Human Molecular Genetics, 2001, Vol. 10, No. 8 881-889
© 2001 Oxford University Press
Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci
1Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Via Jenner, Cagliari 09121, Italy, 2Servizio di Diabetologia Pediatrica, Ospedale G. Brotzu, Via Peretti, Cagliari 09121, Italy, 3Istituto di Clinica Medica, Servizio di Diabetologia, University of Sassari, 07100 Sassari, Italy and 4Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 2XY, UK
Received as Resubmission 2 February 2001; Accepted 8 February 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified
40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The identity of the DNA variants primarily responsible for insulin-dependent diabetes mellitus 1 (IDDM1) has been established, namely a superlocus consisting of a combination of single nucleotide polymorphisms (SNPs) within the exon 2 sequences of the human leukocyte antigen (HLA) class II genes HLA-DQB1 and -DRB1 (1). Susceptibility is dominated in white European or European-derived populations by the two-locus haplotypes DRB1*0301-DQB1*0201 (DR3) and DRB1*04-DQB1*0302 (DR4). In other populations, such as Afro-Caribbeans, and in other haplotypes, such as DR7, type 1 diabetes mellitus (T1DM) risk is best defined as a DRB1-DQA1-DQB1 three-locus haplotype, suggesting that polymorphism of exon 2 of HLA-DQA1 is also implicated in susceptibility/resistance (2). The complexity of the IDDM1 locus provides a good example of the ‘worst case scenario’ in the post-linkage phase of identification of aetiological loci in complex traits. The linked chromosome region appears as a single, albeit broad, LOD score curve (3) but contains more than one disease locus, each with more than one functional or aetiological allele (4).
Furthermore, allelic variation of the HLA-DRB1, -DQA1 and -DQB1 loci does not explain all of the association of the HLA region with T1DM. Polymorphisms as yet unidentified, outside the exon 2 sequences of the DR/DQ loci but within the HLA region, further influence the disease risk. For example, distinct DR3 haplotypes, defined by the presence of different class I HLA-B alleles (e.g. the HLA-B*08 allele), were transmitted at a different rate to affected children from DR3 homozygous parents in families from the USA, leading to the estimate that 50% of DR3 haplotypes are, in fact, not predisposing to T1DM (5). In another example, heterogeneity within DRB1*04 haplotypes, using a case-control design, has been reported from Finland, with the causative variant(s) in linkage disequilibrium (LD) with HLA-B (6). Finally, the microsatellite marker D6S2223 at the telomeric end of the HLA region marks significant heterogeneity in the association of DR3 haplotypes with T1DM in Norwegian and UK families (7). In all three of these examples different HLA haplotypes carry different degrees of disease predisposition despite having identical HLA-DRB1, -DQA1 and -DQB1 exon 2 sequences.
The strong LD observed across the HLA, in particular in its telomeric part where these effects were detected, has hampered the identification of the non-DR/DQ aetiological variants (8). Even the marker D6S2223, 5.86 Mb telomeric of HLA-DRB1, showed strong LD with the DR/DQ loci (7). There is also a problem with the statistical power of such analyses. In order to locate and then identify additional disease loci in the HLA, the genotype data has to be conditioned by DR/DQ haplotypes, i.e. LD with the DR/DQ exon 2 alleles has to be taken into account. The selection of rare parents homozygous for the ‘primary locus’, in this case homozygous for DRB1-DQB1 haplotypes, means that the sample sizes are small and the information from the transmissions from non-homozygous parents to diabetic children is not included (7,9). Another conditional method without this limitation, the haplotype method (HM), was originally proposed by Valdes and Thomson (10) to evaluate which amino acid polymorphisms encoded by the exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1 accounted for the risk of T1DM associated with the HLA. In the present study we have generalized the HM in order to compare the distribution of test SNP and microsatellite marker alleles in patient versus control haplotypes. In the founder population of Sardinia we have applied the generalized HM to test whether the HLA-DQB1 and -DRB1 loci explain all of the HLA association or whether other HLA genes further influence the disease risk. The ‘test loci’ are a series of SNP and microsatellite markers located throughout a 9.452 Mb interval encompassing the whole classical HLA complex, which accounts for about 3.3 Mb of the total, and the ‘primary locus’ is the two-locus HLA-DRB1-DQB1 class II haplotype DR3. The isolated island population of Sardinia has the highest population frequency of HLA-DR3 in the world (haplotype frequency = 0.22 in the general population) (11) and, as such, it provides higher power to identify gene effects modifying the disease risk conferred by DR3 haplotypes. We report that as many as 40% of DR3 haplotypes in Sardinian type 1 diabetic families are not predisposing for T1DM, carrying alleles for at least three non-HLA-DRB1, -DQB1 loci that influence DR3-associated susceptibility to the disease.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Conditional linkage disequilibrium mapping
In the first set of families (n = 257) DR3 haplotypes were present in 58.1% of the patients and 22.5% of affected family-based controls (AFBACs) [odds ratio (OR) = 4.8, P = 4.3 x 10–30]. We compared the distribution of alleles at 28 non-DR/DQ markers in patient and control DR3 haplotypes, evaluating the differences between the two categories for heterogeneity in 2 x 2
2 contingency table tests of significance (i.e. used the HM). Of 28 markers in three regions, 10 (DMB, D6S2445, DOB, D3A, 82-2, D6S273, 82-1, TNFd, TNFc and TNFa) provided some evidence of independent association with T1DM outside the HLA-DQB1 and -DRB1 exon 2 sequences (Table 1).
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The most centromeric source of heterogeneity in the association of the DR3 haplotype with T1DM was located at the region defined by DMB (P = 3.7 x 10–4) and D6S2445 (P = 5.6 x 10–3), 273 and 224 kb centromeric of HLA-DQB1, respectively. The second region was defined by DOB (P = 3.1 x 10–2), 148 kb centromeric of HLA-DQB1. Both these regions are contained within the classically defined HLA class II region. The third site was in the HLA class III region, involving a cluster of markers, TNFc (P = 1.3 x 10–3), D3A (P = 5.4 x 10–3), 82-2 (P = 7.4 x 10–3), 82-1 (P = 1.2 x 10–2), D6S273 (P = 4.0 x 10–2), TNFa (P = 3.2 x 10–2) and TNFd (P = 4.1 x 10–2), spanning 550 kb, between 484 and 1034 kb telomeric of HLA-DQB1. However, only markers DMB and TNFc individually demonstrated a source of significant heterogeneity in the association of the DR3 haplotypes with T1DM at or below the 5% level, after correction by the number (28 markers) of markers tested, (Pc = 1.0 x 10–2 and Pc = 3.6 x 10–2, respectively). Nevertheless, the effect on DR3 susceptibility of haplotypes defined by the combined presence of the most associated markers in the three regions defining the heterogeneity was highly significant (P HM = 8.8 x 10–7). The combination of alleles at the DMB, DOB and TNFc loci split the DR3 haplotype into two groups. The first group, representing a common haplotype having alleles 0101, 1 and 169 at DMB, DOB and TNFc, respectively, was significantly and strongly predisposing to T1DM. This predisposing haplotype accounted for 50.5% of patient chromosomes and 11.8% of control chromosomes (OR = 7.6, P = 1.6 x 10–25). The other group, carrying DMB-DOB-TNFc haplotypes other than 0101-1-169, was not predisposing to T1DM, being present in 8.6% of patient chromosomes and 9.2% of control chromosomes.
In order to extend support to these findings, an additional 128 Sardinian families were genotyped at HLA-DQB1 and -DRB1, DMB, DOB and TNFc. As observed in the first set of families, allele DMB*0101 marked significant heterogeneity in the association of DR3 haplotypes with disease (P HM = 6.2 x 10–4). The same DR3 haplotype, defined by alleles 0101, 1 and 169 at DMB, DOB and TNFc, was positively associated with T1DM (OR = 4.1, P = 1.1 x 10–7), whereas other DR3 haplotypes were not.
In the combined dataset (n = 385 families), the evidence of heterogeneity in the association of the different extended DR3 haplotypes was striking [pairwise OR (POR) = 3.7, P HM = 2.2 x 10–7] (Fig. 1). Thus, in the Sardinian population the risk of T1DM is 3.7 times greater for children carrying the conserved DR3 haplotype defined by alleles 0101, 1 and 169 at DMB, DOB and TNFc, respectively, compared with those carrying DR3 with any other combination of alleles at these loci. Only the DMB*0101-DOB*1-TNFc*169 DR3 haplotype is positively associated with T1DM (47.5% of the patient chromosomes and 12.8% of the control chromosomes, OR= 6.1, P = 6.4 x 10–31). Other DR3 haplotypes combined were neutrally associated (9.2% of the patient chromosomes and 9.1% of the AFBAC chromosomes, OR = 1.0, P is not significant).
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Even though the Sardinian population does not show significant genetic substructure (12), to formally rule out any effects from recent admixture that might invalidate the HM analysis (10), we applied the transmission disequilibrium test (TDT) to parents homozygous for DR3 but heterozygous at DMB, DOB and TNFc. In the total sample set (n = 385), the DR3 haplotype DMB*0101-DOB*1-TNFc*169 was significantly positively transmitted to affected children (transmitted to affected children using the TDT, 14; non-transmitted to affected children using the TDT, 1; 93.3% transmitted; P = 7.9 x 10–4). Note the difference in power between the tests (2.2 x 10–7 versus 7.9 x 10–4 for HM and homozygous parent TDT, respectively).
Independence of the non-DR/DQ regions
In principle, it is possible that the heterogeneity in the association of the DR3 haplotypes defined by the combined presence of alleles at the DMB, DOB and TNFc is caused by an allele of only one non-DR/DQ gene in LD with the predisposing DMB-DOB-TNFc haplotype. To investigate this possibility we applied the HM in the total data to evaluate three-locus haplotypes, conditioning not only on HLA-DRB1 and -DQB1 but also on the most positively associated allele at DOB or TNFc, to assess in turn whether the third marker in this example, DMB, still had an effect. We found that the regions of heterogeneity were significantly independent from each other, thus consistent with at least three independent modifying gene effects (Table 2).
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Finally, we also established the general patterns of LD, measured as normalized D' values (13,14), observed between DMB, DOB and TNFc and the surrounding HLA loci (Figs 2, 3 and 4, respectively). DMB showed strong degrees of LD with DMA (D' = 0.67, P < 1 x 10–7) and HSP2 (D' = 0.56, P < 2 x 10–3). However, DMA and HSP2, albeit in LD with DMB, cannot explain the association with T1DM defined by DMB, because they themselves did not show any independent association with T1DM. Similarly, DOB showed strong degrees of LD with LMP7 (D' = 0.71, P < 1 x 10–7), D6S2445 (D' = 0.69, P < 1 x 10–7) D6S2444 (D' = 0.72, P < 1 x 10–7) and, to lesser extent, with TNFa (D' = 0.46, P < 1 x 10–7) and TNFc (D' = 0.46, P < 1 x 10–7), but likewise, none of them can explain the heterogeneity in the association of DR3 haplotypes defined by DOB, for the reason outlined above. Importantly, both DMB and DOB showed a tendency to a decrease of LD around them consistent with the physical distance (Figs 2 and 3) but more marked in the centromeric part of the map.
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Finally, there was also a tendency to a decrease of LD consistent with the physical distance around TNFc, with a cluster of markers in the class III subregion, notably TNFa (D' = 0.91, P < 1 x 10–7), TNFd (D' = 0.76, P < 1 x 10–7), 82-1 (D' = 0.63, P < 1 x 10–7), C1-2-A (D' = 0. 60, P < 1 x 10–7) and D3A (D' = 0.52, P < 1 x 10–7) and, to a lesser extent, in the telomeric portion of the class II subregion, which included D6S2447 (D' = 0.48, P < 1 x 10–7) and LMP2 (D' = 0.50, P < 1 x 10–7) (Fig. 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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IDDM1 is a superlocus with multiple disease susceptibility components. Its dissection remains a substantial challenge because the analysis of alleles of any locus must fully take into account the LD between it and the alleles of other closely linked loci. We have previously established that HLA-DQB1 and -DRB1 dominate the association of the major histocompatibility complex (MHC) with T1DM in the Sardinian and UK populations (3,15). In this study we have generalized the HM and exploited the unique features of the Sardinian population to verify whether the HLA-DQB1, -DRB1 loci are the only contributors to IDDM1, or, other HLA, non-DR/DQ loci are acting as risk modifiers. We can conclude that in the Sardinian population the HLA-DQB1 and -DRB1 loci do not account for the entire association of the main predisposing haplotype HLA-DR3 (DRB1*0301-DQB1*0201) with T1DM. We found three non-DQB1, -DRB1 regions taht could influence the T1DM risk. These risk modifiers were not only independent of DQ-DR but also independent of each other after taking LD into account. Collectively the impact of haplotypes defined by combinations of these risk modifiers is substantial. For instance, consider that 40% of the Sardinian DR3 haplotypes, defined by the joint presence of certain alleles at the loci DMB, DOB and TNFc, are not associated with T1DM.
Individually, allelic variation at the locus DMB defines, in this Sardinian sample, the region giving the strongest, and replicated, evidence of a modifying effect on the major HLA class II DRB1 and DQB1 disease loci. DMB encodes one of the two subunits of a molecule required for processing and HLA class II presentation of peptides (16). Therefore, DMB itself is a prime candidate. However, our positive results are in contrast to two studies of Italian (17) and French (18) T1DM families which failed to show any evidence of independent association of DMB with T1DM. Using the HM we failed to find any significant evidence of heterogeneity in the association of DR3 haplotypes defined by DMB alleles in a set of 383 T1DM families from the UK and USA (C . Motzo J.A. Todd and F. Cucca, unpublished data). These negative results from non-Sardinian populations are important because they suggest that the DMB effects described in the Sardinian families are not directly attributable to the SNPs within the second and third exons of the DMB locus assessed in our and in previous studies. This underscores the utility of cross-population comparisons for the fine scale mapping and detection of the aetiological modifying genes. For instance, marker D6S2223, previously found to influence the association of DR3 haplotypes with T1DM in Norwegian and UK samples (7), is not associated with the disease in the Sardinian families.
We can exclude the possibility that the DMB, DOB and TNFc modifying effects reported here are secondary to any of the non-DR/DQ markers analysed in these Sardinian samples (Tables 1 and 2). Moreover, as shown by the LD patterns observed between DMB, DOB and TNFc and the other HLA loci (Figures 2–4), the relationship between LD and physical distance, though imperfect, provides evidence against the possibility of the modifying loci being very far from the association peaks defined by the conditional analysis. Taken together, our results could suggest the presence of at least three Sardinian founder mutations, which occurred most likely in proximity with the DMB, DOB and TNFc regions and which modified the T1DM predisposition conferred by an ancestral, common HLA-DR3 haplotype. Since these markers are located within or very close to the HLA class II subregion, these results provide further support for the notion that this subregion is the key chromosome region containing the essential components for the HLA predisposition to T1DM. Furthermore, using a large mixed data set from the UK, the USA and Sardinia, we have recently confirmed and extended evidence for a negative association with T1DM of the DPB1*0402 allele of the third classical class II locus, HLA-DPB1 (F. Cucca and J.A. Todd, submitted). However, this allele is only present on 3.6% of Sardinian DR3 haplotypes and therefore cannot account for the non-DR-DQ effect described here. Thorough resequencing and further association analyses on much larger Sardinian sample sets will allow the exclusion mapping of polymorphisms and the clarification of the contributions of the various loci to the aetiological modifying effects. This will include not only the DMB, DOB and TNFc gene regions, but also potential regulatory sequences of the DR/DQ/DP genes themselves.
The complexity of the association of HLA-IDDM1 with T1DM illustrated in this study is unlikely to be unique. Results for X-linked retinitis pigmentosa (19) and several examples in the non-obese diabetes (NOD) mouse model of T1DM (20–23) indicate that the presence of individual linkage peaks holding multiple disease susceptibility genes may be a common feature of complex traits. Genes of related function which may have arisen through gene duplication are often clustered in a chromosome region, and this common feature of genome organization may explain these findings. Our data illustrate that the HM can be helpful to delineate the role of individual loci within clusters of genes that have multiple associated components in strong LD with each other. This conditional approach can therefore be systematically applied in LD/association mapping studies of common multifactorial diseases in which the aetiological SNPs are sought amongst a background of other SNPs in LD with each other.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Subjects and HLA typing
In this study we employed two independent data sets from Sardinia. The first consisted of 257 Sardinian T1DM families, all from a paediatric department of the southern part of the island (Brotzu Hospital, Cagliari). Each family was ascertained to include one affected child and the parents (average age of patients at disease onset, 8.15 years; standard deviation, ± 4.15; minimum age, 6 months; and maximum age, 22 years). This data set was genotyped for 20 microsatellite markers and 10 SNPs. The primer sequences and genotyping conditions for the microsatellite markers (D6S291, D6S439, D6S1629, D6S1560, D6S1568, D6S2445, D6S2444, D6S273, C1-2-A, D6S265, D6S258, D6S1683, D6S306, TNFa, TNFc, TNFd, D3A, 82-1, 82-2 and D6S2223) and for the SNPs at the expressed genes (DRB1, DQB1, DPB1, LMP2, LMP, DMA, DMB and DOB, HSP70-2 and tapasin) have been previously reported (15). In particular, we refer to the variants having codons GTC (Val) and ATC (Leu), respectively, at position 218 of the fourth exon of the DOB gene, as alleles 1 and 2.
The second data set consisted of 128 Sardinian T1DM families, which included 96 simplex families with only one affected child and parents and 32 multiplex families with two affected children and their parents (average age of patients at disease onset, 8.6 years; standard deviation, ± 4.0; minimum age, 1 year; and maximum age, 16 years). This data set was used only to extend the positive findings obtained in the first data set and was therefore genotyped only for DRB1-DQB1, the SNPs at DMB and DOB and the microsatellite at the TNFc locus in the first intron of the TNF-ß gene. In all the association analyses performed we randomly selected one affected child from all the families with more than one affected sibling.
Statistical analyses
In order to distinguish primary associations from those owing to LD at the established disease predisposing loci, we have used the HM (10). The HM is a test for homogeneity of relative allele frequencies in patients and controls at a test locus on haplotypes identical for alleles at another locus. Specifically, the HM tests the null hypothesis of equality in the distribution in patients and controls of marker haplotypes identical at one variant but different at another closely linked variant. If there is heterogeneity between the patient and control in the distribution of two marker haplotypes identical at a predisposing marker (variant A) but different at a putative predisposing marker at another site (variant B), then this is evidence that variant A does not entirely explain disease predisposition and that variant B itself, or another marker in LD with variant B, is influencing the relative association of variant A and thus the disease susceptibility. The frequencies of the various alleles and haplotypes in the healthy Sardinian population, referred to as controls in the text, were deduced from the AFBAC frequencies, calculated as described by Thomson (9) for single alleles. The distribution of the patient and control haplotypes in the patients and controls were then arranged in a 2 x 2 contingency table and tested by Fisher’s exact or Pearson’s 2 test. In the present study the HM was applied comparing the heterogeneity in the association of the various non-HLA-DQB1 and -DRB1 loci (variant B) on the same DR3 haplotype background (variant A). The most positively associated allele at the test locus (variant B), chosen based on the OR of the various haplotypes (data not shown), was compared with all of the other alleles observed at the same locus, grouped. This grouping strategy alleviates problems of random fluctuations of the numbers in the contingency table related to rare haplotypes. In order to provide sufficient statistical power for the conditional analysis, we considered only markers (or groups of markers) having an AFBAC frequency >2% for the least common haplotype. We have also used the HM to calculate POR, defining the risk of being diagnosed with the disease for individuals carrying a given allele or combination of alleles, relative to the risk for individuals carrying another allele or combinations of alleles in the same haplotype background (in our case, HLA-DR3). The PORs were calculated using the following formula: [(a x d)/(b x c)], where a is the number of times a given haplotype is observed in the affected children; d is the number of times another haplotype, identical to the previous haplotype at a predisposing marker (variant A) but different at the test locus (variant B), is observed in the AFBAC controls; b is the number of times the first haplotype is observed in the AFBAC controls; and c is the number of times the second haplotype is observed in patients. We have also applied another conditional method, the homozygous parent TDT (5,7), which considers the transmissions of alleles, evaluated by TDT, from parents heterozygous at the test locus but homozygous at the primary locus (in our case, HLA-DR3).
Haplotypes were established following the co-segregation of alleles within families and using computer programs written by F. Dudbridge. Only haplotypes certain from parental genotype data, and in the absence of inter-crosses, are considered in the analyses shown in this paper.
ACKNOWLEDGEMENTS
We wish to thank Antonio Cao, Stefano De Virgiliis, Mario Silvetti, Mathias Herr, Annabel Smith and Elisabetta Deidda for help and advice, Cesare Zavattari for writing a program that allows assignment of the allele sizes into their appropriate allele bins, Heather Cordell, David Clayton and Frank Dudbridge for statistical advice, Margi Chessa, Paola Frongia, Rossella Ricciardi and Adolfo Pacifico for help in collecting the Sardinian T1DM families, James Copeman for information about tapasin and Andrew Mungall (Sanger Center) for the establishment of the physical map. We also thank the Italian Telethon, the Regione Autonoma Sardegna (L.R.11, 30-4-90) and the Wellcome Trust for financial support. F.C. and J.A.T. are recipients of a Wellcome Trust Biomedical Research Collaboration Grant and J.A.T. was a Wellcome Trust Principal Research Fellow.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +39 070 6095681; Fax: +39 070 6095558; Email: fcucca@mcweb.unica.it
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REFERENCES |
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