Linkage disequilibrium (LD) mapping of disease genes is complicated by population- and chromosome-region-specific factors. We have analysed demographic factors by contrasting intermarker LD results obtained in a large cosmopolitan population (UK), a large genetic isolate (Sardinia) and a subisolate (village of Gavoi) for two regions of the X chromosome. A dramatic increase of LD was found in the subisolate. Demographic history of populations therefore influences LD. Chromosome-region-specific effects, namely the pattern and frequency of homologous recombination, were next delineated by the analysis of chromosome 6p21, including the HLA region. Patterns of global LD in this region were very similar in the UK and Sardinian populations despite their entirely distinct demographies, and correlate well with the pattern of recombinations. Nevertheless, haplotypes extend across recombination hot spots indicative of selection of certain haplotypes. Subisolate aside, chromosome-region-specific differences in LD patterns appear to be more important than the differences in intermarker LD between distinct populations.

Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome). FOXP3 is necessary for the differentiation of a key immune suppressive subset of T-cells, the CD4؉CD25؉ regulatory T-cells. Previously, we reported a significant malefemale bias in the common, multifactorial form of type 1 diabetes in Sardinia and evidence of linkage of chromosome Xp11 to the disease. These findings indicate that FOXP3 is a prime functional and positional candidate locus for the common form of type 1 diabetes. In the present study, we initially scanned 82 kb of the FOXP3 region for common polymorphisms, including sequencing all of the coding and functionally relevant portions of the gene in 64 Sardinian individuals. Then the most informative polymorphisms in 418 type 1 diabetic families and in 268 male case and 326 male control subjects were sequentially genotyped and tested for disease association. There is no evidence that variants in the FOXP3 regions analyzed are associated with type 1 diabetes and account for the male-female bias observed in Sardinia. Our data indicate that allelic variation in or near the coding regions of the FOXP3 gene does not have a major role in the inherited susceptibility to the common form of type 1 diabetes. Diabetes 53: [1911][1912][1913][1914] 2004 I t is believed that most cases of type 1 diabetes result from an autoimmune, T-cell-dependent destruction of the insulin-producing pancreatic ␤-cells and subsequent irreversible insulin deficiency. Autoimmune diabetes is more commonly inherited as a common multifactorial trait but can also occur in two rare monogenic disorders, APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) and IPEX, both of which are characterized by a severe autoimmune pathology of several organs and tissues. The FOXP3 gene and the mouse orthologue Foxp3 are members of a gene family that encode transcription factors possessing a winged helix or forkhead box ("fox") DNA-binding domain. It has been recently shown that Foxp3 represents a key regulator of the development and function of a subset of CD4 regulatory T-cells, which express the interleukin-2 receptor CD25, and are central in the regulation of both the adaptive and innate immune system (1-4). The elucidation of the molecular bases of these rare Mendelian disorders has provided insights into the etiology of autoimmunity in humans and in mice (2,3,5-9). It is possible that common DNA polymorphisms of FOXP3 also influence susceptibility to the common, multifactorial form of type 1 diabetes. This hypothesis was strengthened by the observation that in common type 1 diabetes in Sardinia there is a strong male bias in disease incidence, and evidence of linkage of disease to the same region of chromosome X that encodes FOXP3 (10,11) has been observed. Furthermore, we have excluded the involvement of a Y-chromosome gene as ...

Background: The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.

Although several lines of evidence suggest that SEL1L might be a candidate for IDDM11-conferred susceptibility to T1DM the present study does not support this hypothesis.