The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.

The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.

Haplotype tagging for the identification of common disease genes.

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.

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

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

A large sample of finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter.

In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166). Their total sample was comprised of 440 Mexican-American affected sib-pairs from 246 sibships. The strongest evidence for linkage was at marker D2S125 and best estimates of lambdas (risk to siblings of probands/population prevalence) using this marker were 1.37 under an additive model and 1.36 under a multiplicative model. We examined this chromosomal region using linkage analysis in a Finnish sample comprised of 709 affected sib-pairs from 472 sibships. We excluded this region in our sample (multipoint logarithm of odds score /= 1.37. We discuss possible reasons why linkage to 2q37 was not found and conclude that this region is unlikely to be playing a major role in NIDDM susceptibility in the Finnish Caucasian population.

Human leukocyte antigen identity and DQ risk alleles in autoantibody-positive siblings of children with IDDM are associated with reduced early insulin response. Childhood Diabetes in Finland (DiMe) Study Group.

To investigate the relationship between human leukocyte antigen (HLA)-associated genetic factors and the development of beta-cell dysfunction, we performed sequential intravenous glucose tolerance tests (IVGTTs) on 81 islet cell antibody (ICA)-positive and/or insulin autoantibody-positive healthy siblings of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A lower glucose disappearance rate (Kg) (P < 0.5) and decreased first-phase insulin response (FPIR) (P < 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones. Siblings carrying the DQB1*0302/0201, -0302/x, or -0201/x genotype also had lower FPIRs (P < or = 0.05) at several time points than those with no DQB1 risk genotype. When all IVGTTs were taken into account, DQB1*0302/0201 heterozygous siblings had an abnormally low FPIR (< 45 mU/l; 3rd percentile) in at least one test more often than did siblings with no DQB1 risk genotype (50.0% vs. 6.1%; P = 0.001). Siblings carrying either the DQB1*0602 or the DQB1*0603 protective allele had lower serum peak ICA and glutamic acid decarboxylase (GAD)65 antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occasions (P < 0.05) than those with the DQB1 risk genotypes. Progression to IDDM was related to both HLA identity and the presence of the DQB1*0302/0201 genotype. Normal Kg and FPIR levels were observed in siblings who were positive for only insulin autoantibody, and none of them developed IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.

The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of IA-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.

Chromosome 4q locus associated with insulin resistance in Pima Indians. Studies in three European NIDDM populations.

Markers on chromosome 4q have recently been shown to be associated with insulin resistance in Pima Indians, a population in which insulin resistance precedes and predicts the development of non-insulin-dependent diabetes mellitus (NIDDM). To examine whether genes in this region could play a major role in susceptibility to NIDDM in other populations, we have examined the allele frequencies of a trinucleotide repeat near the fatty acid-binding protein 2 (FABP2) gene on 4q28-31 in three European populations: Finnish, U.K. Caucasian, and Welsh. The U.K. NIDDM population was selected for insulin resistance by studying patients whose obesity-corrected fasting plasma insulin before treatment was above the 98th percentile. Seven alleles were detected. On cross-tabulation analysis, there were no significant associations between allele frequencies and glucose intolerance in any of the populations. Log-linear analysis of the results from all three populations suggested a moderately significant interaction of glucose tolerance status (normal versus diabetic) and the FABP2 allele (partial chi 2 = 24, df 6, P = 0.027). The parameter describing the interaction of allele A3 and glucose tolerance status was the only such parameter differing significantly from zero (z-score +2.003, P = 0.046). In both the Finnish and U.K. population, the A3 allele was found approximately twice as frequently in NIDDM than in control subjects (Finnish control subjects, impaired glucose tolerance, and NIDDM: 12.2, 22.4, and 26.6%, respectively; U.K. control subjects and NIDDM: 7.8 and 14.6%, respectively). In the Finnish populations, no associations were found between FABP2 alleles and plasma insulin levels or with homeostatic model assessment (HOMA) estimates of beta-cell function and insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases.

Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and self-reactive T-cells, and a genetic association with the major histocompatibility complex. We have previously published evidence, from 1,708 families, for linkage and association of a haplotype of three markers in the D18S487 region of chromosome 18q21 with type 1 diabetes. Here, the three markers were typed in an independent set of 627 families and, although there was evidence for linkage (maximum logarithm of odds score [MLS] = 1.2; P = 0.02), no association was detected. Further linkage analysis revealed suggestive evidence for linkage of chromosome 18q21 to type 1 diabetes in 882 multiplex families (MLS = 2.2; lambdas = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents (P = 9 x 10(-4)). By meta-analysis, both human chromosome 18q12-q21 and the rodent orthologous region show positive evidence for linkage to an autoimmune phenotype (P = 0.004 and 2 x 10(-8), respectively, empirical P = 0.01 and 2 x 10(-4), respectively). In the diabetes-linked region of chromosome 18q12-q21, a candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with human autoimmunity in 3,380 families with type 1 diabetes, MS, and RA. A haplotype ("2-10") of two newly characterized microsatellite markers within DCC showed evidence for association with autoimmunity (P = 5 x 10(-6)). Collectively, these data suggest that a locus (or loci) exists on human chromosome 18q12-q21 that influences multiple autoimmune diseases and that this association might be conserved between species.

Comparison of incidence of IDDM in childhood between Estonia and Finland, 1980-1988.

OBJECTIVE: To compare nationwide incidence of childhood insulin-dependent diabetes mellitus (IDDM) in children aged 0-14 yr between Estonia and Finland during 1980-1988. For Estonia, which has a population genetically and linguistically related to Finland, only limited information was available. Finland has the highest incidence of IDDM in the world. RESEARCH DESIGN AND METHODS: The registration of all new cases of IDDM in Estonia was conducted by the local district pediatricians who reported every newly diagnosed diabetic patient to the Republic Endocrinology Centre. Registration of all new cases of IDDM in Finland was based on the statistics of the Social Insurance Institution, which approves free-of-charge insulin treatment for diabetes. These data were validated with one or more additional data sources. The case ascertainment rate approached 100% in both countries. RESULTS: The average yearly incidence of IDDM standardized for age for the years 1980-1988 in Estonia was approximately 33% of that in Finland. Among males it was 11.3 (95% confidence interval [CI] 10.3-12.3) per 100,000 in Estonia and 35.1 (95% CI 33.4-36.9) per 100,000 in Finland, and among females 10.1 (95% CI 9.2-11.1) per 100,000 in Estonia and 30.4 (95% CI 28.8-32.1) per 100,000 in Finland. When the two periods 1980-1982 and 1986-1988 were compared, the age-standardized incidence in Estonia remained unchanged, whereas in Finland it increased approximately 20%. CONCLUSIONS: The data between two populations who are ethnically and linguistically similar and live geographically close but in a different environment, provides further evidence that both genetic and environmental factors are contributing to the risk of IDDM.

Mapping genes for NIDDM. Design of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study.

OBJECTIVE: To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM. RESEARCH DESIGN AND METHODS: We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study. The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM. Detailed description of the study materials and designs of such studies are important, particularly when comparing the findings in these studies and when combining different data sets. RESULTS: Using a careful selection strategy, we have ascertained 495 families with confirmed NIDDM in at least two siblings and no history of IDDM among the first-degree relatives. These families were chosen from more than 22,000 NIDDM patients, representative of patients with NIDDM in the Finnish population. In a subset of families, a spouse and offspring were sampled, and they participated in a frequently sampled intravenous glucose tolerance test (FSIGT) analyzed with the Minimal Model. An FSIGT was completed successfully for at least two nondiabetic offspring in 156 families with a confirmed nondiabetic spouse and no history of IDDM in first-degree relatives. CONCLUSIONS: Our work demonstrates the feasibility of collecting a large number of affected sib-pair families with NIDDM to provide data that will enable a whole genome search approach, including linkage analysis.

Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes. Childhood Diabetes in Finland Study Group.

To study the frequency of antibodies to glutamic acid decarboxylase (GAD65A) at the diagnosis of insulin-dependent diabetes mellitus (IDDM) and to evaluate the relation of these antibodies to other IDDM-associated autoantibodies and genetic risk markers of the disease, we analyzed 747 newly diagnosed diabetic children younger than 15 yr of age (mean, 8.4 yr) for GAD65A, islet cell antibodies, insulin autoantibodies, and human leukocyte antigen DR alleles. GAD65A were detected in 73.2% of the children, with a higher frequency in females than in males (77.1% vs. 70.1%; P = 0.04) and in index cases aged 10 yr or older than in younger children (79.0% vs. 68.7%; P = 0.004). The index cases positive for GAD65A had higher levels of islet cell antibodies (median, 40 vs. 34 Juvenile Diabetes Foundation units; P = 0.003) and insulin autoantibodies (median, 55 vs. 43 nU/mL; P = 0.03) than those testing negative for GAD65A. Human leukocyte antigen DR3/non-DR4 children had the highest GAD65A levels, whereas DR2-positive cases had levels of GAD65A similar to those found in other subjects. One third of the index cases (33.9%) tested positive for all three autoantibodies, 43.1% for two antibodies, and 18.2% for one antibody, whereas 4.8% were triple negative. The females had multiple antibodies (at least two antibodies) more often than the males (81.3% vs. 73.5%; P = 0.01). There was a significant trend for a higher frequency of multiple antibodies in young children (83.0% in those under 5 yr and 73.2% in those 10 yr or older; P = 0.02) and a higher frequency in DR3/4 heterozygous children than in those with DR3/non-DR4 (83.3% vs. 63.2%; P = 0.02). The results show that GAD65A antibodies are more frequent in girls and adolescents with newly diagnosed IDDM and suggest that DR3/non-DR4 subjects have increased GAD65A levels. Multiple antibodies in diabetic children are associated with young age, female sex, and DR3/4 heterozygosity.

An association between type 1 diabetes and the interleukin-1 receptor type 1 gene. The DiMe Study Group. Childhood Diabetes in Finland.

The polygenic susceptibility to type 1 diabetes is well established and recent studies have demonstrated linkage of a further locus on chromosome 2q to disease. We have studied a polymorphism of the interleukin-1 receptor type 1 gene (IL1R1) on chromosome 2q in type 1 diabetic and control subjects from Finland, the United Kingdom, South India: three populations in which the risk of disease varies from very high to very low. In the medium-risk U.K. population we find a very strong association of IL1R1 with type 1 diabetes (p = 0.0002) but we find no overall association in either the high-risk Finnish or low-risk South-Indian populations. However, we do find heterogeneity of risk at IL1R1 amongst Finnish diabetic subjects according to the possession of HLA-DR associated susceptibility (p = 0.0001); there is an association with IL1R1 in only those Finnish diabetic subjects who do not possess high-risk HLA-DR4 or DR3 haplotypes (p = 0.006), as recently demonstrated for the insulin gene region in this population. We find no such heterogeneity of risk in either the U.K. or South-Indian populations. This study further demonstrates the genetic heterogeneity of disease susceptibility between and within populations and also supports the hypothesis of an interaction of the IL1R1 locus with genes within the HLA and insulin gene regions in the susceptibility to type 1 diabetes.

Evaluation of TAP1 polymorphisms with insulin dependent diabetes mellitus in Finnish diabetic patients. The Childhood Diabetes in Finland (DiMe) Study Group.

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease with a strong association between disease and the HLA class II region. Because abnormal antigen processing, in part characterized by altered class I processing, has been identified in patients with IDDM, the TAP (transporter associated with antigen processing) genes located in the HLA class II region make attractive candidate genes for IDDM. Five coding region variants of TAP1 were typed in a cohort of well characterized Finnish patients with diabetes (n = 119) and compared to racially marched control subjects (n = 92). We found that although no single TAP1 polymorphism was associated with IDDM, a genotypic combination of Ile/Val at codon 333 with Asp/Asp at codon 637 was found more frequently in subjects with IDDM (9.4%) compared to controls (1.2%; p = 0.025). This could not be accounted for by an association with any particular haplotype defined by class I or class II serology.

Islet cell-specific autoantibodies in children with insulin-dependent diabetes mellitus and their siblings at clinical manifestation of the disease. Childhood Diabetes in Finland Study Group.

The aim of this work was to characterize both newly diagnosed insulin-dependent diabetic subjects and their siblings with positive tests for islet cell-specific autoantibodies (ICSAA) and to evaluate whether there is an association between the ICSAA levels detected in the diabetic children and siblings. We analysed 781 probands younger than 15 years of age for islet cell antibodies (ICA) and 755 for insulin autoantibodies (IAA) and 610 of their 3-19-year-old non-diabetic siblings for ICA and IAA upon diagnosis of the proband. Islet cell antibodies were observed in 657 of the probands (84.1%) and IAA in 353 (46.8%). The ICA-positive probands were younger in age and had higher IAA levels than the ICA-negative probands, while the IAA-positive probands were younger and had higher levels of ICA than the IAA-negative probands. Islet cell antibodies were detected in 46 (7.5%) and IAA in 16 (2.6%) siblings, and the ICA-positive siblings had higher IAA levels than the ICA-negative siblings. A falling trend was seen in the frequency of ICA > or = 20 Juvenile Diabetes Foundation units in the siblings with decreasing degrees of HLA identity with the index case. Infections during the preceding year, especially respiratory infections, increased the prevalence of both ICA and IAA in the diabetic children at diagnosis and the frequency of IAA in the siblings. There was a significant, although weak, correlation between the IAA levels of the probands and those of their siblings when 594 pairs were tested (r(s) = 0.15; p < 0.001). No association could be seen between the ICA levels of the probands and those of their siblings, not even when including only HLA-identical proband-sib pairs in the analysis. The lack of any relation between ICA levels in the probands and siblings supports the view that there may be multiple exogenous factors capable of inducing ICA formation or else a common factor but variable responsiveness in the index case and the sibling.

Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group.

Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.

Increase in incidence of insulin-dependent diabetes mellitus among children in Finland.

BACKGROUND: In Finland, the incidence of insulin-dependent diabetes mellitus (IDDM) in children aged < 15 years is the highest in the world. The aim of this study was to determine the temporal variation in incidence and the age distribution at diagnosis of IDDM. SUBJECTS AND METHODS: Data on incidence of IDDM in Finland nationwide were obtained from two sources: the Central Drug Registry for the years 1965-1986 (6195 IDDM cases) and the prospective IDDM registry for the years 1987-1992 (2062 IDDM cases). The annual incidence rates were calculated per 100,000 population. The increase in incidence from 1965 to 1992 was estimated by fitting the linear regression with the annual incidence data. RESULTS: The overall incidence of IDDM between 1987 and 1992 was 36 per 100,000/year. During 1965-1992 the increase was almost linear. The regression-based change in incidence was 2.8% per year. In the 1970s the increase in incidence was steepest in 5-9 year olds and since the mid-1980s in those < 5 years old at diagnosis. CONCLUSIONS: The incidence of IDDM in Finnish children seems to increase further. During the last decades the increase in incidence has been almost linear with occasional peaks. The age-at-diagnosis of IDDM has been moving towards the younger ages, and differences in incidence between age groups have now almost disappeared among Finnish children aged 1-14 years.

HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases.

BACKGROUND: Type I diabetes mellitus (T1DM) and multiple sclerosis (MS), both immune-mediated diseases, rarely co-exist in the same individual or co-segregate in families. HLA susceptibility genes for T1DM (DRB1*0401, DRB1*0404, DQB1*0302, DRB1*0301, DQB1*0201) rarely occur in MS patients. HLA genes known to confer "resistance" to T1DM (DRB1*1501, DQB1*0602-DQA1*0102) predispose to MS. To test the hypothesis of mutually exclusive HLA patterns, patients affected by T1DM plus MS were compared to those of patients affected by either of the diseases alone in a case-control study. METHODS: Blood was sampled for analysis of HLA class I and class II alleles from 66 patients of German ancestry, of whom 33 had T1DM plus MS, and 33 had MS-only. For comparison to patients with T1 DM-only we referred to published data. HLA typing was performed using conventional serology (immuno-magnetic beads) and genotyping (SSP-PCR Dynal(R) SSP low/high resolution kits). RESULTS: Individuals with co-existing MS plus T1DM displayed the expected T1DM associated HLA-pattern (75.8% carried DRB1*04, 69.7% carried DQB1*0302, 42% were DR4, DR3 heterozygous), but failed to display the expected MS associated HLA-pattern (0% carried DQB1*0602, 3.1% carried DQA1*0102). The expected MS associated HLA-pattern of Caucasoid patients, however, was found in the MS-only patients (42% carried DRB1*1501-DQB1*0602, 58% carried DQA1*0102), while the prevalence of T1DM susceptibility and 'resistance' alleles was not different from the general population. The allele frequency of DRB1*1501 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQB1*0602 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQA1*0102 was 18/66, 27.3%, in the 33 MS-only patients, and 1/66 1.5% in the 33 MS plus T1DM patients. CONCLUSION: These data confirm the hypothesis of mutually exclusive HLA-patterns of T1DM and MS, and are consistent with a low rate of co-morbidity of both diseases.

Occurrence of chronic inflammatory rheumatic diseases among parents of multiple offspring affected by juvenile idiopathic arthritis.

OBJECTIVE: The rarity of reports on extended multiplex families points out that the genetic component in juvenile idiopathic arthritis (JIA) might not be particularly strong. Our objective was to determine the frequency of chronic inflammatory rheumatic diseases among the parents who had two or more offspring affected by JIA. METHODS: During the last 17 years patients with JIA treated at the Rheumatism Foundation Hospital in Heinola and their parents have been systematically asked about the familial occurrence of rheumatic diseases. A total of 45 families with more than one sibling affected by JIA were found among about 2,300 JIA cases. In these "multicase families", 9 parents from 8 families also had a diagnosis of chronic inflammatory rheumatic disease. Their case histories were studied. RESULTS: Four of the parents had had JIA (one subsequently developed ankylosing spondylitis), and 4 had rheumatoid factor-negative chronic arthritis (one had also had chronic iritis since the age of 10, resembling that seen in JIA). Three of them had features of JIA and only one met the classification criteria for rheumatoid arthritis. One had ankylosing spondylitis. CONCLUSIONS: Since the expected number of JIA cases among the 90 parents was about 0.2, there was drastic increase in JIA frequency among the parents in families with multiple offspring also affected by JIA. These results suggest that JIA susceptibility genes may likely be clustered in these families.

Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region.

OBJECTIVES: To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN: Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. SETTING: Two communities in Finland. SUBJECTS: Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. MAIN OUTCOME MEASURES: Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. RESULTS: Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). CONCLUSIONS: These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.