GAD65 and IA-2 autoantibodies are common in a subset of siblings of Sardinian Type 2 diabetes families

Type 1 diabetes in Sardinia is very common in children, and we hypothesized that Latent Autoimmune Diabetes of Adult (LADA) might constitute a significant proportion of diabetes in adult Sardinian subjects. Since Type 2 diabetes is a familial disorder, we tested this hypothesis by investigating the prevalence of GAD65 and IA-2 autoantibodies (Ab) in Type 2 diabetes multiplex families of Sardinian ancestry enrolled in the Study Group for the Genetics of Diabetes in Sardinia. METHODS: A total of 684 individuals were ascertained from 252 Sardinian Type 2 diabetes multiplex families with 2.4 affected siblings per family comprising 190 families with two affected, 37 with three, 15 with four, 7 with five, and 3 with six, in addition to 80 unaffected siblings. Controls were household contacts representing 204 healthy spouses of affected siblings. Diagnosis was at 35-69 years of age and insulin was not given in the first 4 years after diagnosis. GAD65Ab and IA-2Ab were determined in standard radioligand binding assays. RESULTS: Among affected siblings GAD65Ab were positive in 8.8% of insulin-treated (n = 137; P = 0.0006), in 2.5% of non-insulin-treated (n = 467), and in 1.2% of non-diabetic siblings (n = 80) compared with 0.5% of controls (n = 204). IA-2Ab was positive in 6.6% insulin-treated (P = 0.04), 2.1% non-insulin-treated, and 2.5% non-diabetic siblings compared with 1.5% of controls. CONCLUSION: A high frequency of GAD65Ab and IA-2Ab as markers of Type 1 diabetes was found among Type 2 diabetes siblings from Sardinian multiplex families despite excluding those who had been treated with insulin during the first 4 years of disease. Our data support the hypothesis that LADA may be common in Sardinian Type 2 diabetes and stress the importance of investigating markers of Type 1 diabetes in studies of Type 2 diabetes.     

Prevalence of diabetes mellitus,coronary heart disease and hypertension in the families of insulin dependent and insulin independent diabetics

Summary During an epidemiological study concerning the fate of diabetics in Warsaw, 2,356 subjects (aged 35–68 years with duration of diabetes mellitus of 3–11 years) were investigated with particular relevance to the presence of diabetes mellitus, coronary heart disease, and hypertension in their parents and siblings. Diabetics were classified into the following groups: insulin dependent, insulin independent nonobese, insulin independent obese, and a group in whom the distinction between insulin dependence and insulin independence was unclear. The findings in these groups were compared with the frequencies of these diseases in a random sample of the general population. There was an excess of diabetes in close relatives of all the diabetic groups. This was highest for insulin independent non-obese diabetics. There was no difference in the prevalence of coronary heart disease and hypertension in close relatives of insulin dependent diabetics when compared with the general population, but these were twice as prevalent in close relatives of the insulin independent non-obese group. Obese insulin independent diabetics reported a similar excess of coronary heart disease and hypertension in siblings, but the excess was less marked in parents. The prevalence of these diseases in families of probands with unclassified diabetes was intermediate between the other two groups. These results demonstrate an aggregation of diabetes mellitus with coronary heart disease and hypertension in families of insulin independent non-obese diabetics. This provides further evidence for heterogeneity in diabetes mellitus.     

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.     

THYROID AUTOANTIBODIES IN HLA-GENOTYPED TYPE 1 DIABETIC FAMILIES: SEX-LIMITED DR5 ASSOCIATION WITH THYROID MICROSOMAL ANTIBODY

Thyroid autoantibodies are common in Type 1 diabetics and their first degree relatives and may be part of the autoimmune diathesis present within such families. We have measured the prevalence of microsomal (M-Ab) and thyroglobulin (Tg-Ab) autoantibodies in 84 HLA-typed families having a Type 1 diabetic child, using enzyme-linked immunosorbent assay techniques. Thyroid autoantibodies were detectable in 201/407 (49%) individuals in these families. Both autoantibodies were significantly more frequent in the subsets of parents, diabetic children and their non-diabetic siblings than in groups of control adults and children. The prevalence of these autoantibodies in the diabetic families was increased in both sexes with a female:male ratio of 1.4:1. Antigen DR5 was significantly associated with M-Ab production but only for male subjects (P = 0.005 after correction for the number of DR antigens tested). No significant associations were encountered for Tg-Ab. Within-family analyses indicated that thyroid autoantibodies occurred with increased prevalence in HLA-identical or haplo-identical siblings of autoantibody-positive index cases in comparison to control children. We conclude the DR association with thyroid autoantibody production in this diabetes-selected population was thyroiditis-related and not diabetes-related, and the DR5 association was restricted to males and the production of M-Ab. These data are consistent with the hypothesis that multiple genetic and non-genetic factors played a role in the high prevalence of thyroid autoantibodies in this population.     

Familial association between type 1 diabetes and other autoimmune and related diseases

Aims/hypothesis  In the era of genome-wide association studies, familial risks are used to estimate disease heritability and success in gene identification. We wanted to estimate associations between type 1 diabetes mellitus and 33 autoimmune and related diseases in parents, offspring, singleton siblings and twins. Methods  The availability of a Multigeneration Register in Sweden provides reliable access to families throughout the last century. The diseases in individual family members were obtained through linkage to the Hospital Discharge Register. Standardised incidence ratios (SIRs) were calculated as relative risks of contracting type 1 diabetes in family members of affected patients compared with those lacking affected family members. Results  Among a total of 450,899 patients, 21,168 were diagnosed with type 1 diabetes. Familial cases amounted to 10.3% of all type 1 diabetes patients. SIR for type 1 diabetes was 8.23 in offspring of affected parents, 11.92 in singleton siblings, 39.22 in multiplex families and 21.88 in twins; the calculated risk for monozygotic twins was 32.33. Type 1 diabetes in offspring was associated with 13 diseases in parents, including Addison’s disease (SIR 2.41), asthma (1.38), coeliac disease (2.73), Graves’ disease/hyperthyroidism (1.86), Hashimoto disease/hypothyroidism (2.35), pernicious anaemia (3.09), primary biliary cirrhosis (3.63), rheumatoid arthritis (2.12), sarcoidosis (1.62), systemic lupus erythematosus (2.04), ulcerative colitis (1.23) and Wegener’s granulomatosis (2.12). Conclusions/interpretation  The concordant familial risks for type 1 diabetes were high and the calculated risk for multiplex families and monozygotic twins may be explained by epistatic gene × gene or gene × environment interactions. Familial associations with several autoimmune and related diseases suggest genetic sharing and challenge to gene identification.     

Severe clinical onset of diabetes and increased prevalence of other autoimmune diseases in children with coeliac disease diagnosed before diabetes mellitus

AIMS/HYPOTHESIS: To analyse whether the time of diagnosis of coeliac disease with respect to the clinical onset of diabetes could differentiate subgroups of varying severity in patients with both diseases. METHODS: We investigated 383 patients with Type I (insulin-dependent) diabetes mellitus for coeliac disease. Sex distribution, age at diagnosis of diabetes, prevalence of ketoacidosis at the onset of diabetes and prevalence of other autoimmune diseases were compared in patients. We divided these patients according to whether coeliac disease was diagnosed before (Group A, n=8) or after (Group B, n=24) diabetes onset and whether they had presented clinical symptoms of coeliac disease. Group C (n=351) included diabetic patients without coeliac disease. RESULTS: Out of 383 Type I diabetic patients we found 32 coeliac subjects (8.3%). There was a higher number of girls (p=0.003), but similar age and prevalence of ketoacidosis compared with Group C; 18.7% had a third autoimmune disorder. The higher number of girls was confirmed in Groups A and B in comparison to Group C (p=0.013), while higher prevalence of both ketoacidosis (p=0.009) and other autoimmune diseases (p=0.001) was found only in Group A. Compared with symptomatic patients, asymptomatic subjects in Group B had a lower number of girls, older age at diabetes onset, lower prevalence of ketoacidosis and no other associated autoimmune disease. CONCLUSIONS/INTERPRETATION: A wide clinical spectrum characterises the association of coeliac disease and diabetes mellitus, with a severe clinical presentation (higher prevalence of ketoacidosis at the onset and occurrence of other autoimmune diseases) when coeliac disease is diagnosed before diabetes. Distinct phenotypes might imply the contribution of a peculiar genetic background.     

Increased prevalence of primary sclerosing cholangitis among first-degree relatives

BACKGROUND/AIMS: The aim of the present study was to investigate the familial occurrence of autoimmune diseases in a large group of patients with primary sclerosing cholangitis (PSC). METHODS: All patients with PSC treated at Huddinge University Hospital between 1984 and 1999 were included (n=145). For every patient with PSC and inflammatory bowel disease (IBD) (n=126) we randomly selected a control patient with IBD (n=126), matched for age, sex and type of IBD. A questionnaire comprising information about autoimmune diseases among first-degree relatives was answered by all patients and controls. RESULTS: We identified 22 index cases with PSC from 21 families with a first-degree relative with either chronic liver disease and/or IBD. Five patients with PSC had a first-degree relative with PSC (3.4%). The prevalence of PSC among first-degree relatives was 0.7% (5/717). In siblings the prevalence was 1.5% (4/269). The prevalence of first-degree relatives with autoimmune diseases outside the liver was similar in PSC patients and controls. CONCLUSIONS: First-degree relatives of patients with PSC have a PSC prevalence of 0.7%. This represents a nearly 100-fold increased risk of developing PSC compared with the general population, supporting the hypothesis that genetic factors are of importance for development of PSC.     

Prevalence of pernicious anaemia in patients with Type 1 diabetes mellitus and autoimmune thyroid disease.

AIMS: To determine the prevalence of pernicious anaemia in patients with Type 1 diabetes mellitus and autoimmune thyroid disease. METHODS: A randomly selected asymptomatic group of 63 patients with Type 1 diabetes who also had autoimmune thyroid disease was studied. Blood samples were taken and assayed for serum B12. Those subjects with serum B12 concentrations below the reference range had a further blood sample taken for determination of intrinsic factor antibody. RESULTS: One patient had been diagnosed previously to have pernicious anaemia. Three patients had low serum B12 concentration and positive intrinsic factor antibody, confirming the diagnosis of pernicious anaemia. The prevalence of pernicious anaemia in this population with Type 1 diabetes and concomitant autoimmune thyroid disease was 6.3%. In female patients the prevalence of pernicious anaemia was 8.5%. CONCLUSIONS: Patients who have both Type 1 diabetes mellitus and autoimmune thyroid disease are at risk of developing pernicious anaemia.     

A nationwide population-based study of the familial aggregation of Type 1 (insulin-dependent) diabetes mellitus in Denmark

Summary The objective of the present study was to assess the prevalence of familial aggregation of Type 1 (insulin-dependent) diabetes mellitus among Danish families with a diabetic child aged 20 years or less and to compare epidemiological data for familial and sporadic cases. We attempted to identify all patients with Type 1 diabetes aged 0–19 years in Denmark treated at paediatric departments or at departments of internal medicine. This comprises more than 98% of all patients with Type 1 diabetes in this age group. Patients were identified through the local diabetic out-patient registry and asked to complete a questionnaire regarding data on diabetes onset and family history. Of 1574 probands 1419 agreed to participate (90.2%). Additional cases of Type 1 diabetes were found in 171 families (12.8%). Of these 115 were parent-offspring affected families, and in 56 families at least two siblings had Type 1 diabetes and healthy parents. Significant correlation in age at onset of Type 1 diabetes in concordant siblings was observed (r=0.5, p=0.0004). Significantly more probands had an affected father with Type 1 diabetes than a mother affected (p<0.0001). Heterogeneity in epidemiological characteristics was observed between familial and sporadic cases, i.e. familial index cases were younger at onset of the disease, their parents were younger at birth of the index case, and there was no difference in gender of familial cases in contrast to sporadic cases where significantly more males were found. Over a 4-year period (1986–1989) an increasing trend in incidence was observed. However, an increase in incidence compared to previous Danish data from the 1970s and 1980 s could not be demonstrated.The Danish Study Group of Diabetes in Childhood is an association of paediatricians with a special interest in diabetes research. For participating departments in the present study see Acknowledgements     

Co-existence of type 1 diabetes and other autoimmune ailments in subjects with autoimmune thyroid disorders

Background and aimsAutoimmune thyroid dysfunction (AITD) is a significant autoimmune disorder affecting the population across age groups. The clustering of autoimmune diseases tends to occur within the same patients and families. Thus, this study aimed to determine the association of Type 1 diabetes and other autoimmune ailments in patients with autoimmune thyroid disorders.MethodsWe performed a cross-sectional study, evaluating 500 subjects with a diagnosis of AITD (130 with Graves' disease; 370 with Hashimoto's thyroiditis) on presentation to our tertiary care centre to ascertain the prevalence of associated autoimmune disorders.ResultsThe frequency of Type 1 diabetes and other autoimmune disorders was 18.5% in Graves' disease and 27.8% in Hashimoto's thyroiditis patients. Coeliac disease (8.8%) (found in 6.9% of Graves' disease and 9.5% of Hashimoto's thyroiditis patients) and type 1 diabetes (7.8%) (found in 3.1% of Graves' disease and 9.5% of Hashimoto's thyroiditis patients) were the most common coexisting autoimmune disorders. Rheumatoid arthritis was the most common non-endocrine autoimmunity (2.8%). Female sex and duration of AITD more than five years were associated with increased odds of associated autoimmune disorders.ConclusionA high prevalence of associated autoimmune disorders was observed in subjects with autoimmune thyroid dysfunction. We suggest the patients who remain symptomatic and those who develop other symptoms even with appropriate treatment undergo screening for associated autoimmune disorders, thus preventing a delay in diagnosis.     

Prevalence of coeliac disease in siblings of patients with Type I diabetes is related to the prevalence of DQB1*02 allele

Aims/hypothesis: Coeliac disease is more prevalent among patients with Type I (insulin-dependent) diabetes mellitus and coeliac disease-related antibodies have been reported to increase in frequency in their first-degree relatives. Our aim was to find out if coeliac disease is more common among siblings of children with Type I diabetes than in the normal population. Methods: IgA endomysium antibodies were measured by indirect immunofluorescence in 550 subjects (mean age 11.8 years, range 3.1–26.9 years) with a sibling with Type I diabetes. We performed jejunal biopsy on as many subjects with positive antibodies as agreed. HLA-DQB1 genotyping was done in 427 subjects. Results: Endomysium antibodies were positive in nine subjects (1.6 %). Jejunal biopsy was diagnostic for coeliac disease in five out of seven patients. An additional patient with coeliac disease, one already on a gluten-free diet, was identified by questionnaire. The prevalence of coeliac disease was 1.1 %. Five of six patients with coeliac disease had HLA-DQB1^*02 allele, compared with 118 of 421 of those without coeliac disease (p = 0.009). The sixth patient was positive for HLA-DQB1^*0302 allele, which was also found in 241 of 421 of those without coeliac disease (p = 0.4). Conclusion/interpretation: We found the prevalence of coeliac disease among siblings of children with Type I diabetes to be similar to figures reported from recent population-based studies and to be correlated with the prevalence of coeliac disease associated HLA-DQB1 alleles. We propose that routine screening for coeliac disease among all first-degree relatives of patients with Type I diabetes is not warranted. [Diabetologia (2001) 44: 1051–1053] Received: 11 January 2001 and in revised form: 27 April 2001     

Shared genetic susceptibility of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin

Summary Epidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.     

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.     

Is coeliac disease more prevalent in young adults with coexisting Type 1 diabetes mellitus and autoimmune thyroid disease compared with those with Type 1 diabetes mellitus alone?

AIM: It is known that patients with Type 1 diabetes mellitus are more prone to develop coeliac disease and that autoimmune thyroid disease occurs more frequently in patients with coeliac disease. We therefore assessed whether coeliac disease, either known or occult, occurs more frequently in young/middle aged adults with Type 1 diabetes and coexisting autoimmune thyroid dysfunction than in adults with Type 1 diabetes alone. METHODS: The prevalence of known coeliac disease was assessed in 509 (301 males, aged 16-55 years) patients with Type 1 diabetes, 28 (5.5%) of whom had treated autoimmune thyroid disease. In a second study 38 patients with Type 1 diabetes and coexisting autoimmune thyroid disease along with 112 patients with Type 1 diabetes alone were then screened for coeliac disease using serum IgA endomysial antibodies and IgA gliadin antibodies. RESULTS: Seven of the 509 patients (1.4%) had been diagnosed with coeliac disease and two of these had later developed autoimmune thyroid disease (both hypothyroid). The subsequent screening exercise found that one of the 38 patients with both Type 1 diabetes and thyroid disease had positive endomysial antibodies on screening. However, duodenal biopsy was negative for coeliac disease. There were two patients with positive endomysial antibodies in the group of 112 patients with diabetes only. Both had duodenal biopsy but only one was consistent with coeliac disease. CONCLUSION: The prevalence of known coeliac disease in this young adult Type 1 diabetes clinic in North-west England was 7/509 (1.4%). Two of these seven patients with coeliac disease were from the group of 28 who had autoimmune thyroid disease as well. Therefore we suggest that patients with known coeliac disease and Type 1 diabetes should be screened for autoimmune thyroid disease. The second screening study then found 3/150 (2%) to have a serological marker for coeliac disease. However, patients with both Type 1 diabetes and autoimmune thyroid disease were not more likely to have occult coeliac disease compared with those with Type 1 diabetes only.     

First-degree Relatives Are Frequently Affected in Coeliac Disease and Dermatitis Herpetiformis

Background: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. Methods: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. Results: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. Conclusions: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

First-degree relatives are frequently affected in coeliac disease and dermatitis herpetiformis

BACKGROUND: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. METHODS: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. RESULTS: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1,000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. CONCLUSIONS: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.     

The sardinian autoimmunity study. 4. Thyroid and islet cell autoantibodies in sardinian pregnant women at delivery: a cross-sectional study.

A high incidence of autoimmune Type 1 diabetes mellitus (DM) has been clearly established in Sardinia. Although systematic epidemiological studies are still not available, an increased prevalence of thyroid autoantibodies (ATA) has been documented in the Sardinian adult population as compared to other Italian regions, suggesting that thyroid autoimmune disease may also have increased. We carried out a preliminary study with the aim of determining the prevalence of serological markers of thyroid (anti-thyroperoxydase antibodies, TPOAb) and islet cell (ICA) autoimmunity in a large number (no.=2249) of sera obtained from cord-blood of Sardinian pregnant women at delivery. The prevalence of TPOAb was 11.9%, while ICA were detected in 59 cases (2.6%). A higher prevalence of TPOAb (6/17=35.3%) was found in sera with high ICA titers (> or = 20 JDF-U), as compared to sera with low ICA titers (5-19 JDF-U) and to ICA-negative sera (3/42=7,1%; chi2=5.4, p=0.02 and 258/2190=11,8%; chi2=6.8, p=0.009 respectively). Fourteen women (all ICA-negative) were diabetic: 4 had Type 1 and 10 had gestational DM; due to the low number, no correlation could be established between DM type and TPOAb prevalence and/or titer. These preliminary data indicate that ATA are frequently observed in the general population of Sardinian pregnant women at term. As a consequence, even the frequency of postpartum thyroiditis is expected to be high. Although ATA were not increased in women with clinical overt diabetes, a higher prevalence of ATA was found in women with high titers of circulating ICA. Our results also confirm that Sardinia represents, perhaps for its peculiar genetic characteristics, an ideal place to study organ-specific autoimmunity.     

Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene

The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.     

Lymphocyte subset abnormalities,autoantibodies and their relationship with HLA DR types in children with Type 1 (insulin-dependent) diabetes and their first degree relatives

Summary Type 1 (insulin-dependent) diabetes mellitus is associated with abnormalities of circulating lymphocyte subsets and autoantibodies. To investigate the prevalence of these in non-diabetic siblings and non-diabetic parents of children with Type 1 diabetes, we analysed T-cell subsets of function and activation in 31 families with an index case of Type 1 diabetes and related these to autoantibodies and HLA DR type. Using two and three colour cytofluorimetry, we studied total and activated (HLA-DR+) CD3+, CD4+, CD8+ lymphocytes and on CD4+ lymphocytes the CD45RA/RO “naive” and “memory” cell phenotypes. Diabetic children (mean duration of disease 3.1 years) had a reduced total lymphocyte count (p <0.05), their non-diabetic siblings a reduced CD4+ T-helper cell count (p <0.05), and their parents a reduced percentage and number of CD3+ T cells (p <0.01 and p <0.05) compared with age-matched control subjects. Diabetic children, their siblings and parents all had significantly increased levels of activated CD4+ T-helper cells (p <0.01, p <0.05 and p <0.01). In diabetic children and their siblings there was a significant over-expression of the CD45RO “memory” cell marker and significant under-expression of the CD45RA “naive” cell marker, whilst these were normal in the parents. Islet cell antibody positive diabetic children had significantly higher levels of CD45RO-expressing CD4+ lymphocytes than those who were islet cell antibody negative (p <0.05). Amongst the siblings and parents, possession of HLA-DR4 was associated with lower percentages of CD4+ and higher percentages of CD8+ T cells. These findings extend current knowledge about the role of immunoregulatory CD45RA/ RO cells in Type 1 diabetes. In addition, they demonstrate lymphocyte subset abnormalities in unaffected family members, some of which may be influenced by HLA DR alleles. [Diabetologia (1994) 37: 155–165] Received: 1 March 1993 and in final revised form: 16 August 1993     

HLA-associated susceptibility to Type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study

Summary Epidemiologic data suggest that a parental history of Type 2 (non-insulin-dependent) diabetes mellitus increases the risk of Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 and Type 2 diabetes. We have previously reported evidence that HLA-DR4-linked factors may represent a homogeneous subset of diabetes susceptibility. First, HLA-DR4 frequency was higher in Type 1 diabetic study subjects with a Type 2 diabetic parent than in Type 1 diabetic subjects whose parents were not diabetic. Second, a DR4-haplotype was transmitted from the Type 2 diabetic parent to the Type 1 offspring more often than expected. These data are consistent with the hypothesis that families with a Type 2 diabetic parent and Type 1 diabetic child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility. In this report, we further explore the relationship between the high-risk HLA antigen (HLA-DR4) in study subjects with differing glycaemic status (National Diabetes Data Group criteria). In this community-based study, we find evidence that HLA-DR4 is increased in study subjects with Type 2 diabetes and may be a marker for Type 2 diabetes susceptibility.