Conclusion/interpretation. The incidence of Type I diabetes is increasing worldwide both in low and high incidence populations. By the year 2010 the incidence will be 50 per 100 000 a year in Finland and also in many other populations it will exceed 30 per 100 000 a year.

title: Genetic Determinants of Type 1 Diabetes Across Populations
abstract: T1D results from autoimmune‐mediated destruction of the pancreatic β cells, a process that is conditioned by multiple genes and environmental factors. The main genetic determinants map to the major histocompatibility complex (MHC), and in particular DR and DQ, although, genes outside the MHC contribute, including the insulin gene, PTPN22, and CTLA‐4. There are remarkable differences in genetic susceptibility to T1D between populations. We believe this variation reflects differing frequencies of diabetes causative and protective alleles and haplotypes, and thus remains a major genetic influence linked to the MHC region not accounted for by DR and DQ alleles. In this article, we discuss global variations in genetic susceptibility to T1D in view of current genetic understanding.

title: A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population
abstract: SummaryIn 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).

title: Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB Substudy 2 Study Group.
abstract: To explore whether perinatal factors are associated with the development of childhood type 1 diabetes.



We studied hospital records from 892 cases of childhood type 1 diabetes compared with 2,291 population-based control subjects in seven study centers in Europe.



In a pooled analysis incorporating stratification by center, we confirmed the previous findings that older maternal age, maternal preeclampsia, neonatal respiratory disease, and jaundice caused by blood group incompatibility are significant risk factors for type 1 diabetes, whereas being a firstborn child, having a low birth weight, or having a short birth length were protective. Cesarean section delivery and neonatal infectious diseases were not significantly associated with the risk of type 1 diabetes in this study. The strongest association was found for blood group incompatibility (AB0 and Rh factor) with an odds ratio (OR) of 2.96 (95% CI 1.88-4.65). AB0 incompatibility (OR = 3.92) was a more common and also a stronger risk factor than Rh incompatibility (OR = 1.62). The effect of AB0 blood group incompatibility was independent of treatment effects in logistical regression analysis.



Different perinatal events are associated with an increased risk of type 1 diabetes. The effect of maternal-child blood group incompatibility is strong and indicates a true effect that must be further explored.

title: Environmental Triggers and Determinants of Beta-Cell Autoimmunity and Type 1 Diabetes
abstract: Type 1 diabetes mellitus is perceived as a chronic immunemediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible subjects. The most important genes contributing to disease susceptibility are located in the HLA-DQ locus on the short arm of chromosome 6 . Nevertheless only a relatively small proportion, i.e. less than 10%, of genetically susceptible individuals progress to clinical disease. This implies that additional factors are needed to trigger and drive beta-cell destruction in genetically predisposed subjects. Clinical Type 1 diabetes represents end-stage insulitis, and it has been estimated that at the time of diagnosis only 10–20% of the insulin-producing beta cells are still functioning. Environmental factors have been implicated in the pathogenesis of Type 1 diabetes both as triggers and potentiators of beta-cell destruction [2–4]. Several lines of evidence support a critical role of environmental factors in the pathogenesis of type 1 diabetes. Studies in monozygotic twins indicate that only 13–33% are pair-wise concordant for Type 1 diabetes [5,6], suggesting that there is either acquired post-conceptional genetic discordance, or differential exposure to the putative environmental factor(s). The geographic variation in the incidence of Type 1 diabetes in children is conspicuous even among Caucasians, with one of the lowest annual rates reported from northern Greece amounting to less than 5/100,000 children under the age of 15 years [7] and the highest rate observed in Finland reaching 50 in 1998 [Reunanen, personal communication]. This tenfold difference in incidence can hardly be explained by genetic factors. A substantial increase in the incidence of Type 1 diabetes among children has been documented over the last decades particularly in Europe, and e.g. in Finland the incidence has increased more than four times from the early 1950’s . Such an increase cannot be the consequence only of enhanced genetic disease susceptibility in the population but must mostly be due to changes in life style and environment. Migrant studies have been little utilized in epidemiological surveys of Type 1 diabetes. Data available indicate, however, that the incidence of Type 1 diabetes has increased in population groups who have moved from a low incidence region to a high incidence area emphasizing the influence of environmental conditions . This review aims at providing a brief account of the environmental factors that have been implicated as triggers and risk factors in human Type 1 diabetes (Table 1) with an emphasis on the most recent candidates.

title: A Case-Control Investigation of Perinatal Risk Factors for Childhood IDDM in Northern Ireland and Scotland
abstract: To identify perinatal risk factors for childhood insulin-dependent diabetes mellitus (IDDM) and determine if they differ between early-onset and lateonset disease.  We selected 258 diabetic children in Northern Ireland and 271 diabetic children in Scotland from population-based registers. For each diabetic child, five matched control subjects were drawn from the same population. All perinatal data were recorded routinely at birth. Odds ratios (ORs) were estimated for parental age, social class, breast-feeding, deprivation measures, and other perinatal variables.  Scottish data indicated an increased risk among children born to older mothers (OR = 2.43, 95% confidence interval [CI] 1.49–3.97 for mothers >35 years of age relative to those <25 years of age). Northern Ireland data showed no such effect. Only Northern Ireland data showed an excess risk in children of professional or managerial families (OR = 1.51, 95% CI 1.11–2.04). A small but nonsignificant reduction in risk among breast-fed children was observed only after adjustment for social class (OR = 0.76, 95% CI 0.54–1.07). Deprivation measures were associated with reductions in risk. Children delivered by cesarean section were at increased risk in both Northern Ireland (OR = 1.66,95% CI 1.10–2.50) and Scottish (OR = 1.70,95% CI 1.12–2.59) data. In Northern Ireland data only, children of first pregnancies were at increased risk (OR = 1.41, 95% CI 1.03–1.93). Both data sets indicated that a first pregnancy was a more important risk factor for early-onset disease than for late-onset disease.  Many reported risk factors are weak and show inconsistencies between studies. They may be secondary to more direct, as-yet-undiscovered risk factors. Although irrelevant in the majority of cases, the increased risk associated with delivery by cesarean section deserves further study.

title: Low-Birth-Weight Infants Show Earlier Onset of IDDM
abstract: Pancreatic β-cell mass increases rapidly during gestation and early infancy. Infants who are small for gestational age, which is a marker for poor intrauterine nutrition, have reduced β-cell mass. We examined whether weight and length in early infancy, and in inference β-cell mass, is related to age at onset of insulindependent diabetes mellitus (IDDM).  Data from infant records of 232 patients with IDDM, including birth weight, birth length, gestational age, weight at 6 months of age, and feeding history during the first 6 months of life, were analyzed. Maternal recall was not used for data collection.  Low-birth-weight infants (<2.5 kg) showed a significantly earlier onset of diabetes (4.3 [3.2–6.0] years vs. 9.0 [5.3–11.8] years, median [25–75th percentile]; P < 0.0001). Infants small for gestational age also had earlier onset than those with birth weight above the 10th percentile after correction for gestational age (6.2 [3.6–10.5] vs. 9.2 [5.4–11.8] years; P < 0.0001). Infants with corrected birth weight: length ratio below the 10th percentile had earlier onset, as did infants with corrected 6-months weight below the 10th percentile (4.9 [2.8–6.0] years vs. 8.8 [5.2–11.8] years; P < 0.0001). Infants who were exclusively breast-fed for 6 months showed a slightly later onset of diabetes than those who were bottle- or mixed-fed, independent of weight (9.4 [5.0–11.3] years vs. 8.3 [4.2–11.7] years; P < 0.0001).  Weight and growth parameters in utero and early infancy may influence the age at onset of IDDM. β-cell mass is likely to be a significant factor.

title: No association between birth weight and Type 1 diabetes mellitus – a twin‐control study
abstract: To investigate, by means of a twin‐control study, whether there is a relationship between birth weight and Type 1 diabetes mellitus.

title: Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood Type 1 diabetes: a UK regional retrospective cohort study
abstract: To investigate perinatal risk factors for childhood Type 1 diabetes in a UK population cohort.

title: Testing the accelerator hypothesis: body size, beta-cell function, and age at onset of type 1 (autoimmune) diabetes.
abstract: The "accelerator hypothesis" predicts that fatness is associated with an earlier age at onset of type 1 diabetes. We tested the hypothesis using data from the SEARCH for Diabetes in Youth study.



Subjects were 449 youth aged <20 years at diagnosis who had positive results for diabetes antibodies measured 3-12 months after diagnosis (mean 7.6 months). The relationships between age at diagnosis and fatness were examined using BMI as measured at the SEARCH visit and reported birth weight, both expressed as SD scores (SDSs).



Univariately, BMI SDS was not related to age at diagnosis. In multiple linear regression, adjusted for potential confounders, a significant interaction was found between BMI SDS and fasting C-peptide (FCP) on onset age (P < 0.0001). This interaction remained unchanged after additionally controlling for number and titers of diabetes antibodies. An inverse association between BMI and age at diagnosis was present only among subjects with FCP levels below the median (<0.5 ng/ml) (regression coefficient -7.9, P = 0.003). A decrease of 1 SDS in birth weight (639 g) was also associated with an approximately 5-month earlier age at diagnosis (P = 0.008), independent of sex, race/ethnicity, current BMI, FCP, and number of diabetes antibodies.



Increasing BMI is associated with younger age at diagnosis of type 1 diabetes only among those U.S. youth with reduced beta-cell function. The intrauterine environment may also be an important determinant of age at onset of type 1 diabetes.

title: The relation between size at birth and risk of type 1 diabetes is not influenced by adjustment for the insulin gene (-23HphI) polymorphism or HLA-DQ genotype
abstract: have been described between higher birthweight and increased risk of type 1 diabetes, and of insulin (INS) and human leucocyte antigen (HLA) genotypes that protect against diabetes with larger size at birth. We studied simultaneously the effects of size at birth, INS and HLA genotypes on the risk of type 1 diabetes to test whether the relation between size at birth and risk of type 1 diabetes would be strengthened after adjustment for INS and HLA genotypes.Subjects and methodsWe designed a population-based case–control study in Norway with 471 cases of childhood-onset type 1 diabetes and 1,369 control subjects who were genotyped for the INS -23HphI polymorphism (surrogate for INS variable number of tandem repeats) and HLA-DQ alleles associated with type 1 diabetes. Data on birthweight and other perinatal factors were obtained from the Medical Birth Registry of Norway by record linkage.ResultsThe data fitted a multiplicative model for the protective INS class III allele both within the INS locus and for the model with INS- and HLA-DQ-conferred risk of type 1 diabetes. We found no overall significant association between weight or head circumference at birth and the risk of type 1 diabetes, and adjustment for INS and HLA genotype did not influence this result. There was also no evidence for association of INS or HLA with size at birth among control subjects. contrast to suggestions from previous indirect studies, direct adjustment for INS and HLA genotypes did not lead to a stronger relation between birthweight and the risk of type 1 diabetes.

title: Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study
abstract: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus.  Population based case-control study.  Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry.  Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband.  Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD).  There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42).  Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.  By linking two nationwide population based reg- isters the effect of intrauterine growth on the risk for childhood onset insulin dependent diabetes is estimated There was a clear trend in the risk for childhood onset diabetes according to differences in birth weight by gestational age expressed as multiples of SD from population means The adjusted odds ratio for babies who were small for gestational age was significantly decreased and for large for gestational age babies was significantly increased A poor intrauterine growth decreases and an excess growth increases the risk of development of childhood insulin dependent diabetes

title: The maternal-fetal relationship in human pregnancy: an immunogenetic perspective.
abstract: Although the mechanisms by which the fetal allograft escapes rejection are still poorly understood, abundant evidence has accumulated suggesting multiple roles for major histocompatibility complex (MHC) genes in pregnancy. Specific maternal MHC genotypes and maternal-fetal histocompatibility have been associated with recurrent spontaneous abortion, decreased fecundity, segregation distortions, altered sex ratios, fetal growth rates, and maternal autoimmune disease progression. In this review, the evidence for a variety of MHC gene effects in human pregnancy is considered.

title: High birth weight is associated with human leukocyte antigen (HLA) DRB1*13 in full-term infants.
abstract: In cord blood banking, substantial amounts of data on infants and cord blood are gathered at high cost, including birth weights and human leukocyte antigen (HLA) genotypes. As certain HLA alleles have been associated with protective host responses, it is possible that an HLA allele, or another factor linked to it, might even affect normal intrauterine growth. We explored cord blood bank data (n = 1381 infants) to elucidate whether there is an association between birth weight and HLA class II (DRB1) alleles. HLA DRB1 data were available from 1263 infants. We observed an association between birth weight and HLA DRB1*13, which was over-represented among full-term infants with the highest birth weights. The association remained when the birth weight was corrected for varying gestational age (relative birth weight) according to gender (P = 0.015). After correction of the P-value for multiple comparisons, the association was not statistically significant. However, when the birth weights of all infants were analysed for the effect of DRB1*13, infants positive for HLA DRB1*13 (n = 319) were found to have higher birth weights than infants negative for this allele (n = 944; median 3690 g vs. 3650 g, respectively; P = 0.044). Although the difference in median birth weight was only 40 g, it may be considered significant because it appeared after segregation of the infants into two groups according to the single HLA class II allele group earlier associated with protection against, for example, childhood type 1 diabetes and certain infectious diseases. The present finding may thus suggest identification of a new factor affecting normal intrauterine growth.

title: Diabetes-associated HLA genotypes affect birthweight in the general population
abstract: hypothesisThe aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight.MethodsHLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW).ResultsGenotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08–1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56–0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors.interpretationHLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

title: Relationship between increased relative birthweight and infections during pregnancy in children with a high-risk diabetes HLA genotype
abstract: with high-risk type 1 diabetes HLA genotype have increased risk of high relative birthweight (HrBW), while cord blood islet autoantibodies decrease the risk. As gestational infections may affect offspring type 1 diabetes risk, the aims were to test whether: (1) children of mothers reporting gestational infections have increased HrBW; (2) gestational infections explain islet autoantibody reduction of HrBW; and (3) gestational infections affect the association between HLA and HrBW.Subjects and methodsHLA genotypes and autoantibodies to glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin were determined in cord blood of children born to non-diabetic mothers in the Diabetes Prediction in Skåne (DiPiS) study. Mothers reported gestational infections when the child was 2 months old.ResultsFever or gastroenteritis during pregnancy was reported by 2,848/19,756 mothers (14%); 339 in more than one trimester. Children whose mothers reported infections had increased risk of HrBW (p = 0.0003), particularly in the absence of cord blood islet autoantibodies (interaction between HrBW, islet autoantibodies and infections, p = 0.0005). The effect on HrBW by high-risk HLA-DQ2/8 was aggravated by infections in more than one trimester (odds ratio [OR] = 5.24; p = 0.003) (interaction; p = 0.022). When infections were reported, cord blood islet autoantibodies decreased HrBW (OR = 0.34; p = 0.0002).Conclusions/interpretationThis study revealed that: (1) gestational fever, gastroenteritis, or both, increased the risk of HrBW; (2) cord blood islet autoantibodies decreased the risk of HrBW only in combination with infections; and (3) infections aggravated the association between HLA-DQ2/8 and HrBW. These data suggest an interaction between HLA, gestational infections, islet autoantibodies and fetal growth.

title: Fetal growth is increased by maternal type 1 diabetes and HLA DR4-related gene interactions
abstract: growth in non-diabetic pregnancies is reported to be influenced by type 1 diabetes susceptibility genes. In particular, the high-risk HLA DR4_DQB1*0302 haplotype is associated with increased birthweight. The aim of this study was to determine whether HLA DR4 was associated with increased birthweight in a maternal diabetes environment and whether effects persisted during early childhood.Subjects and methodsBirthweight and gestational age were obtained in singleton births from mothers with type 1 diabetes (n = 1161) or whose fathers or siblings have type 1 diabetes (n = 872). Weight and height at ages 2 and 5 years were obtained from paediatric records. Data were adjusted for (gestational) age and sex and expressed as percentiles of German reference data. HLA DR typing was obtained for all children and 1090 children also had insulin gene (INS) variable number of tandem repeats (VNTR) typing.ResultsMaternal type 1 diabetes was associated with increased birthweight, gestational age and birthweight percentiles (all p < 0.0001). In children of mothers with type 1 diabetes, birthweight percentile was further related to maternal HbA1c during pregnancy (r = 0.26; p < 0.0001) and was independently increased if children had HLA DR4 alleles (76th vs 64th percentile; p < 0.0001). HLA DR4 was not associated with birthweight in children of non-diabetic mothers. Birthweight was not associated with INS VNTR genotypes. High birthweight, but not HLA DR4 was associated with increased weight and BMI at ages 2 and 5 years (p < 0.0001).Conclusions/interpretationOur findings are consistent with the hypothesis that a diabetic intrauterine environment interacts with gene(s) marked by the type 1 diabetes susceptibility HLA DR4 alleles to increase fetal growth.

title: Diabetes-associated HLA-DQ genes and birth weight.
abstract: An association has recently been described between increased birth weight and increased risk of childhood-onset type 1 diabetes. Whether this relationship is explained by genes associated with both increased birth weight and increased risk of type 1 diabetes is unknown. In the present study, we tested the association between birth weight and HLA-DQ genotypes known to confer risk for type 1 diabetes among 969 nondiabetic children randomly selected from the Norwegian population. We found that HLA genotypes previously shown to confer risk for type 1 diabetes were associated with reduced birth weight (the mean difference in birth weight between the DQB1*0602/DQB1*0602 and DQ8/DQ2 genotypes was 354 g [95% CI 105-604]), which was opposite of that expected if HLA genes explained the birth weight-type 1 diabetes association.

title: Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?
abstract: FOR THE POPULATION GENETICIST, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene (cf. Allan, 1933; Pincus and White, 1933, 1934; Harris, 1950; Steinberg and Wilder, 1952; Lamy, Frezal and de Grouchy, 1957; Steinberg, 1959; Post, 1962a). If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of the obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent phenomenon, what changes in the environment are responsible for the increase? Current developments in the study of this disease suggest an explanation with important biological ramifications.

title: Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group.
abstract: To evaluate whether the increased risk of type 1 diabetes conferred by an early introduction of cow's milk supplements can be mediated by accelerated growth in formula-fed infants.



All children < or = 14 years of age who were diagnosed with type 1 diabetes from September 1986 to April 1989 were invited to participate in the study. Birth date- and sex-matched control children were randomly selected from the Finnish Population Registry. At least three weight measurements from the first year of life were obtained for 435 full-term diabetic subjects and 386 control subjects from well-baby clinics and school health care units.



Increase in body weight was greater in the diabetic girls than in the control girls, and the difference increased from 111 g (95% CI 0-218, P = 0.04) at 1 month of age to 286 g (95% CI 123-450, P = 0.0006) at 7 months. For boys, the difference in weight between the diabetic subjects and the control subjects remained stable during infancy (difference 95 g, 95% CI-2-205, P = 0.09). Increased weight was associated on average with a 1.5-fold risk of type 1 diabetes. Early introduction of formula feeding (< 3 vs. > or = 3 months) was also associated with an increased risk of type 1 diabetes after adjustment for the individual weight gain curve (adjusted odds ratio 1.53, 95% CI 1.1-2.2). No evidence for interaction was observed.



These observations indicate that an early exposure to cow's milk formula-feeding and rapid growth in infancy are independent risk factors of childhood type 1 diabetes.

title: Why are babies getting bigger? Temporal trends in fetal growth and its determinants.
abstract: To describe temporal trends in fetal "growth" and to examine the roles of sociodemographic, anthropometric, and other determinants.



Hospital-based cohort study of 61,437 nonmalformed singleton live births at 22 to 43 weeks' gestational age. Four main measures were examined: (1) birth weight, (2) birth weight-for-gestational-age Z score, (3) small-for-gestational-age (SGA), and (4) large-for-gestational age (LGA), with the latter 3 measures based on a recently developed population-based Canadian reference. Gestational age was based on the last normal menstrual period if confirmed (+/- 1 week) by early ultrasonogram.



The mean birth weight and Z score increased significantly (P <.0001) among infants > or =37 weeks, with a corresponding reduction in % SGA and a rise in % LGA. No consistent trends were seen among births 34 to 36 or < or =33 weeks. When simultaneous changes in maternal prepregnancy body mass index, gestational weight gain, height, cigarette smoking, and other clinical and sociodemographic factors were controlled by using multiple logistic regression, the temporal trends for term infants were no longer evident.



Increases in maternal anthropometry, reduced cigarette smoking, and changes in sociodemographic factors have led to an increase in the weight of infants born at or after term.

title: Early life risk factors for obesity in childhood: cohort study
abstract: To identify risk factors in early life (up to 3 years of age) for obesity in children in the United Kingdom.  Prospective cohort study.  Avon longitudinal study of parents and children, United Kingdom. Participants 8234 children in cohort aged 7 years and a subsample of 909 children (children in focus) with data on additional early growth related risk factors for obesity. Main outcome measures Obesity at age 7 years, defined as a body mass index 3 95th centile relative to reference data for the UK population in 1990.  Eight of 25 putative risk factors were associated with a risk of obesity in the final models: parental obesity (both parents: adjusted odds ratio, 10.44, 95% confidence interval 5.11 to 21.32), very early (by 43 months) body mass index or adiposity rebound (15.00, 5.32 to 42.30), more than eight hours spent watching television per week at age 3 years (1.55, 1.13 to 2.12), catch-up growth (2.60, 1.09 to 6.16), standard deviation score for weight at age 8 months (3.13, 1.43 to 6.85) and 18 months (2.65, 1.25 to 5.59); weight gain in first year (1.06, 1.02 to 1.10 per 100 g increase); birth weight, per 100 g (1.05, 1.03 to 1.07); and short (< 10.5 hours) sleep duration at age 3 years (1.45, 1.10 to 1.89).  Eight factors in early life are associated with an increased risk of obesity in childhood.

title: Stability of the association between birth weight and childhood overweight during the development of the obesity epidemic.
abstract: To assess whether changes in the birth weight distribution or changes in the association of birth weight with the later risk of childhood overweight have contributed to the development of the obesity epidemic.



A Danish population-based cohort study of 124,615 girls and 128,346 boys (ages 6 to 13 years), born between 1936 and 1983, were studied. Birth weight and annual measurements of height and weight were obtained from school health records. Overweight was defined by BMI in relation to internationally accepted criteria. The relative risk of being overweight by birth weight was calculated separately for each age, sex, and time period.



The birth weight distribution remained relatively stable over time. Compared with children with a birth weight of 3.0 to 3.5 kg, the risk of overweight increased consistently with each increase in birth weight category among girls and boys and at all ages between 6 and 13 years. Furthermore, the association between birth weight and increased risk of overweight in childhood remained stable across a 48-year period.



The increase in the prevalence of overweight could not be explained by time trends in the distribution of birth weight or by changes in the association between birth weight and the later risk of overweight over time. This implies that, unless the prenatal environment influences the later risk of overweight without increasing birth weight, the environmental influences contributing to the obesity epidemic in children of school age operate in the early postnatal period.

title: Secular trends in overweight and obesity among Finnish adolescents in 1977–1999
abstract: To study the trends in overweight and obesity among Finnish adolescents in 1977–1999.DESIGN: Mailed surveys every other year. Nationally representative samples of 12, 14, 16 and 18-y-olds (n=64 147, response rate 78.9%).METHODS: Overweight and obesity were measured by body mass index (BMI) and relative weight (RW) based on self-reported height and weight. BMI ≥the 85th percentile cut-off point for BMI in each age- and sex-specific group in the entire data set was considered as overweight, and BMI ≥95th percentile cut-off point as obesity. RW ≥110% and ≥120%, calculated as the individual's weight divided by the mean weight in each age- and sex-specific height percentile group in the entire data set, were considered as overweight and obesity, respectively. The trends in overweight and obesity are described by the change in the 85th and 95th percentile cut-off points of BMI over time. The prevalence of overweight and obesity is also reported using BMI reference values recommended for international comparisons. Because of the similarity of the BMI and the RW criteria in classifying adolescents as overweight and obese, only results based on BMI are presented. Overweight and obesity increased linearly in all sex and age groups from 1977 to 1999. Depending on the age group, the average increase in the 85th percentile cut-off point of the BMI per 10 y was 0.6–1.1 kg/m2 in boys and 0.3–0.7 kg/m2 in girls. The 95th percentile cut-off point of the BMI for boys and girls increased by 1.1–1.6 kg/m2 and by 0.6–1.0 kg/m2 per 10 y, respectively. In boys, the increase in overweight and obesity was largest in the two youngest age groups. In girls, the increase in overweight was largest in the oldest age group, and that of obesity both in the 14 and 18-y-olds. Overweight and obesity increased more in boys than in girls in all age groups except in the 18-y-olds among whom the increase was similar in both sexes. Examination of the entire BMI distribution showed that there was little or no change over time at the lower (5th, 15th) and middle (50th) percentiles, but increasing differences at the upper end of the distribution, the increases in the 95th percentile being even more marked than those in the 85th percentile curves. According to international reference values, the age-standardized prevalence of overweight increased in boys from 7.2 to 16.7%, and in girls from 4.0 to 9.8%, between 1977 and 1999. The prevalence of obesity in boys was 1.1% in 1977 and 2.7% in 1999, and in girls 0.4 and 1.4%, respectively. Overweight and obesity increased remarkably among Finnish adolescents from 1977 to 1999. The changes concentrated at the upper end of the BMI distribution, suggesting that factors behind this development have influenced only a part of the adolescent population.

title: Role of pancreatic beta-cells in the process of beta-cell death.
abstract: Studies on the pathogenesis of type 1 diabetes have mainly focused on the role of the immune system in the destruction of pancreatic beta-cells. Lack of data on the cellular and molecular events at the beta-cell level is caused by the inaccessibility of these cells during development of the disease. Indirect information has been collected from isolated rodent and human islet cell preparations that were exposed to cytotoxic conditions. This article reviews in vitro experiments that investigated the role of beta-cells in the process of beta-cell death. beta-Cells rapidly die in necrosis because of toxic levels of oxidizing radicals or of nitric oxide; they progressively become apoptotic after prolonged culture at low glucose or with proinflammatory cytokines. Their susceptibility to necrosis or apoptosis varies with their functional state and thus with the environmental conditions. A change in cellular phenotype can alter its recognition of potentially cytotoxic agents and its defense mechanisms against cell death. These observations support the view that beta-cells are not necessarily passive victims of a cytotoxic process but can actively participate in a process of beta-cell death. Their role will be influenced by neighboring non-beta-cells, which can make the islet internal milieu more protective or toxic for the beta-cells. We consider duct cells as potentially important contributors to this local process.

title: A high weight gain early in life is associated with an increased risk of Type 1 (insulin-dependent) diabetes mellitus
abstract: SummaryGrowth during the first years of life in relation to type of feeding in infancy was retrospectively studied in an unselected population-based group of 297 children who had been diagnosed with Type 1 (insulin-dependent) diabetes mellitus before the age of 15 years (probands) and 792 individually-matched referent subjects. Reliable data were collected from child welfare clinics. Probands weighed slightly less at birth but their weight gain at 6, 9, 18 and 30 months of age was significantly greater (p<0.02) than that of referent children. The weight gain of children who had never been breast-fed was more marked than that of breast-fed children; this was found for both probands and referent children. But also among exclusively breast-fed children (> 2 months), probands gained significantly more in weight from birth up to 18 and 30 months of age than exclusively breast-fed referent children. Early weight gain appears to be a risk factor for development of Type 1 diabetes. The lower weight gain in breast-fed compared to non-breast-fed children may explain the protective effect of breast feeding against Type 1 diabetes observed in several studies.

title: Etiological aspects of insulin-dependent diabetes mellitus: an epidemiological perspective.
abstract: The mechanism of beta-cell destruction leading to insulin dependent diabetes is probably a cell mediated auto-immune process occurring in genetically susceptible individuals. Since 50-70% of monozygotic twins will not get the disease non-genetic risk factors must play an important role in the etiology of the disease. During the past decade population based epidemiological studies have identified several risk determinants for insulin dependent diabetes. Based on these studies a multifactorial hypothesis of causation is proposed. Some risk determinants (maternal child blood group incompatibility, fetal viral infections, early exposure to cow's milk proteins, a high exposure level of nitrosamines) may independently initiate the autoimmune process by causing the initial damage of the beta-cell, leading to antigen release. Other risk determinants may promote an already ongoing autoimmune destructive process through induction of lymphokine release or by causing an increased work load on the beta-cell. Risk factors that may increase the peripheral need for insulin (infectious diseases, cold environment, a high growth rate and stressful life events) may act as promoters of the beta-cell destruction but also disclose the beta-cell impairment and make the disease clinically overt. Possibilities of different risk profiles in different age groups and of synergism between different risk factors are also discussed.

title: Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2
abstract: Secular growth changes have not been linked with type-1 diabetes. Longitudinal growth analysis in prediabetic type-1 children indicated increased body mass index (BMI) in the first year of life and an increased growth in length in the next 2 years. These heavier and taller children presented with autoantibodies against pancreatic islet tyrosine phosphatases at diagnosis many years later. It is possible that increased BMI during the first year of life and the development of such autoantibodies represents an additional risk marker towards earlier clinical onset of disease.

title: The relative contributions of birth weight, weight change, and current weight to insulin resistance in contemporary 5-year-olds: the EarlyBird Study.
abstract: For more than a decade, the fetal programming hypothesis has taught that insulin resistance and its associated metabolic disturbances result from poor gestational environment, for which low birth weight is a surrogate. Low birth weight, however, is now uncommon in industrialized societies. We have investigated the relevance of birth weight, "catch-up" weight, and current weight to insulin resistance in 300 contemporary British children. Insulin resistance at 5 years was not related to birth weight but was correlated with current weight and weight catch-up in both sexes, more strongly so in girls (r = 0.33, P < 0.001 vs. r = 0.18, P = 0.03), who were intrinsically more insulin-resistant than boys. Weight change merely co-correlated with current weight (r = 0.67, P < 0.01 in both sexes) and did not improve on the prediction of insulin resistance. Most important, insulin resistance at 5 years was the same in children of heavier birth weight, whose weight SD score had not changed, as in those of lighter birth weight, matched for current weight, who had experienced so-called catch-up (boys 0.89 and 0.88 units, respectively, P = 0.96; girls 1.26 and 1.13 units, P = 0.41). Insulin resistance in contemporary children seems to be a function of excess current weight rather than of low birth weight or change in weight.

title: Unique HLA antigen frequencies in the Finnish population.
abstract: The Finnish Bone Marrow Donor Registry was established 1992 to serve Finnish patients in urgent need of bone marrow transplantation. This study details the HLA antigen frequencies, including those of the A 19 subtypes, in the Finnish population. Large regional variations were found in antigen frequencies between the different geographical areas of Finland. In particular, antigens A9, B12, B35, Cw4 and DR3 display regional frequency deviations, but B7, B8 and B15 also exhibit regional variations. The present population is the largest (n = 10,000) ever HLA-typed in Finland. 97% of the donors were HLA-A-B-DR typed. Confirmation of the serological HLA type was performed by DNA typing on 3% of the donors in the registry. A potential donor was found for 52% of Finnish patients in need of a matched unrelated donor for a bone marrow transplantation. Due to the ethnic origin of the Finns, it is not easy to find suitable bone marrow donors for Finnish patients in worldwide registries. It is thus important to maintain a national bone marrow donor registry which recruits donors from all over the country.

title: Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients.
abstract: The aims of our analysis were to obtain the empirical risk estimates for type 1 diabetes in the siblings of a Finnish population-based cohort of childhood-onset diabetic patients and search for demographic and other factors predicting the risk of type 1 diabetes in siblings. We defined the diabetes status of all siblings of all probands who are included in the nationwide register of Finnish cases for whom type 1 diabetes was diagnosed before age 18 years between 1965 and 1979. Siblings' diabetes status was ascertained by a record search of nationwide registries through 2001, and the type of diabetes and date of its manifestation were obtained from medical records. The total number of person-years during the follow-up was 405,685. Of the 10,168 siblings at risk, 647 (6.4%) had been diagnosed with type 1 diabetes by 2001. The cumulative incidence of type 1 diabetes by ages 10, 20, 30, 40, and 50 years in all siblings was 1.5, 4.1, 5.5, 6.4, and 6.9%, respectively. A young age at diagnosis in the index case, paternal young-onset diabetes, male sex, and older parental age at delivery considerably increased the risk of type 1 diabetes for siblings. This large prospective family study of type 1 diabetes in siblings of childhood-onset diabetic patients provides reliable empirical estimates for the sibling recurrence risk.

title: Nordic Medical Birth Registers in epidemiological research
abstract: This review discusses the use of Nordic Medical Birth Registers (MBRs) in epidemiological studies, paying special attention to the topics that have been investigated and to other data sources that increase the usefulness of MBRs. We divided the reviewed studies into four groups according to the data sources on which they were based: (1) studies using MBR data only; (2) studies combining maternal or paternal background information, obtained from other data sources, with MBR data; (3) studies combining MBR data with subsequent outcome information on newborns; and (4) studies using information about consecutive pregnancies and generations. Our review shows that MBRs are good sources for studying the following topics: maternal biological and obstetric background; interventions and health care during pregnancy and birth; newborns' short-term outcome; and the relations between these factors. In addition, the usefulness of MBRs increases when the data they contain are combined with data from other sources. We found that data from more than twenty different sources have been linked with MBR data in the Nordic counties. As time passes, national MBRs become a useful source of information for studies on consecutive pregnancies or generations. In addition, the associations between pregnancy, delivery, perinatal health and long-term outcome can be studied by using an MBR as the basic data source.

title: A uniform regimen enables decentralized care of diabetic pregnancies
abstract: A nationwide recommendation to standardize the care of diabetic pregnancies in different hospitals was given in Finland in 1993. The Medical Birth Register (MBR) was used to investigate whether these recommendations have been accepted and how they have affected the outcome of newborns.