Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia

University of Cambridge, Cambridge, England, United Kingdom
Human Molecular Genetics (Impact Factor: 6.39). 01/2001; 9(20):2967-72. DOI: 10.1093/hmg/9.20.2967
Source: PubMed


There is considerable uncertainty and debate concerning the application of linkage disequilibrium (LD) mapping in common multifactorial diseases, including the choice of population and the density of the marker map. Previously, it has been shown that, in the large cosmopolitan population of the UK, the established type 1 diabetes IDDM1 locus in the HLA region could be mapped with high resolution by LD. The LD curve peaked at marker D6S2444, 85 kb from the HLA class II gene DQB1, which is known to be a major determinant of IDDM1. However, given the many unknown parameters underlying LD, a validation of the approach in a genetically distinct population is necessary. In the present report we have achieved this by the LD mapping of IDDM1 in the isolated founder population of Sardinia. Using a dense map of microsatellite markers, we determined the peak of LD to be located at marker D6S2447, which is only 6.5 kb from DQB1. Next, we typed a large number of SNPs defining allelic variation at functional candidate genes within the critical region. The association curve, with both classes of marker, peaked at the loci DRB1-DQB1. These results, while representing conclusive evidence that the class II loci DRB1-DQB1 dominate the association of the HLA region to type 1 diabetes, provide empirical support for LD mapping.

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Available from: Francesco Cucca, May 14, 2014
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    • "often said that the incidence appears to follow a decreasing trend from north to south, with interesting exceptions, such as Sardinia (Marrosu et al. 2001; Zavattari et al. 2000), thus making reference only to the geographical position and particularly to the latitude. The results of this study seem to suggest another view: it may be important also to consider the disposition of the land with respect to sea water, the ratio between continental and coastal areas. "
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    ABSTRACT: Complex multifactorial disorders usually arise in individuals genetically at risk in the presence of permissive environmental factors. For some of these diseases, predisposing gene variants are partly known while the identification of the environmental factors is much more difficult. We present the results of a study that aimed to investigate whether there are correlations between the incidence of two complex traits, multiple sclerosis and type 1 diabetes, and some chemical elements and compounds present in soils and stream sediments in Europe. We obtained from published literature and we analysed by calculating the mean values of each element and of disease incidence for each Country, respectively 17 for multiple sclerosis, and 21 for type 1 diabetes. Correlation matrices and regression analyses were used in order to compare geochemical data and incidence data. R correlation index and significance were evaluated. The results revealed significant positive correlations between barium and sodium oxide on one hand and multiple sclerosis and diabetes incidences on the other, that may suggest interactions to be evaluated between silicon-rich litologies and/or marine environments. The negative correlations shown by cobalt, chromium and nickel (typical of silicon-poor environment), in this case can be interpreted as protective effects against the two diseases onset; this observation makes the split between favourable and protective environments even more obvious. In conclusion, if confirmed, these results suggest the involvement of the above elements and compounds in the etiology of these pathologies, then to plan strategies to reduce the spread of these serious pandemics.
    Full-text · Article · Sep 2013
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    • "In fact, the prevalence of Type 2 diabetes in Sardinia is similar to that of other non high risk populations, while after Finland, it has the highest prevalence in the world of Type 1 diabetes mellitus and Type 1 diabetes- related Autoimmune Diseases, such as Multiple Sclerosis, Celiac Disease, Autoimmune Thyroid Disease [7-11]. Compared to other Caucasian populations Sardinia has an unusual distribution of haplotypes and genotypes, with the highest population frequency of HLA DR3 in the world, which partially explains the high incidence of Type 1 diabetes [12,13]. For these reasons Sardinia is an ideal population to study environmental, genetic and immunological factors involved in the pathogenesis of different diseases. "
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    ABSTRACT: We previously reported a high prevalence (22.3%) of gestational diabetes mellitus (GDM) in a large group of Sardinian women, in contrast with the prevalence of Type 2 diabetes. Sardinia has an unusual distribution of haplotypes and genotypes, with the highest population frequency of HLA DR3 in the world, and after Finland, the highest prevalence of Type 1 diabetes and Autoimmune-related Diseases. In this study we preliminarily tested the prevalence of serological markers of Type 1 diabetes in a group of Sardinian GDM patients. We determined glutamic decarboxylase antibodies (anti-GAD65), protein tyrosine phosphatase ICA 512 (IA2) antibodies (anti-IA2), and IAA in 62 GDM patients, and in 56 controls with matching age, gestational age and parity. We found a high prevalence and very unusual distribution of antibodies in GDM patients (38.8%), the anti-IA2 being the most frequent antibody. Out of all our GDM patients, 38.8% (24 of 62) were positive for at least one antibody. Anti-IA2 was present in 29.0 % (18 out of 62) vs. 7.1% (4 out of 56) in the controls (P < 0.001). IAA was present in 14.5% (9 out of 62) of our GDM patients, and absent in the control subjects (P < 0.001). Anti-GAD65 was also present in GDM patients, with a prevalence of 3.2% (2 out of 62) while it was absent in the control group (P = NS). Pre-gestational weight was significantly lower (57.78 +/- 9.8 vs 65.9 +/- 17.3 P = 0.04) in auto-antibodies- positive GDM patients. These results are in contrast with the very low prevalence of all antibodies reported in Italy. If confirmed, they could indicate that a large proportion of GDM patients in Sardinia have an autoimmune origin, in accordance with the high prevalence of Type 1 diabetes.
    Full-text · Article · Jun 2008 · Reproductive Biology and Endocrinology
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    • "The protective effects of DQB1*0602 are dominant to the susceptibility effects of DQA1*0301/DQB1*0302 and DQA1*0501/DQB1*0201[50,53,54]. This study confirms the susceptibility of the genotypes DQA1*0301/DQB1*0302 and DQA1*0501/DQB1*0201 in agreement with studies of most other Caucasian popula- tions[16,5556575859. The genotypic combinations DQA1*0103/DQB1*0603 and DQA1*0102/DQB1*0602 are never present in diabetic patients. "
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    ABSTRACT: The objective was to evaluate HLA DR/DQ alleles and their risk factor for type 1 diabetes in the Abruzzo region (central Italy). Sixty incident cases from the Abruzzo region were studied together with 120 unrelated control subjects living in the same administrative areas. The relative risk of diabetes associated with the alleles under study was calculated by deriving the odds ratio (OR) maximum likelihood estimates and their 95% confidence intervals (CI) by the exponentiation of the logistic regression beta-parameter. The combination DRB1*03/DQA1*0501/DQB1*0201 was found in 20.0% of patients and 7.1% of the control subjects, conferring an OR of 4.04 and a CI of 1.97-8.49. The combination DRB1*04/DQA1*0301/DQB1*0302 was found in 23.3% of diabetic patients and 6.7% of controls, giving an OR of 5.69 and a CI of 2.77-12.05. DRB1*11/DQA1*0505/DQB1*0301 and DQA1*0505/DQB1*0301 were negatively associated with type 1 diabetes (OR=0.27, CI 0.11-0.57; OR=0.07, CI 0.02-0.19). The DQA1 genotype at risk was found to be DQA1*0301/DQA1*0501: OR=23.80, CI 2.97-190.89, as it occurred with the highest frequency in the patient group. The DQB1 genotype at risk was found to be DQB1*0201/DQB1*0302, which occurred in 13.3% of patients but in only 1.1% of the control group (OR=29.75, CI 5.36-549.25). Our results shed further light on the risk of development of this disease during a specific time period in an area where the overall incidence of type 1 diabetes is known.
    Full-text · Article · Aug 2005 · Clinical and Experimental Medicine
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