Publications (8)43.17 Total impact
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Article: Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21
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ABSTRACT: Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by affected sibpair linkage analysis is not practical and allelic association or linkage disequilibrium mapping will have to be employed to attempt to detect founder chromosomes. Given prior evidence of linkage of the Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated the 12 informative microsatellite markers in the region for linkage with disease by the transmission disequilibrium test (TDT) in a UK data set of type 1 diabetic families (n = 195). Increased transmission of allele 4 of marker D18S487 to affected children was detected ( P = 0.02). Support for this was extended in a total of 1067 families from four different countries by isolating, and evaluating by the TDT, two novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to nonaffected siblings. Analysis of an additional 390 families by the TDT did not extend the evidence further, and reduced support in the total 1457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sibpair allele sharing was strong ( P = 3.2 x 10(-5)) in the second data set. Heterogeneity in TDT results between data sets was, in part, accounted for by the presence of more than one common disease-associated haplotype (allelic heterogeneity) which confounds the analysis of individual alleles by the TDT. Guidelines for strategies for the mapping of polygenes are suggested with the emphasis on collections of large numbers of families from multiple populations that should be as genetically homogeneous as possible.Human Molecular Genetics 08/1997; · 7.64 Impact Factor -
Article: Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene ( IDDM7 ) to chromosome 2q31-q33
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ABSTRACT: The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7 , to within two centiMorgans of D2S152 . This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5 . These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases.Nature Genetics 02/1995; · 35.53 Impact Factor -
Article: Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene
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ABSTRACT: Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C> T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C> T SNP showed evidence of negative association ( P = 0.014). There was some evidence for an interaction between -3233 C> T and the T1D locus IDDM2 in the insulin gene region ( P = 0.001 in the combined and P = 0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one. -
Article: Suggestive evidence for association of human chromosome 18q12-q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases
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ABSTRACT: Some immune system disorders, such as type 1 diabetes, multiple sclerosis (MS), and rheumatoid arthritis (RA), share common features: the presence of autoantibodies and serf-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; λs = 1.2; P = 0.001), and by meta-analysis the orthologous region (also on chromosome 18) is linked to diabetes in rodents ( P = 9 × 10<sup>-4</sup>). 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 × 10-8, respectively, empirical P = 0.01 and 2 × 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 × 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. As much as 5% of the population suffers from autoimmune disease, a failure of the homeostatic regulation of the immune system to prevent tissue damage and maintain self-tolerance. Predisposition to autoimmune disease is universally associated with alleles of the major histocompatibility complex (MHC) genes on chromosome 6p21 (1). However, the MHC is not sufficient to explain disease occurrence, and non-MHC susceptibility genes are predicted. In type 1 diabetes in humans, the evidence for non-MHC genes is incomplete (2,3), owing to the small, statistically underpowered data sets analyzed so far. In rodent models of disease, however, the existence and location of several non-MHC loci are established (1). It has also been shown in humans and mice that autoimmunity loci, mapped in a variety of autoimmune disease models, including those for type 1 diabetes and multiple sclerosis (MS), cluster significantly (1,4,5). Furthermore, congenic strains conclusively show that Idd3 , a mouse non-MHC type 1 diabetes susceptibility locus, also influences susceptibility to experimental allergic encephalomyelitis (EAE), a model of MS (6), and iddm4 in rats may be a universal autoimmunity locus (7). In addition to the well-established linkage and association of the MHC region to multiple autoimmune phenotypes, the CTLA-4 gene locus on human chromosome 2 has been reported to be either linked or associated with type 1 diabetes, Graves' disease, and MS (8,9,10). Previously, we reported some positive evidence of linkage ( P = 0.005) and association ( P<sub>c</sub> = 0.01) of diabetes to chromosome 18q21 in the vicinity of D18S487 (provisionally designated IDDM6) (11,12,13). In the present study, we were unable to replicate the D18S487 association result, but we have consolidated evidence of linkage of the region to type 1 diabetes by analysis of 882 families and by metaanalyses of other linkage studies of a variety of autoimmune diseases in humans and rodents. Finally, a large family-based study suggests that the human deleted in colorectal carcinoma (DCC) gene region of chromosome 18q21 is associated with autoimmune disease. -
Article: Fine mapping of the diabetes-susceptibility locus, IDDM4 , on chromosome 11q13
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ABSTRACT: Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 ( IDDM4 ). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (λ<sub>s</sub> = 1.09) with linkage (MLS ≥ 0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [ P = .02, corrected P = .72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P = 3 x 10<sup>-4</sup>, corrected P = .01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917 *03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P = 1.5 x 10<sup>-6</sup>, corrected P = 4.3 x 10<sup>-4</sup>). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated. -
Article: Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6)
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ABSTRACT: Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant. -
Article: Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11
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ABSTRACT: A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway Sardinia and Italy provided additional support for linkage at D10S193 ( P = 0.006, P (c) = 0.17). Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results ( P = 0.009, P (c) = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings ( P = 0.0008, P (c)= 0.02). This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families. These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families. -
Article: Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele
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ABSTRACT: The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians; INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans -inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.
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1995–1997
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University of Oxford
- Wellcome Trust Centre for Human Genetics
Oxford, ENG, United Kingdom
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