Human Molecular Genetics, 2002, Vol. 11, No. 14 1599-1603
© 2002 Oxford University Press
Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11–13 in African families
1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK, 2Hôpital Ignace Deen, Conakry, Guinea, 3Department of Paediatrics and Child Health, 4MRC Centre for Molecular and Cellular Biology and Department of Medical Biochemistry, University of Stellenbosch, South Africa and 5Medical Research Council Laboratories, Banjul, The Gambia
Received January 9, 2002; Accepted May 13, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Host genetics plays an important role in individual susceptibility and resistance to infectious diseases, but no genes have yet been identified using genome-wide screens. Twin studies have indicated that tuberculosis susceptibility has a significant host genetic component, and several genes appear to be involved. Recently, a genome-wide linkage analysis of 136 African families identified chromosome 15q11–13 as a region with suggestive evidence of linkage, with a LOD score of 2.0. We tested 10 microsatellite markers and 5 positional candidate genes in this chromosomal region for deviation from random transmission from parents to affected offspring. The polymorphisms, lying in a region of 14 cM, were initially typed in the same 79 Gambian families used in the genome screen. A borderline significant association with a 7 bp deletion in UBE3A (P=0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P=0.002). These fine-mapping data suggest that UBE3A or a closely flanking gene may be a tuberculosis-susceptibility locus.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Tuberculosis is one of the major global causes of mortality, accounting for perhaps three million deaths per year. An increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis, the global pandemic of HIV/AIDS (which increases susceptibility to tuberculosis) and the long period of chemotherapy required make tuberculosis control very difficult. There is thus an urgent need for a better understanding of natural resistance to this infection and disease to allow the design of improved control strategies.
More twin studies have been done in tuberculosis than in any other infectious disease, and the four published studies (1–4) concur in demonstrating a significant host genetic component to variable susceptibility. Epidemiological data suggesting that only 1 in 10 M. tuberculosis-infected persons will progress to clinical disease allow for an important effect of genetically determined host resistance factors. Numerous candidate genes have now been assessed in case–control studies of this disease, and three genes have shown associations in more than one population. These are the HLA-DR2 allele at the HLA-DRB1 locus in the major histocompatibility locus (5–8), the vitamin D receptor gene (9) and the NRAMP1 gene, a candidate suggested initially by positional cloning of its murine homologue as a susceptibility locus for various intracellular pathogens in mice (10–12). However, the effects of each of these loci is modest, and even cumulatively they can only account for a minor proportion of the host genetic component identified in twin studies.
We have reported a two-stage genome-wide scan using non-parametric linkage analysis of African sibling pairs with tuberculosis in an attempt to map any major susceptibility loci for tuberculosis in this region (13). The first-stage scan analysed 67 families from The Gambia and 16 families from KwaZulu-Natal (KZN) in South Africa. Most families consisted of affected sib pairs with a few sib trios. In the second stage, 12 more families from The Gambia and 41 from the high-incidence population near Tygerberg Hospital in the Western Cape, South Africa were studied. The 12 families from The Gambia all consisted of affected sibpairs, the families from South Africa were quite large, and varied between two and six affected siblings. 299 microsatellite markers covering all 23 chromosomes were typed in the first screen and 7 regions were followed up in a second screen. No region of the genome showed significant evidence for linkage, making it unlikely that there would be a major susceptibility locus in these families. The best evidence of linkage was found on chromosome 15q11–13, where the LOD score for the two screens combined was 2.00.
Here we report progress in the fine mapping of the putative susceptibility locus on chromosome 15q11–13. The strategy that we adopted to follow up the results from this genome screen was to test for association with microsatellite markers and polymorphisms in genes mapping to this approximately 14 cM region. Ten microsatellite markers and five polymorphisms in known genes were tested for association with tuberculosis in the families used in the genome screen as well as in 44 further families from Guinea–Conakry (11). Initial tests of intra-familial association were performed on the Gambian families alone. If the resulting test statistic was significant, further testing was done on the entire dataset. The Gambian families were chosen for the initial screening, since these composed the largest data set available from a single population. A single genetic variant, a 7 bp deletion in the UBE3A gene, was associated with tuberculosis with borderline statistical significance and this polymorphism was then further typed in all the available African families, identifying a highly significant association (P=0.002). We show that this gene is expressed in macrophage-like cell lines in which M. tuberculosis grows, and we speculate on a possible role for this positional candidate gene in tuberculosis.
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RESULTS |
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Of the 15 polymorphisms newly typed in this chromosome 15q11–13 region (Fig. 1), 2 were not polymorphic in the Gambian samples. The repeat in exon 16 and the deletion in intron 7 were therefore excluded from analysis after no difference in length was found amongst 95 samples. Those polymorphisms in the UBE3A gene had been described in autistic patients from the USA, and no estimates were available for a general African population. The results of the analysis of the 13 polymorphic loci using TRANSMIT (see Materials and Methods) are reported in Table 1.
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Only the 7 bp deletion in OP2 indicated a significant deviation (asymptotic P=0.03, bootstrap P=0.01) from the expected transmissions of the parents to the affected offspring. Following the suggestive evidence for linkage and association in OP2, we further typed OP2 in the Guinean families as well as in the South African families (Table 2). The most significant association (P=0.01) was found in the West African families analysed together. The estimated frequency of the 7 bp deletion is similar in the Guinean population and in the Gambian population (about 20%), indicating ethnic similarity. In the South African populations, the frequency of the deletion is quite different, especially between the Zulus (10%) and the Cape Coloureds (36%).
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Because there is previous evidence of linkage, it was essential to do a test of association. By only scoring the same alleles that were transmitted to both sibs, it is possible to get a more powerful test of association even if the number of informative families is strongly reduced (14). Analysing only the complete families of two parents and sibpairs, the total number of transmissions is 12 for the wild allele against 1 for the deletion. This gives a chisquared test statistic of 9.3, which on 1 df is 0.002. This is strong evidence of association. It is worth noting that all the individuals from KZN were homozygous and thus did not contribute to the association analysis.
Because UBE3A is in an imprinted region, it was potentially relevant to control for the effect of sex. We analysed the transmissions from the parents to the offspring, taking into account the sex of the parent of origin as well as the sex of the affected offspring. To differentiate between the sex of the affected siblings, it is possible to use a specific option in the TRANSMIT program. Treating only the affected males or the affected females as informative, the overall chi-squared value of 6.26 splits into a chi-squared test for male transmissions of 3.32, and for female of 2.61. Those two values do not provide any significant evidence for a differential effect between males and females. To differentiate between the sex of the parent of origin, one can score separately the transmissions from a heterozygous mother and the transmissions from a heterozygous father. If both parents are heterozygous, it is not possible to determine which allele was transmitted from which parent, in the diallelic case. Looking at the transmissions from families that included both parents, the breakdown of the transmissions is as follows: 14 times the deletion allele was transmitted from a heterozygous father to the affected offsprings and 27 times the deletion was not transmitted; 3 times the deletion allele was transmitted from a heterozygous mother and 5 times it was not transmitted. Only few mothers were found to be heterozygous. These numbers are relatively small, but do not show any evidence for differential transmission based on the sex of the parent.
Following these results, it was interesting to find out whether OP2 in UBE3A was expressed in macrophages. To achieve this, two macrophage cell lines called THP1 and MM6 were used. The OP2 primers were used to amplify ‘UBE3A’ RNA and OCA2 primers to amplify ‘P’ RNA. As a control, primers that are situated in intron 2 of UBE3A were used. All three primers amplified DNA product under the same conditions.
As can be seen in Figure 2, OP2, situated in the promoter region of UBE3A, and OCA2, situated in exon 14, were amplified successfully. The negative controls did not amplify any product as expected. This demonstrates that OP2 and OCA2 are expressed in these macrophage-like cell lines, and suggests that these genes will be expressed in vivo in macrophages too.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The region of suggestive linkage identified in the genome scan of African sibling pairs with tuberculosis (13) spans over 10 cM near to the centromere on the long arm of chromosome 15. This region has been of particular interest because it shows genomic imprinting and contains the susceptibility loci of the related disorders Angelman syndrome and Prader–Willi syndrome (15). The latter is paternally imprinted and maps to the region of the necdin gene centromeric to the Angelman syndrome gene UBE3A, which shows maternal imprinting (16,17). However, imprinting of UBE3A is confined to the hippocampus and possibly other brain regions, but is not observed in other tissues (18–20). The existence of paternal imprinting in this region has facilitated fine mapping of the tuberculosis locus: because we found no evidence of a parent-of-origin effect for any marker in this region, this renders it unlikely that necdin and its immediately flanking DNA contain the tuberculosis locus.
Despite the intensive study of these syndromes, sequencing of this region of the genome has been relatively slow until recently, and many putative loci remain unidentified. Inspection of the genes known to map to this region identified none that could clearly play a role in tuberculosis susceptibility. The P gene situated towards the telomeric end of the region of linkage might conceivably play a role if it is expressed in macrophages as well as melanosomes, and our preliminary RT–PCR data support this possibility. The P gene appears to encode a transporter influencing melanosome pH (21) and might, like the NRAMP1 cation transporter (22,23) influence the macrophage intraphagolysosomal milieu in which M. tuberculosis grows. However, the markers that we studied in and near to the P gene showed no evidence of association with tuberculosis.
Of the 13 polymorphisms studied in this chromosomal region in the 79 Gambian families, one did show evidence of non-random transmission from the parents to the affected offspring. The 7 bp deletion in the OP2 clone was transmitted to the affected offspring less often than would be expected under the hypothesis of no linkage and no association (P=0.03). Adding the 44 families from Guinea to this analysis increased the significance level slightly to 0.01. In a test of association independent of linkage based on the sibpairs alone, the exact symmetry test, the overall P-value was 0.002, providing stronger evidence of association that is robust to the number of comparisons made. In contrast there was no evidence of significant association in the South African families.
This variant is situated in the 5' end of the UBE3A gene and, like the first exon, it is expressed but not translated and therefore may not itself play a functional role. A 4.5 kb transcript of OP2 has been detected in brain, placenta, lung, liver, kidney and pancreas, but was particularly abundant in skeletal muscles, which does not seem to relate to Angelman syndrome (24). We show here that OP2 is also expressed in the macrophage-like cell lines (Fig. 1). Additional transcripts have been detected in the brain tissue: a 3.5 kb sense transcript that embedded in the 3'-untranslated region of UBE3A and an antisense transcript about 6.5 kb from the UBE3A stop codon (25).
UBE3A encodes a ubiquitin ligase that plays a key role in the uniquitination and degradation of specific proteins (26). The role of UBE3A in response to infectious agents has previously been studied in human papilloma virus (HPV) infection. UBE3A is also known as E6-associated protein because it mediates the association of the E6 protein of HPV with p53 (26). More recently, the substrate specificity of this ubiquitin ligase has been studied and it has been found to play a role in the degradation of the T-lymphocyte Src kinase enzyme Lck (27). Lck plays a key role in transducing T-cell receptor signalling in T cells, and it seems possible that altered expression or activity of UBE3A could thus influence the type or magnitude of T-cell responses to infectious agents such as M. tuberculosis (28). Although quite speculative, this scenario provides a possible and potentially testable mechanism whereby this enzyme could affect human resistance to tuberculosis.
The data reported here will encourage more detailed analysis of variation in UBE3A and its immediately flanking DNA in these and further populations to evaluate the possibility that this represents a major gene for tuberculosis susceptibility.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Marker selection
The following 10 microsatellites were selected, ordered as follows from the centromere (Fig. 1): D15S541, D155S1021, D15S122, D15S10, D15S210, D15S986, GAB155, GAB69, D15S822, D15S156. Of these GAB69 and GAB155 are CA repeats situated in the GABA receptor subunit ß3. GAB155 is in GABRB3 about 5 kb centromeric to the first three exons. The second polymorphism, GAB69, lies 150 kb centromeric to GAB155, close to exon 4 (29). Four insertion/deletion polymorphisms were typed in UBE3A. The first is a 7 bp deletion in OP2. OP2 is a genomic clone that contains the 5' end of the gene, including exon 1. The second polymorphism studied is a 3 bp deletion in intron 2. The third deletion is a 3 bp deletion in intron 7 and the fourth is a repeat within exon 16 (30). A single base change in the P gene has been analysed. IVS13 +26 represents an A-to-G change in intron 13. The frequency of allele ‘A’ was estimated in the African population to be 67% and that of allele ‘G’ to be 33% (31).
Genotyping
The single base change (IVS13) was analysed by hybridization of the product with allele-specific oligonucleotides. All the other polymorphisms were analysed on ABI 373A sequencers using fluorescently labelled primers and Genescan software.
Statistical analysis
The transmission disequilibrium test (TDT) (32) is probably the most commonly used test for association and linkage in families. The TDT was designed to test the transmissions from parent to offspring in complete trios, two parents and one affected sib, in the diallelic test. Generalizations of the TDT have recently been developed to account for multiple alleles and more complex family structures. We selected TRANSMIT (33) which tests for association and linkage in multiallelic loci in families with multiple sibs and missing parental genotypes (for a critical discussion, see 34). TRANSMIT had the main advantage of simplicity of use, because it can handle different familial structures and because it is possible to directly apply the test to a standard pedigree file. Because all the families contained at least two affected siblings, the test statistic is not an independent test of association. Therefore, to test exclusively for association, the exact symmetry test was also used (14).
RT–PCR
Total RNA was isolated from two macrophage cell lines, THP1 and MM6, using the Qiagen Rneasy kit and protocol. It was then amplified according to the manufacturer's instructions (Boehringer Mannheim protocol for Titan One Tube RT–PCR Kit). The final product was checked on a 1–2% agarose gel along with a 
x174 marker and can be seen in Figure 2. The expected product size for OP2 is 336 bp and that for OCA2 is 241 bp.
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ACKNOWLEDGEMENTS |
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A.C.L.C. is supported by Ministry of National Education and Scientific Research (Luxembourg) Grant BFR96/082. A.V.S.H. is a Wellcome Trust Principal Research Fellow.
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FOOTNOTES |
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* To whom correspondence should be addressed at: Room 7501, Level 7 John Radcliffe Hospital, Oxford OX3 9DU, UK. Email: adrian.hill{at}imm.ox.ac.uk
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REFERENCES |
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