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.
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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.
    Reproductive Biology and Endocrinology 06/2008; 6(1):24. DOI:10.1186/1477-7827-6-24 · 2.23 Impact Factor
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    ABSTRACT: The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0-25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8-22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms.
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