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     

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     

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.     

Familial clustering of diabetic retinopathy in South Indian Type 2 diabetic patients.

AIM: The aim of the study was to determine whether there is familial clustering of diabetic retinopathy among South Indian Type 2 diabetic subjects. METHODS: During the period September 1991 to September 1997, 322 families with at least two diabetic siblings who were registered at our centre and had undergone a retinal examination were selected for the study.The sibling with the longest duration of diabetes was defined as the proband. The prevalence of retinopathy was compared between the siblings of probands with and without retinopathy. RESULTS: Diabetic retinopathy was diagnosed in 11.2% of the siblings of the probands without diabetic retinopathy and in 35.3% of the siblings of the probands with diabetic retinopathy (P < 0.0001). The increased prevalence of retinopathy among siblings of probands with retinopathy represented all grades of retinopathy, namely non-proliferative diabetic retinopathy with and without maculopathy and proliferative diabetic retinopathy, although the latter did not reach statistical significance due to the small numbers. Hypertension, metabolic control and the duration of diabetes among the probands did not affect the clustering of retinopathy. The odds ratio for retinopathy in the siblings of probands with retinopathy after adjusting for age, glycosylated haemoglobin, duration of diabetes, proteinuria and other confounding variables was 3.37(95% confidence interval 1.56-7.29, P = 0.002). CONCLUSIONS: Familial clustering of diabetic retinopathy was three times higher in siblings of Type 2 diabetic subjects with diabetic retinopathy.     

Excess maternal transmission and familial aggregation of Type 2 diabetes in Sri Lanka

INTRODUCTION: An excess of maternal transmission of Type 2 diabetes mellitus has been reported in Europid populations, but not in South India. METHOD: A questionnaire-based survey was carried out in 1000 (502 male) people with Type 2 diabetes to establish whether there is an excess of maternal transmission and familial aggregation in a Sri Lankan population. RESULTS: Mean age of onset was 47+/-12 (+/-S.D.) years and duration of diabetes was 9+/-7 years. Thirty-seven percent reported parents with diabetes, 46.9% had no parents with diabetes, 16.1% did not know the diabetes status of at least one parent and there was no diabetes in the other. Of the probands, 59.4% had at least one affected relative. When both parents' diabetes status was known and only one was affected, diabetes was more common among mothers (n = 156) than fathers (n = 125) of probands (P < 0.001). A further 54 probands had both parents with diabetes. Mean age of onset and duration of the disease among probands with parental diabetes was 43.1+/-(11.1) and 9.6+/-(6.8). In the previous generation, 21.2% of maternal grandmothers and 17.3% of maternal grandfathers in the maternal diabetes group and 4.8% of maternal grandmothers and 17% of maternal grandfathers in the paternal diabetes group had diabetes. Diabetes in siblings and children was more common in those with mothers who had diabetes (53.8% and 4.5%) when compared with those in whom fathers had diabetes (42.4% and 1.6%) (P < 0.0001 and P < 0.01). CONCLUSION: Familial aggregation and excess maternal transmission were observed in people with Type 2 diabetes in Sri Lanka.     

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     

Clinical characterization of familial isolated pituitary adenomas

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.     

Familial risk factors for microvascular complications and differential male-female risk in a large cohort of American families with type 1 diabetes

CONTEXT: Type 1 diabetes (T1D) complications are responsible for much of the disease morbidity. Evidence suggests that familial factors exert an influence on susceptibility to complications. OBJECTIVES: We investigated familial risk factors and gender differences for retinopathy, nephropathy, and neuropathy. DESIGN AND SETTING: This study was a case-control design nested on a cohort of T1D families. We collected data (questionnaire, medical records) starting in 1988. Follow-up has been ongoing since 2004. PATIENTS: There were 8114 T1D patients among 6707 families. All patients had T1D onset age younger than 30 yr and required insulin treatment. Patients who remained without a complication after more than 15 yr of diabetes were considered to be without that complication for our analyses. RESULTS: A complication in a sibling increased the risk for that complication among probands: odds ratio 9.9 (P < 0.001) for retinopathy, 6.2 for nephropathy (P < 0.001), and 2.2 for neuropathy (P < 0.05). Compared with male probands, a female T1D proband had 1.7-fold higher retinopathy risk (P < 0.001) and 2-fold higher neuropathy risk (P < 0.001). T1D cases with onset between ages 5 and 14 yr had an increased complications risk compared with subjects diagnosed either at a very young age or after puberty. The presence of one complication significantly increased the risk for others. If a parent had type 2 diabetes, the risk for nephropathy increased (odds ratio 1.9, P < 0.01, but T1D in a parent did not increase the risk). CONCLUSIONS: We confirmed that familial factors influence T1D microvascular pathologies, suggesting a shared genetic basis for complications, perhaps independent of T1D susceptibility. We also found an unexpected increased female risk for complications.     

A comparison of clinical and immunogenetic features in familial and sporadic rheumatoid arthritis

Clinical and immunogenetic factors were compared in 214 patients with sporadic rheumatoid arthritis (RA) and 117 patients from 52 multiplex families. Sex distribution, articular disease severity and seropositivity for rheumatoid and antinuclear factors were similar in familial and sporadic disease. There was a trend for Sj?gren's and Felty's syndromes to be more frequent in familial RA but extraarticular disease features were otherwise similar in the 2 RA disease groups. Mean age of onset was 41.1 years in familial and 46.5 years in sporadic RA (p less than 0.0006); 67% of family probands, 74% of affected relatives and 57% of sporadic patients were HLA-DR4 positive (p less than 0.05 affected relatives vs sporadic). The similarity of clinical features found in familial and sporadic RA justifies the use of families with RA to study aspects of disease pathogenesis.     

Clustering of colorectal cancer in families of probands under 40 years of age

Although sporadic colorectal cancer (CRC) is relatively uncommon in the young, it may constitute an elevated genetic risk for CRC in these individuals. PURPOSE: This study was designed to determine extent of colorectal cancer in families of probands under 40 years of age. METHODS: Medical records of all consecutive patients, 40 years of age or younger at the time of CRC surgery, during the time period 1986 to 1994 were examined. Cases of familial adenomatous polyposis and ulcerative colitis were excluded.Via interviews of surviving probands or nearest relatives, dates of birth and death, causes of death, and diagnosis of cancer were recorded on all first-degree relatives (parents, siblings, and offspring), second-degree relatives (grandparents, aunts, and uncles), and any other relatives. RESULTS: A total of 128 patients, 40 years of age or less at time of CRC resection, were identified. Of these, 45 probands/families were reached by phone, and 45 detailed family histories were obtained. Age range of these 45 probands was 19 to 40 (mean, 33.1) years. In 25 families there was no history of CRC in first-degree, second-degree, or third-degree relatives. Eight of 45 probands (17.8 percent) had at least one first-degree relative with CRC, and three of these eight families fulfilled the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC). In all three families, inheritance of CRC appeared to segregate with the maternal side of the family. In addition, 5 of 43 non-HNPCC probands had at least one first-degree, second-degree, or third-degree relative less than 40 years of age, at time of CRC diagnosis. CONCLUSION: Ascertainment of a detailed family history in early age of onset CRC patients identifies frequent familial clustering of CRC and HNPCC in 17.8 percent of cases.Dr. Guillem is recipient of a Career Development Award from the American Cancer Society and a research grant from The New York District Council of Carpenters Benefits Fund.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

Juvenile idiopathic arthritis in multicase families

OBJECTIVE: To characterize juvenile idiopathic arthritis (JIA) patients from multicase families. METHODS: The study series comprised 80 affected siblings belonging to 37 families. Comparisons were made with a population-based series of JIA patients from Finland and with a sibling series from the United States. RESULTS: The distribution of cases according to onset type was similar in the sibling and population-based series. The age at diagnosis was significantly lower in the sibling series (4.8 years vs 7.4 years; p < 0.001). There was more intra-pair similarity in onset and course types in the United States series compared to the Finnish series and the proportion of girls was higher in the former. CONCLUSION: The only significant difference between familial and sporadic cases with JIA is an earlier onset of disease in familial cases. There is no essential difference in clinical features of the disease between patients in the multicase and sporadic groups. Differences between the Finnish and US series may be due to selection bias in the latter.     

The Bf system in diabetes-gene interaction or linkage disequilibrium?

Summary HLA and Bf genotypes have been determined in 75 Type 1 (insulin-dependent) diabetic probands ascertained from two family studies. The Bf associations were similar in those families with two affected children compared with those families with one affected child. The strong association of B18 with the rare allele BfF1 was confirmed but, with rare exception, the gene encoding for BfF1 only occurred on chromosomes coding for both B18 and CW5. These findings are similar to the strong allelic association between these specificities found more frequently in Southern Europe and Spain, but no HLA-A locus association was found in the present study. All HLA-B 8 positive subjects and 15 out of 16 BW62 positive probands possessed BfS. In contrast to other reports, we could not find any evidence to support the idea that BfF1 is associated with a younger age of onset of diabetes. It is concluded that there is no specific susceptibility gene for Type 1 diabetes linked to the Bf locus and that the Bf associations can be explained purely on the basis of the known allelic association, or linkage disequilibrium, within the HLA system.     

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.     

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.     

Familial aggregation of diabetic kidney disease in Type 2 diabetes in south India.

The study was done to assess whether there was a familial aggregation of diabetic kidney disease (DKD) in Type 2 diabetic subjects. The profile of associated complications was also studied. Two groups of diabetic siblings of Type 2 diabetic patients, matched for age, body mass index (BMI) and duration of diabetes mellitus were studied. The siblings also had Type 2 diabetes. Group A comprised of siblings of probands with diabetic nephropathy and retinopathy (n = 30, M:F = 20:10) and Group B were siblings of probands without diabetic nephropathy or microalbuminuria (MAU) (n = 30, M:F = 14:16). Anthropometry, measurement of blood pressure and tests for proteinuria, MAU and retinopathy and ECG and biothesiometry were carried out for all study subjects. Persistent proteinuria was present in 15 (50%) siblings in group A and none in group B. MAU was detected in 26.7% (n = 7) in Group A and 3.3% (n = 1) in Group B (P = 0.057). Thus a total of 22 out of 30 cases in Group A had albuminuria. In Group A, seven (23.3%) had proteinuria and hypertension. Hypertension was present in nine (30.0%) in group A, and in five (16.7%) in group B (NS). Occurrence of retinopathy was found to be significantly higher in group A than in group B (33.3 vs 6.7%, chi2 = 5.1, P = 0.023). Abnormal ECG changes were present in 10% and 6.7% in Group A and Group B, respectively. In Group A, one patient had peripheral vascular disease (PVD) while in Group B none had PVD. A comparison of sib pairs, matched for age, duration of diabetes and the level of metabolic control showed that there was strong familial clustering of diabetic kidney disease in south Indians with Type 2 diabetes. This was independent of the familial clustering of diabetes. Prevalence of other vascular complications were also higher in Group A.     

Fertility is reduced in women and in men with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium (T1DGC)

Aims/hypothesis

A recent Finnish study described reduced fertility in patients with childhood-onset type 1 diabetes. The Type 1 Diabetes Genetics Consortium (T1DGC) is an international programme studying the genetics and pathogenesis of type 1 diabetes that includes families with the disease. Our aim was to assess fertility, defined as number of offspring, in the affected and unaffected siblings included in the T1DGC.

Methods

Clinical information from participants aged ≥18 years at the time of examination was included in the present analysis. The number of offspring of affected and unaffected siblings was compared (in families including both) and the influence of birth year, disease duration and age of onset was assessed, the last in affected siblings only, using Poisson regression models.

Results

A total of 3010 affected and 801 unaffected adult siblings that belonged to 1761 families were assessed. The mean number of offspring was higher in the unaffected than in the affected individuals, and the difference between the two groups was more pronounced in women than men. Poisson regression analysis showed that both sex and birth cohort significantly affected the differences between groups. In the affected siblings, adult onset (≥18 years), female sex and older birth cohort were associated with higher fertility.

Conclusions/interpretation

Patients with type 1 diabetes have fewer children than their unaffected siblings. This effect is more evident in women and in older birth cohorts. Onset of type 1 diabetes as an adult rather than a child is associated with a higher number of offspring, even after accounting for birth cohort and disease duration.     

IRS1, KCNJ11, PPARγ2 and HNF‐1α: do amino acid polymorphisms in these candidate genes support a shared aetiology between type 1 and type 2 diabetes?

AIMS: Type 1 diabetes mellitus (T1DM) is a chronic disorder primarily triggered by environmental and immunological factors in genetically susceptible individuals. Despite the fact that there are indications of common aetiological features of T1DM and type 2 diabetes (T2DM), variation in genes involved in insulin secretion and insulin signalling has to a large extent been ignored as potential modifiers in the pathogenesis of T1DM. Recent studies suggest, however, that proven T2DM susceptibility gene variants may be involved in the pathogenesis of T1DM. The objective of this study was to estimate the impact of four selected amino acid polymorphisms -IRS-1 Gly972Arg, Kir6.2 Glu23Lys, HNF-1alpha Ala98Val and PPARgamma2 Pro12Ala in a Danish population of T1DM families. METHODS: All variants were genotyped in 490 simplex- and multiplex-T1DM families applying polymerase chain reaction-restriction fragment length polymorphism, and results were evaluated by means of a transmission disequilibrium test (TDT) analysis. RESULTS: TDT analysis revealed that the Arg972 IRS-1, the Lys23 Kir6.2 and the Val98 HNF-1alpha variants were transmitted from heterozygous parents to affected probands at frequencies of 49.1%, 47.0% and 54.1%, respectively (p > 0.05 for all). This was similar to the rate of transmission to unaffected siblings. The transmission rate of the Ala12 PPARgamma2 variant to affected probands was 46.5% (p > 0.05) which differed significantly from the transmission to unaffected offspring (p = 0.024). A combined analysis of the present and published pertinent data of 1691 transmissions showed a significantly decreased transmission of the PPARgamma2 Ala12 allele to affected probands (p = 0.0045). CONCLUSIONS: The Pro12Ala variant of PPARgamma2 is associated with T1DM, the minor Ala allele conferring a reduced risk. This same finding has been reported in patients with T2DM.     

Familial lupus erythematosus. Clinical and immunologic features of 125 multiplex families

Evidence for a genetic susceptibility to systemic lupus erythematosus (SLE) in humans is based on the high concordance rate observed in identical twins and on the relatively high incidence of familial cases. Although recent genetic studies have lead to significant advances in the identification of new susceptibility genes in SLE, no large clinico-pathologic study of familial SLE has been reported to date. In the present study, we describe the main clinical and immunologic features of 125 lupus multiplex families including at least 2 cases of SLE and/or discoid lupus erythematosus (DLE), recruited through a French national survey starting in July 1997. Medical records of all affected members were reviewed by the same investigator, all available family members were interviewed using the same standardized procedure, and blood was drawn for autoantibodies typing. Clinical and immunologic features of 90 probands from multiplex SLE families were compared with those of 100 sporadic SLE patients sharing the same French Caucasian origin. The 125 lupus multiplex families included 282 affected members (2.3 patients per family); of the 125 families, 96 were of French Caucasian origin. One hundred multiplex families included 2 affected relatives, while 25 included 3 or more affected individuals. The relationship between affected members was sibs (45%), parent-offspring (31%), and second-degree (24%). An autosomal dominant mode of inheritance was strongly suggested in 1 extended pedigree with 6 clinically affected members, and a recessive pattern was suspected in 5 other families. No obvious mode of inheritance could be suspected in most of the remainder. Among French Caucasians, sex ratio, mean age at onset, and clinical and biologic SLE-related manifestations were not significantly different in multiplex compared with sporadic SLE cases. The analysis of these 125 multiplex families suggests a genetic heterogeneity that should be considered for ongoing genomic screening.     

Familial B-cell Chronic Lymphocytic Leukemia in a Population of Patients from Southern Italy

We investigated the prevalence of chronic lymphocytic leukemia (CLL) in 9650 relatives of 510 CLL patients from 5 different regions (Apulia, Basilicata, Campania, Calabria, and Sicily) of Southern Italy. Data collection included a family history questionnaire. In our series of 510 CLL patients, 53 families with 2 or more individuals who had chronic lymphoproliferative disease (CLD) or other hematological malignancies were identified. In these families, 27 cases of CLL, 10 of indolent non-Hodgkin's lymphoma, and 7 of multiple myeloma were identified in relatives of CLL probands. Twenty-two relatives developed hematological malignancies other than CLD (19, acute leukemia; 3, chronic myeloid leukemia). In this study the prevalence of CLD in relatives of 510 CLL patients was 8.6% (44/510), and the prevalence of CLL in the same series was 5.2% (27/ 510). Considering the presence of clusters of individuals with hematological malignancies, overall our series contained 4 families showing a cluster with more than 2 cases. The most frequent pattern of affected family members was represented by 39 families (39/53 [73%]) with affected siblings or cousins only. Twenty siblings had CLL. The other families showed a multigenerational pattern with an affected parent-offspring relationship in only 11 (21%) of the cases and with a combination of the first 2 categories in 3 (6%) of the families. In 8 families belonging to both the last 2 mentioned groups, the affected offspring had an earlier disease onset than their parents, suggesting anticipation. We estimated the size and examined the pattern of familial aggregation of hematological malignancies, in particular CLL/CLD, in a specific geographical area. CLL was the most frequent disease in relatives, mainly siblings, of our CLL patients. Our results may be a contribution to the characterization of the epidemiological distribution pattern of CLL.     

Comparison of clinical and laboratory variables in familial versus sporadic systemic onset juvenile idiopathic arthritis

OBJECTIVE: To compare patients with familial versus sporadic juvenile idiopathic arthritis (JIA) with respect to clinical and laboratory variables. METHODS: The familial JIA group comprised 11 affected siblings belonging to 4 families, while the comparative group comprised 22 patients selected by systematic sampling from JIA patients presenting to our pediatric rheumatology clinic; the first patient was chosen randomly and the subsequent patients chosen at intervals of 3. The 2 groups were compared with respect to demographic information, age at onset of disease, disease activity, disease damage, and laboratory variables. RESULTS: The 2 groups were comparable with respect to age, sex, and onset type of disease. All patients from the familial group were from a southern province of Saudi Arabia (p = 0.001). The familial group had an earlier age at onset of disease (p = 0.039), the mean number of actively inflamed joints was higher (p = 0.009), and functional capacity as measured by Childhood HAQ was worse (p = 0.048), compared with the sporadic group. Other variables showed no significant differences. CONCLUSION: The comparison of patients with familial versus sporadic JIA revealed a significant difference in origin of patients and age at onset of disease. These differences may be helpful in identifying the predisposing genes in familial patients with JIA.