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Biomedical subjects

G Joner

Publications and source records attributed to G Joner.

At least 19 recordsLinked to original sources
PubMed2006

Low cumulative incidence of proliferative retinopathy in childhood-onset type 1 diabetes: a 24-year follow-up study.

AIMS/HYPOTHESIS: We estimated cumulative incidence of proliferative diabetic retinopathy (PDR) and risk factors for developing diabetic retinopathy (DR) in childhood-onset type 1 diabetes. MATERIALS AND METHODS: A sample of 294 patients with childhood-onset type 1 diabetes (<15 years) diagnosed in Norway between 1973 and 1982 was examined for retinopathy at baseline between 1989 and 1990 and at follow-up from 2002 to 2003. At follow-up, mean age was 33 years (range: 21-44), mean diabetes duration 24 years (19-30) and total person-time contributed 7,152 person-years. Retinal photographs were taken at baseline and follow-up. Associations between baseline factors and PDR were estimated using Cox regression models. RESULTS: Overall, 262 of 294 (89.1%) developed DR from diabetes onset, of whom 31 developed PDR. The 25-year cumulative incidence of PDR was 10.9% (95% CI 7.3-14.5). Among 194 without retinopathy at baseline, 163 (84%) developed DR and nine (5%) progressed to PDR. Among 97 patients with non-proliferative DR at baseline, 19 (20%) progressed to PDR. Significant predictors for developing PDR were retinopathy at baseline (relative risk [RR]=3.71, 95% CI 1.59-8.68), HbA(1c) (RR=2.05, 1.44-2.93), and triglycerides (RR=1.55, 1.06-1.95). CONCLUSIONS/INTERPRETATION: Nine out of every ten patients diagnosed with type 1 diabetes developed DR, but only one out of ten developed PDR within their first 25 years of diabetes duration. The cumulative incidence of PDR is lower than previously reported from other countries. Potentially modifiable risk factors predict the development of DR and PDR.

Adolescent↗
PubMed2006

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.

AIMS/HYPOTHESIS: Associations 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 METHODS: We 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. RESULTS: The 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. CONCLUSIONS/INTERPRETATION: In 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.

Adolescent↗
PubMed2005

Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway.

AIMS/HYPOTHESIS: We examined long-term total and cause-specific mortality in a nationwide, population-based Norwegian cohort of patients with childhood-onset type 1 diabetes. MATERIALS AND METHODS: All Norwegian type 1 diabetic patients who were diagnosed between 1973 and 1982 and were under 15 years of age at diagnosis were included (n=1,906). Mortality was recorded from diabetes onset until 31 December 2002 and represented 46,147 person-years. The greatest age attained among deceased subjects was 40 years and the maximum diabetes duration was 30 years. Cause of death was ascertained by reviews of death certificates, autopsy protocols and medical records. The standardised mortality ratio (SMR) was based on national background statistics. RESULTS: During follow-up 103 individuals died. The mortality rate was 2.2/1000 person-years. The overall SMR was 4.0 (95% CI 3.2-4.8) and was similar for males and females. For ischaemic heart disease the SMR was 20.2 (7.3-39.8) for men and 20.6 (1.8-54.1) for women. Acute metabolic complications of diabetes were the most common cause of death under 30 years of age (32%). Cardiovascular disease was responsible for the largest proportion of deaths from the age of 30 years onwards (30%). Violent death accounted for 28% of the deaths in the total cohort (35% among men and 11% among women). CONCLUSIONS/INTERPRETATION: Childhood-onset type 1 diabetes still carries an increased mortality risk when compared with the general population, particularly for cardiovascular disease. To reduce these deaths, attention should be directed to the prevention of acute metabolic complications, the identification of psychiatric vulnerability and the early detection and treatment of cardiovascular disease and associated risk factors.

Adolescent↗
PubMed2004

Atopic disorders and risk of childhood-onset type 1 diabetes in individuals.

BACKGROUND: Data on the relationship between Th2-biased atopic disorders and Th1-biased autoimmune diseases such as type 1 diabetes are conflicting. Many studies have not defined the time sequence of disease appearance, and few have investigated the role of candidate risk factors. OBJECTIVE: The objective was to investigate whether the presence of parents' report of physician-diagnosed atopic disorders is lower among cases of type 1 diabetes before diagnosis, as compared with population-based control subjects, and whether this may be explained by candidate risk factors such as day-care attendance, breastfeeding habits, and perinatal factors. METHODS: We designed a population-based case-control study in Norway with 545 cases of childhood-onset type 1 diabetes and 1668 control subjects. Families were contacted by mail, and they completed a questionnaire on physician-diagnosed atopic eczema, allergic rhino-conjunctivitis and asthma, and other relevant factors. Data on birth order, maternal age at delivery, birth weight, gestational age, pre-eclampsia, and caesarean section were obtained from the Medical Birth Registry of Norway by record linkage. RESULTS: Atopic eczema was inversely associated with risk of type 1 diabetes, odds ratio=0.55 (95% confidence interval 0.35-0.87) after adjustment for age, sex, maternal education, day-care attendance, duration of exclusive breastfeeding, and perinatal factors. Allergic rhino-conjunctivitis and asthma were not significantly associated with type 1 diabetes. CONCLUSIONS: Atopic eczema was associated with a lower risk of type 1 diabetes, independent of a number of candidate risk factors, suggesting that it may confer partial protection against type 1 diabetes.

Adult↗
PubMed2001

Maternal and paternal age at delivery, birth order, and risk of childhood onset type 1 diabetes: population based cohort study.

OBJECTIVE: To estimate the associations of maternal and paternal age at delivery and of birth order with the risk of childhood onset type 1 diabetes. DESIGN: Cohort study by record linkage of the medical birth registry and the national childhood diabetes registry in Norway. SETTING: Norway. SUBJECTS: All live births in Norway between 1974 and 1998 (1.4 million people) were followed for a maximum of 15 years, contributing 8.2 million person years of observation during 1989-98. 1824 cases of type 1 diabetes diagnosed between 1989 and 1998 were identified. MAIN OUTCOME MEASURES: Incidence of type 1 diabetes. RESULTS: There was no association between maternal age at delivery and type 1 diabetes among firstborn children, but among fourth born children there was a 43.2% increase in incidence of diabetes for each five year increase in maternal age (95% confidence interval 6.4% to 92.6%). Each increase in birth order was associated with a 17.9% reduction in incidence (3.2% to 30.4%) when maternal age was 20-24 years, but the association was weaker when maternal age was 30 years or more. Paternal age was not associated with type 1 diabetes after maternal age was adjusted for. CONCLUSIONS: Intrauterine factors and early life environment may influence the risk of type 1 diabetes. The relation of maternal age and birth order to risk of type 1 diabetes is complex.

Adult↗
PubMed2001

Birth weight and childhood onset type 1 diabetes: population based cohort study.

OBJECTIVE: To assess the associations between birth weight or gestational age and risk of type 1 diabetes. DESIGN: Population based cohort study by record linkage of the medical birth registry and the National Childhood Diabetes Registry. SETTING: Two national registries in Norway. PARTICIPANTS: All live births in Norway between 1974 and 1998 (1 382 602 individuals) contributed a maximum of 15 years of observation, a total of 8 184 994 person years of observation in the period 1989 to 1998. 1824 children with type 1 diabetes were diagnosed between 1989 and 1998. MAIN OUTCOME MEASURES: Estimates of rate ratios with 95% confidence intervals for type 1 diabetes from Poisson regression analyses. RESULTS: The incidence rate of type 1 diabetes increased almost linearly with birth weight. The rate ratio for children with birth weights 4500 g or more compared with those with birth weights less than 2000 g was 2.21 (95% confidence interval 1.24 to 3.94), test for trend P=0.0001. There was no significant association between gestational age and type 1 diabetes. The results persisted after adjustment for maternal diabetes and other potential confounders. CONCLUSION: There is a relatively weak but significant association between birth weight and increased risk of type 1 diabetes consistent over a wide range of birth weights.

Adolescent↗
PubMed2001

Diabetes-associated HLA-DQ genes and birth weight.

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.

Birth Weight↗
PubMed2000

[Genetic and immunologic risks for development of type 1 diabetes--experiences from an intervention trial].

BACKGROUND: Type 1 diabetes is a common multi-factorial disease. Recently, promising attempts have been made at preventing the disease in individuals at risk. We present our experiences as participants in an international multicentre intervention trial, the European Nicotinamide Diabetes Intervention Trial (ENDIT). The aim is to prevent prediabetic individuals from becoming overtly diabetic by the use of nicotinamide. MATERIAL AND METHODS: First degree relatives of type 1 diabetes children attending paediatric clinics in Norway were recruited. The level of islet cell antibodies (ICA) was determined. Individuals with ICA titer above 20 Juvenile Diabetes Foundation Units (JDFU) were allocated to treatment with nicotinamide or placebo in a double-blind design. In the Norwegian patients in the trial HLA-DQ genotypes were also determined. RESULTS: 56 individuals had ICA > 20 JDFU; 36 agreed to participate in the trial. Assessment of genetic and immunological risk did not seem to emotionally upset the majority of participants; so far, no serious adverse events have been observed. The final results of this trial are expected in year 2003. INTERPRETATION: Prevention of type 1 diabetes may be feasible in the future.

Adult↗
PubMed2000

Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring.

AIMS/HYPOTHESIS: To test whether cod liver oil or vitamin D supplements either taken by the mother during pregnancy or by the child in the first year of life is associated with lower risk of Type I (insulin-dependent) diabetes mellitus in children. METHODS: We carried out a population-based case control study in Vest-Agder county of Norway, evaluating the use of supplements by a mailed questionnaire. We received responses from 85 diabetic subjects and 1,071 control subjects. Odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression analyses. RESULTS: When mothers took cod liver oil during pregnancy their offspring had a lower risk of diabetes. The unadjusted OR was 0.30, 95% CI: (0.12 to 0.75), p = 0.01. This association changed very little and was still significant after adjusting for age, sex, breastfeeding and maternal education. Mothers taking multivitamin supplements during pregnancy [adjusted OR= 1.11, 95% CI: (0.69 to 1.77)], infants taking cod liver oil in the first year of life [adjusted OR = 0.82, 95 % CI: (0.47 to 1.42) and the use of other vitamin D supplements in the first year of life [adjusted OR = 1.27, 95 % CI: (0.70 to 2.31)] was not [corrected] significantly associated with the risk of diabetes. CONCLUSION/INTERPRETATION: We found that cod liver oil taken during pregnancy was associated with reduced risk of Type I diabetes in the offspring. This suggests that vitamin D or the n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid in the cod liver oil, or both, have a protective effect against Type I diabetes.

Breast Feeding↗
PubMed1999

The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene.

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21, encodes a major part of the genetic predisposition to develop type 1 diabetes, designated "IDDM1." A primary role for allelic variation of the class II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major histocompatibility complex (MHC)-linked genes are participating in IDDM1. The strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between class II alleles and alleles at other MHC loci. We have scanned 12 Mb of the MHC and flanking chromosome regions with microsatellite polymorphisms and analyzed the transmission of these marker alleles to diabetic probands from parents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approach is useful for the analysis of other loci linked to common diseases, to verify if a candidate polymorphism can explain all of the association of a region or if the association is due to two or more loci in linkage disequilibrium with each other.

Alleles↗
PubMed1998

[Differences in morbidity between the Eastern central city district and the suburban Western district of Oslo].

Oslo, the capital of Norway, has a population of 500,000. Living conditions vary considerably within the city, and the mortality rate in the most deprived area is almost three times as high as in the most affluent one. We wanted to explore how morbidity varies within Oslo. We used four town-wide disease registers to study the prevalence of the four diseases in the most deprived and the most affluent part of the city. We found that tuberculosis occurs more frequently in the poor area, while type 1 diabetes mellitus in children occurs more frequently in the most affluent area. For multiple sclerosis and rheumatoid arthritis we could not find any differences between the areas.

Adult↗
PubMed1998

Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13.

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLS>=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Chromosome Mapping↗
PubMed1998

Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6).

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.

Child↗
PubMed1997

HLA associations in insulin-dependent diabetes mellitus: no independent association to particular DP genes.

Genes in the HLA complex are associated with susceptibility to develop insulin-dependent diabetes mellitus (IDDM). Several studies, from different populations, have demonstrated strong associations between particular DR and DQ alleles and disease susceptibility or protection. Whether also particular DP alleles may independently contribute is more controversial. Some studies have found a greater frequency of DPB1*0301 among IDDM patients compared to controls, apparently independently of linkage disequilibrium with high risk DR and DQ alleles. To address this question in an ethnically homogeneous population (Norwegian), we have DPA1 and DPB1 genotyped 237 IDDM patients and 287 DRB1-DQA1-DQB1 matched controls, carrying high risk DR3/4 or DR4/4 genotypes. We were unable to detect any significant independent associations between DP alleles and IDDM susceptibility or protection in this population. Thus, our results do not support previous reports on an independent association between some DP alleles and susceptibility to develop IDDM.

Alleles↗
PubMed1997

Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21.

Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by affected sibpair linkage analysis is not practical and allelic association or linkage disequilibrium mapping will have to be employed to attempt to detect founder chromosomes. Given prior evidence of linkage of the Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated the 12 informative microsatellite markers in the region for linkage with disease by the transmission disequilibrium test (TDT) in a UK data set of type 1 diabetic families (n = 195). Increased transmission of allele 4 of marker D18S487 to affected children was detected (P = 0.02). Support for this was extended in a total of 1067 families from four different countries by isolating, and evaluating by the TDT, two novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to nonaffected siblings. Analysis of an additional 390 families by the TDT did not extend the evidence further, and reduced support in the total 1457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sibpair allele sharing was strong (P = 3.2 x 10(-5)) in the second data set. Heterogeneity in TDT results between data sets was, in part, accounted for by the presence of more than one common disease-associated haplotype (allelic heterogeneity) which confounds the analysis of individual alleles by the TDT. Guidelines for strategies for the mapping of polygenes are suggested with the emphasis on collections of large numbers of families from multiple populations that should be as genetically homogeneous as possible.

Adolescent↗
PubMed1997

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11.

A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006, Pc = 0.17). Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results (P = 0.009, Pc = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings (P = 0.0008, Pc = 0.02). This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families. These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families.

Adolescent↗