Evidence for importance of gender and birth cohort for risk of IDDM in offspring of IDDM parents

Summary The risk of developing diabetes is higher in offspring of fathers than of mothers with insulin-dependent diabetes mellitus (IDDM). The reasons for this sex differential are unclear, as early studies were often selected and relatively small. We conducted a prospective study on the risk of IDDM in a cohort of 9,453 offspring from 5,255 Finnish parents with diabetes diagnosed before age 30 years. Age of first admission to the hospital was considered to be the age of diagnosis of IDDM in the offspring; IDDM occurred in 248 offspring. The risk of IDDM tended to be lower in the offspring of the same gender as the diabetic parent (adjusted risk ratio (RR) 0.78; p=0.50). When offspring were of same gender as the diabetic parent, male offspring had a higher risk of IDDM than female offspring (RR 2.28; 95% confidence interval 1.53–3.38), whereas if the gender of the diabetic parent and the offspring were different, the risk in male offspring was lower (RR 0.43; 95% confidence interval 0.31–0.62). For the offspring of diabetic fathers, the cumulative risk by the age of 20 was higher (7.6%) than for those with diabetic mothers (3.5%) (p<0.0001). In a multivariate analysis statistically significant predictors of IDDM in the offspring were the sex of the parent, the year of birth and the birth order of the offspring. The risk of IDDM in the offspring increased by 9% per year of birth cohort. By age 20, the cumulative risk of developing IDDM in the offspring of diabetic parents was 5.3%, 10 times higher than in the background population. It is likely that genetic factors seem to have played a major role in the continuous increase of IDDM incidence in Finnish children.Abbreviations IDDM Insulin-dependent diabetes mellitus - CI confidence interval - RR risk ratio     

Predictors of IDDM recurrence risk in offspring of Danish IDDM patients

Summary It has previously been observed that offspring of mothers with insulin-dependent diabetes mellitus (IDDM) have a lower risk of IDDM than offspring of IDDM affected fathers. To assess the offspring IDDM recurrence risk in a Danish population-based study and to investigate parental and offspring-related biological variables that might influence this risk, we identified 2726 IDDM probands and their 2826 offspring from a background population of 1.725 million people (33 % of the Danish population). Current age of probands was 20–65 years and their age at IDDM onset was 30 years or less. Sixty-nine offspring (2.4 %) were affected with IDDM. The sex difference in the parental-offspring IDDM transmission rate was confirmed. The cumulative IDDM risk up to age 30 years was found to be significantly decreased in maternal offspring compared to paternal offspring (2.3 ± 0.6 and 5.7 ± 0.9 %, RR = 2.40, 95 % CI 1.30–4.47; p = 0.004) only if parents were diagnosed with IDDM before birth of the offspring. However, due to the low number of diabetic offspring of probands diagnosed with IDDM after offspring birth, this observation needs to be confirmed in a larger population. In a subpopulation of the 2380 offspring, whose parents were all diagnosed with IDDM before offspring birth, the recurrence risk was significantly increased in offspring of male probands diagnosed up to age 17 years compared to offspring of fathers diagnosed at older ages (8.5 ± 1.8 and 3.6 ± 1.0 %; RR = 2.27, 95 % CI 1.21–4.25; p = 0.006). No such relation was found in maternal offspring. Using the Cox proportional hazards model on this offspring subpopulation we found that paternal age at IDDM onset was the only statistically significant predictor of IDDM recurrence risk. Our findings may be important for counselling families in which one parent has IDDM. [Diabetologia (1998) 41: 666–673] Received: 14 July 1997 and in revised form: 29 December 1997     

Is there an excess in maternal transmission of NIDDM?

Summary Family studies have demonstrated that there is a strong genetic component to the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), although the mode of inheritance is unknown. A number of recent family history studies, including one in Mexican Americans, have suggested that there is an excess of maternal transmission of NIDDM. Family history studies are subject to various types of bias, however, and the potential for bias in many of these studies has not been thoroughly evaluated. We therefore tested the hypothesis that diabetes is more likely to be transmitted from mothers than from fathers using data collected from a large family study of low-income Mexican Americans in San Antonio, Texas. The parents and offspring from 318 different nuclear families attended our medical clinic, where they received a 2-h oral glucose test. Diabetes was diagnosed on the basis of World Health Organization criteria. The sibships were classified into diabetic sibships (at least one sibling in the sibship was diabetic; n=54) and non-diabetic siblings (no diabetic siblings; n=264). The prevalence of diabetes among mothers of diabetic siblings was 61.4% (27 of 44) compared to 64.3% (18 of 28) among fathers of diabetic siblings (rate ratio=0.95; 95% confidence interval: 0.51–1.84). For the non-diabetic sibships, the prevalence of diabetes was 31.7% (78 of 246) and 28.9% (37 of 128) among mothers and fathers, respectively (rate ratio=1.09; 95% confidence interval: 0.73–1.67). These data provide no evidence for an excess maternal transmission of diabetes in Mexican Americans.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - OGTT glucose tolerance test - IDDM insulin-dependent diabetes     

Familial factors determine the development of diabetic nephropathy in patients with IDDM

Summary To evaluate familial factors in the development of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) we examined concordance for diabetic nephropathy in families with multiple IDDM siblings. Families (n=110) were identified through Joslin Clinic patients (probands) with a sibling having IDDM. To be eligible, the probands' and siblings' ages at IDDM diagnosis were less than 21 years, and IDDM duration was more than 15 years for probands and more than 10 years for siblings. Mean post-pubertal diabetes duration was 23 years for probands (n=110) and 21 years for siblings (n=125). Nephropathy history was determined by medical record review for deceased patients and those with persistent proteinuria or end-stage renal disease to ascertain the date of onset of persistent proteinuria. For patients without documented nephropathy, the albumin/creatinine ratio was measured in multiple urine samples. The cumulative incidence of persistent proteinuria according to post-pubertal duration of IDDM was determined by life-table analysis. For probands and siblings combined, the cumulative incidence of advanced diabetic nephropathy after 30 years of IDDM was 35%, but the risk in siblings varied according to the proband's renal status. The cumulative risk in siblings after 25 years of IDDM (post-puberty) was 71.5% if the proband had persistent proteinuria but only 25.4% if the proband did not (p<0.001). A difference of nearly 50% in the risk to IDDM siblings, depending upon the IDDM proband's renal status, is consistent with a major gene effect that predisposes an individual with IDDM to develop advanced diabetic nephropathy.Abbreviations IDDM Insulin-dependent diabetes mellitus - C.I. confidence interval     

Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: a prospective study

Summary To study the possible temporal association between primary cytomegalovirus infection and the appearance of islet cell autoantibodies or the development of insulin-dependent diabetes mellitus (IDDM) cytomegalovirus antibodies were analysed from follow-up sera of 46 initially non-diabetic siblings of diabetic children who either manifested clinical IDDM (22 siblings) or turned islet cell antibody positive (24 siblings) during the prospective observation (mean follow-up time 2.9 years). Secondly, cytomegalovirus antibodies were analysed during pregnancy in 96 mothers whose child presented with IDDM before the age of 7 years and in 96 control mothers who gave birth to a non-diabetic child. Thirdly, a case-control series including 90 newly-diagnosed young children with IDDM and their 90 control subjects was analysed. No seroconversions were found in cytomegalovirus antibodies during the follow-up of the 46 siblings indicating no temporal association with islet cell antibody seroconversion or manifestation of clinical diabetes. During the follow-up 17 (37%) siblings were constantly seronegative and 29 (63%) seropositive for cytomegalovirus IgG and there was no difference between islet cell antibody positive and negative siblings. Cytomegalovirus IgG and IgM were not different in pregnant mothers who gave birth to a subsequently diabetic child compared to control mothers, or in newly-diagnosed diabetic children compared to control children. Cytomegalovirus IgA was higher in newly-diagnosed diabetic children than in control children (p<0.005). This difference disappeared when only cytomegalovirus IgG positive individuals were analysed. No correlation was found between islet cell antibodies and cytomegalovirus antibodies in newly-diagnosed diabetic patients. The results do not support the hypothesis that primary cytomegalovirus infections could initiate the cascade leading to autoimmune destruction of the beta cells.Abbreviations IDDM Insulin-dependent diabetes mellitus - ICA islet cell autoantibodies - CMV cytomegalovirus - EIA enzyme immunoassay - EIU enzyme immunoassay unit     

Familial Aggregation of Type 2 (Non-insulin-dependent) Diabetes Mellitus in South India; Absence of Excess Maternal Transmission

The family histories of 976 South Indian Type 2 diabetic patients were recorded in a questionnaire-based survey to establish whether the excess maternal transmission of Type 2 diabetes reported in low prevalence Europid populations was also evident in this medium prevalence population. In 450 families (46.1 %), no parental history of diabetes was reported. In 423 families with one parent diabetic, 222 fathers (52.5 %) and 201 (47.5 %) mothers were diabetic. In the remaining 103 (10.6 %) families, both parents were diabetic. In contrast to previous studies, we found no evidence for substantial maternal excess in the transmission of diabetes (325 diabetic fathers vs 304 mothers; p = 0.4; p = 0.07 when compared using life table methods). The age of diagnosis of diabetes in probands was lower than that of their diabetic parents (p < 0.001): furthermore increasing parental history of diabetes was associated with an earlier diagnosis of diabetes in probands (p < 0.001). These results emphasize the extensive familial aggregation of Type 2 diabetes in this population but fail to replicate the evidence for excess maternal transmission evident in lower prevalence Europid populations, suggesting ethnic differences in the extent of this phenomenon.     

Risk of incidence of diabetes mellitus in relatives of patients with diabetes type I in retrospective questionnaire study

It is commonly known that there is a higher risk of diabetes type 1 in relatives of patients with diabetes type 1. According to some reports in families of these patients the incidence of diabetes type 2 is also higher. The aim of our study was the evaluation of incidence of diabetes type 1 and 2 in 1st and 2nd degree relatives of patients with diabetes type 1. Our study was conducted in the years 1993-2000 in the Department of Endocrinology for Children and Adolescents in Wroc?aw and in the Department of Endocrinology of Jagiellonian University in Cracow among relatives of all the patients in the age of 0-19 years with newly diagnosed diabetes type 1. Special prepared questionnaires were used in which patients were asked about: number of relatives of 1st and 2nd degree, age, sex and diagnosis of diabetes in the relatives. Data from families of 332 patients were obtained. They concerned 4080 relatives. Diabetes occurred in 121 relatives (2.96%). 20 of them were 1st degree relatives and 101--2nd degree relatives. In 31 relatives (0.76%) diabetes type 1 was diagnosed and in 88 relatives (2.16%) diabetes type 2 was diagnosed. Except for one individual (patient's mother) diabetes type 2 occurred in 2nd degree relatives. Diabetes type 1 was diagnosed in 16 1st degree relatives and 15 2nd degree relatives. They were: 1st degree relatives: 9 fathers, 3 brothers, 2 mothers and 2 sisters. 2nd degree relatives: in 8 cases siblings of patient's parents, in 7 grandparents. In families of diabetic children and adolescents relatives with type 1 and type 2 diabetes were observed, with a dominance of relatives with diabetes type 2 in 2nd degree relatives.     

Mother to child transmission of diabetes mellitus: does gestational diabetes program Type 2 diabetes in the next generation?

AIM: Type 2 diabetes is frequently familial. Hyperglycaemia in pregnancy might act in addition to genetic factors to cause diabetes in the children of mothers with gestational diabetes mellitus (GDM). The first manifestation of this in female offspring is likely to be GDM in their own pregnancies. We compared the incidence of GDM in daughters of diabetic mothers and diabetic fathers to determine if in utero exposure to hyperglycaemia increased the risk of a diabetes-prone phenotype in offspring. METHODS: We analysed the outcome of a GDM screening programme in women with a family history of diabetes in their mother (n = 535), father (n = 566), both parents (n = 77) or neither (n = 4672). RESULTS: GDM was twice as common in the daughters of diabetic mothers (11%) than diabetic fathers (5%, P = 0.002). Women with two diabetic parents were no more likely to have GDM than women with only a diabetic mother. CONCLUSIONS: Genetic predisposition to GDM should be equally shared by daughters of diabetic mothers and fathers. An excess of maternal transmission of diabetes is consistent with an epigenetic effect of hyperglycaemia in pregnancy acting in addition to genetic factors to produce diabetes in the next generation.     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 μg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 μg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1–107) vs 15.6 (0.2–98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K_itt index: 3.7 (0.7–6.2) vs 4.8 (0.7–6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy. [Diabetologia (1997) 40: 1191–1196] Received: 4 March 1997 and in revised form: 9 May 1997     

Transmission of Helicobacter pylori infection in families of preschool-aged children from Minas Gerais, Brazil

We evaluated the role of the family in the transmission of Helicobacter pylori infection in preschool-aged children from a rural district in the State of Minas Gerais, Brazil. Sixty-six families (66 index children, 63 mothers, 60 fathers and 134 siblings), defined as at least one parent living in the same household with at least one offspring up to 8 years old, were studied. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression controlling for age, gender, number of children in household and H. pylori status of the father, mother and siblings. The prevalence of the infection was 69.7% (469 of 673) and it increased with age (P < 0.001). Positive mothers were a strong and independent risk factor for infection (OR 22.70; 95% CI 2.31-223.21). Positive siblings were also positively associated with infection (OR 1.81; 95% CI 1.01-3.30).     

Epidemiology of childhood diabetes mellitus in Finland--background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group.

Summary A nationwide study of childhood Type 1 (insulin-dependent) diabetes mellitus was established in 1986 in Finland, the country with the highest incidence of this disease worldwide. The aim of the project called Childhood Diabetes in Finland is to evaluate the role of genetic, environmental and immunological factors and particularly the interaction between genetic and environmental factors in the development of Type 1 diabetes. From September 1986 to April 1989, 801 families with a newly-diagnosed child aged 14 years or younger at the time of diagnosis were invited to participate in this study. The vast majority of the families agreed to participate in the comprehensive investigations of the study. HLA genotypes and haplotypes were determined in 757 families (95%). Our study also incorporates a prospective family study among non-diabetic siblings aged 3–19 years, and two case-control studies among the youngonset cases of Type 1 diabetes. During 1987–1989, the overall incidence of Type 1 diabetes was about 35.2 per 100,000 per year. It was higher in boys (38.4) than in girls (32.2). There was no clear geographic variation in incidence among the 12 provinces of Finland. Of the 1,014 cases during these 3 years only six cases were diagnosed before their first birthday. The incidence was high already in the age group 1–4-years old: 33.2 in boys and 29.5 in girls. Of the 801 families 90 (11.2%) were multiple case families, of which 66 had a parent with Type 1 diabetes at the time of diagnosis of the proband. The prevalence of Type 1 diabetes in the parents of these newly-diagnosed diabetic children was higher in fathers (5.7%) than in mothers (2.6%).     

HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance.

Insulin-dependent diabetes mellitus (IDDM) susceptibility determinants are known to be associated with both HLA-DR3 and -DR4. We monitored the inheritance of HLA-DR alleles in 37 families in which IDDM affected one parent and at least one offspring in order to try to learn more about the modes of inheritance of IDDM determinants. Ninety-seven insulin-dependent diabetics whose parents did not have diabetes and 158 nondiabetics were used as control groups for estimates of DR allele frequencies in the overall diabetic and general populations. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency of DR4 in the nondiabetic population (16%), but it was significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. These proportions suggest that inheritance of the DR4-associated IDDM susceptibility determinant is not recessive, because in recessive inheritance expression of a trait depends on each parent contributing a susceptibility determinant. The proportions of diabetic and nondiabetic parents who transmitted the DR allele associated with the susceptibility determinant would then equal one another. The transmission of predominantly DR4 from affected parents to affected offspring suggests that susceptibility to IDDM is inherited primarily via a single dose of a potent determinant associated with DR4, as in dominant inheritance. When DR3 was transmitted at all it was usually by the nondiabetic parent. Only 8% of diabetic parents transmitted DR3 but 35% of nondiabetic parents transmitted DR3. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population (29%), but it was significantly higher than the gene frequency of DR3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring with the genotype DR3DR4 (35%) was identical to the percentage of individuals in the overall IDDM population with this genotype (35%). Numerous population data indicate that the DR3DR4 genotype carries a higher relative risk for IDDM than any other genotype, which suggests synergism between the DR3- and DR4-associated determinants.The family data reported here support this synergism but suggest that the DR4-associated determinant can give substantial susceptibility independent of the DR3-associated determinant and that the DR3-associated determinant is often expressed as enhancing susceptibility in the presence of the dominant DR4- associated determinant.     

Transmission of hepatitis C virus between parents and children

Egyptian children with infected parents are at high risk of infection with hepatitis C (HCV). Analysis of data collected during surveys of rural communities show children whose parents had antibodies to HCV (anti-HCV) were at higher risk for having anti-HCV than children whose parents did not. The association was greater with mothers than fathers and when the parent had HCV RNA. For instance, 87 (14%) of 612 children had anti-HCV whose mothers had HCV RNA compared with 28 (7%) of 401 whose mothers only had anti-HCV and 79 (2.6%) of 3,086 whose mothers were seronegative. These associations persisted after controlling for age, parenteral exposures, and serologic status of the other parent. Sequencing isolates from 13 families with parent(s) and children having HCV RNA showed 10 of 18 had genetically similar viruses. These findings suggest Egyptian children are at high risk of being infected with HCV by their parents and identification of the transmission routes would allow for preventive measures.     

Significance of cow's milk protein antibodies as risk factor for childhood IDDM: interactions with dietary cow's milk intake and HLA-DQB1 genotype

Summary Dietary factors are suspected to play an aetiological role in the development of insulin-dependent diabetes mellitus (IDDM). We analysed cow's milk formula, betalactoglobulin, and bovine serum albumin antibodies by an enzyme-linked immunoassay in unselected children with newly diagnosed IDDM and in their non-diabetic siblings and enquired about infant feeding practices by questionnaire. Among 410 diabetic sibling pairs matched for age and sex, by logistic regression analysis – including overall duration of breast-feeding, age at introduction of dairy products, recent consumption of cow's milk and HLA-DQB1 genotype (“high/moderate” vs “low/decreased” risk of IDDM) – bovine serum albumin IgG antibody levels (OR 2.12, 95 %CI 1.25–3.57) and genetic risk (OR 3.81, 95 %CI 2.43–5.17) were positively associated with IDDM; cow's milk formula IgM antibodies were inversely associated with the risk of IDDM (OR 0.50, 95 %CI 0.29–0.87). Of the diabetic sibling pairs, 42 were identical for HLA-DQB1 alleles associated with IDDM risk or protection (DQB1^*0201, *0301, ^*0302 and *0602/03). In these 42 pairs, children with IDDM had higher median levels of bovine serum albumin IgG, of betalactoglobulin IgG, and of cow's milk formula IgG and IgA antibodies than the non-diabetic siblings (p < 0.05). In conclusion, children with IDDM have higher levels of cow's milk protein antibodies than their HLA-DQB1-matched sibling controls, and these high levels of antibodies are independent risk markers for IDDM. [Diabetologia (1998) 41: 72–78] Received: 13 June 1997 and in revised form: 26 August 1997     

Prevalence of non-insulin-dependent diabetes mellitus in Asian Indian families with a single diabetic parent

Offspring of one parent diabetic (OPDR-A) and offspring of one parent diabetic with a first-degree family history on the non-diabetic parental side (OPDR-B) were studied to assess the influence of familial aggregation on the prevalence of non-insulin-dependent diabetes mellitus (NIDDM). All parents and offspring were tested for diabetes by oral glucose tolerance test. All parents had NIDDM. The prevalence of diabetes was 36% and 54% in the OPDR-A and OPDR-B families, respectively. The prevalence rate in OPDR-B was higher compared to OPDR-A families (P less than 0.01). The prevalence of diabetes in OPDR families was not different whether the father or the mother had diabetes. There was a male predominance among the diabetic offspring. The age at diagnosis was lower in the offspring compared to that in their parents in both groups. The expected risk of diabetes was greater in OPDR-B families compared to OPDR-A families. Thus it is seen that there is high prevalence of NIDDM in our population even in families with only one diabetic parent.     

Sexual dimorphism in transmission of expression of islet autoantibodies to offspring

Summary To help elucidate the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), we measured GAD (glutamic acid decarboxylase) autoantibodies (GAD65Ab), insulin autoantibodies (IAA), and cytoplasmic islet cell autoantibodies (ICA) in 292 sequentially screened non-diabetic offspring of patients with IDDM. The prevalence of these islet autoantibodies was higher in offspring of diabetic fathers than in offspring of diabetic mothers. The prevalences of GAD65Ab, IAA, and ICA in the offspring of diabetic fathers were 11.5%, 10.8%, and 8.1% vs 2.1%, 1.4%, and 2.8%, respectively in the offspring of diabetic mothers (p<0.002, p<0.001, and p=0.06 NS). Amongst autoantibody-positive relatives the IAA and ICA levels were significantly higher in offspring of diabetic fathers than of diabetic mothers (p<0.002 and p<0.01, respectively). The frequencies of these autoantibodies were equal in male and female offspring. We conclude that IDDM mothers transmitted islet autoimmunity less frequently to their offspring than IDDM fathers. Given the markedly lower frequency of autoantibodies in offspring of mothers, larger sample sizes will be required to determine whether islet autoantibodies are influenced by age of IDDM onset of mothers, maternal age of pregnancy, and presence of diabetes in these mothers prior to conception.Abbreviations IDDM Insulin-dependent diabetes mellitus - GAD glutamic acid decarboxylase - GAD65Ab glutamic acid decarboxylase autoantibodies - IAA insulin autoantibodies - ICA cytoplasmic islet cell autoantibodies - JDF Juvenile Diabetes Foundation     

Long-term risk of IDDM in first-degree relatives of patients with IDDM

Summary Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean observation times (age) (± SD) for siblings (n = 553) and offspring (n=359) were 59.4 ± 16.1 years and 33.8 ± 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4% to 22.4% of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48% of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4% and up to age 60 years of 9.6%. For offspring the risk up to age 34 years was 6.3%. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports.Abbreviations IDDM insulin-dependent diabetes mellitus - SE standard error     

Risk of diabetes in siblings of index cases with Type 2 diabetes: implications for genetic studies.

AIMS: The goal was to estimate the sibling recurrence-risk ratio for Type 2 diabetes in families with diabetes occurring in middle age. Because diabetes aetiology involves environmental exposures and genetic susceptibility, we sought to identify determinants of the recurrence risk. METHODS: We surveyed patients diagnosed at ages 35-59 years (n = 563) to obtain information on the occurrence of diabetes in their relatives, particularly siblings (n = 1675). Age-specific prevalences of diabetes in the US population were used for comparison. RESULTS: The overall sibling recurrence-risk ratio for diabetes was low, about 1.8 in the Joslin families and even lower in three other studies that were reanalysed for comparison. In all studies, the diabetes risk in siblings of index cases without a history of diabetes in a parent was similar to that in the general population, suggesting that genetic factors contributed to the occurrence of diabetes in only a minority of these siblings. The fact that recurrence-risk ratios were elevated only in families with one or two diabetic parents indicates that susceptibility to Type 2 diabetes is transmitted primarily through an affected parent. In addition, the sibling recurrence-risk ratios were elevated even further in families with diabetes in both a parent and grandparent of the index case, and in siblings of non-obese index cases (percent ideal body weight < 120%). CONCLUSIONS: The selection of families with non-obese index cases and vertical transmission of diabetes through three generations may improve the success of efforts to map susceptibility genes for Type 2 diabetes.     

Anti-islet autoantibodies detected by monoclonal antibody 1A2: further studies suggesting a role in the pathogenesis of IDDM

Summary Insulin-dependent diabetes mellitus (IDDM) is associated with autoantibodies to several pancreatic islet antigens. We have described an assay in which autoantibodies displace a radiolabelled monoclonal anti-islet antibody. Sera from 87 % of 429 children at time of diagnosis of IDDM were positive, while sera from control groups had much lower prevalences (1.3–19 %). Sera from 41.9 % of diabetic subjects remained positive after 20 years duration of IDDM. Sera from 23.6 % of parents and 37.9 % of non-diabetic siblings were positive. Twenty relatives who subsequently developed IDDM had the same prevalence of the antibodies (85 %) as did the patients at time of diagnosis. These findings confirm that the autoantibodies detected by monoclonal antibody (mAb) 1A2 are common at the onset of IDDM and their presence prior to the onset of hyperglycaemia suggests that this method may be useful in screening non-diabetic populations. The high prevalence of antibodies in relatives reduces the efficacy for diabetes prediction, but suggests either that generation of these antibodies is an autosomal dominant trait, or that the antigen detected by these antibodies is cross-reactive with a common environmental antigen. Differentiation between these hypotheses will await the identification of the specific islet-cell antigen detected by mAb 1A2. [Diabetologia (1996) 39: 1365–1371] Received: 15 February 1996 and in final revised form: 10 June 1996     

Familial Risk of Type I diabetes in European Children

Summary The characteristics of familial Type I (insulin-dependent) diabetes mellitus – that is Type I diabetes in a first degree relative were investigated for children diagnosed before the age of 15 years using data from an international network of population-based registries (the Eurodiab Ace network) and from a case-control study (Eurodiab Ace Substudy 2) conducted by eight of the network's centres. Ecological analysis across the 18 centres showed a positive association between the population incidence rate of Type I diabetes and the prevalence of Type I diabetes in fathers of affected children (Spearman's rank correlation coefficient r _s = 0.70, p < 0.001). A similar association was observed with the prevalence in sibling (r _s = 0.71, p < 0.001), but the association with prevalence in mothers was weaker and not significant. Pooling results from all centres showed that a greater proportion of fathers (3.4 %) of affected children had Type I diabetes than mothers (1.8 %) giving a risk ratio of 1.8 (95 % CI 1.4 to 2.5). Affected girls were more likely to have a father with Type I diabetes than affected boys (odds ratio 1.56, 95 % CI 1.07 to 2.27), but there was no evidence of a similar finding for mothers or siblings. Children with disease onset in the 0–4 year age-range were more likely to have an affected father than were children who were older at onset, and similar although weaker associations were seen in mothers and siblings. This suggests that familial Type I diabetes patients have a younger age at onset than non-familial patients. In conclusion, a positive association between the prevalence of familial Type I diabetes and the population Type I diabetes incidence rate was shown and the characteristics of familial Type I diabetes (younger age at onset and preferential transmission of disease from tather to child and particularly from father to daughter) were described. [Diabetologia (1998) 41: 1151–1156] Received: 16 February 1998 and in revised form: 4 May 1998