The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vorechovsky, I.
Right arrow Articles by Webster, A. D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vorechovsky, I.
Right arrow Articles by Webster, A. D. B.
Right arrowPubmed/NCBI databases
*OMIM
The Journal of Immunology, 2000, 164: 4408-4416.
Copyright © 2000 by The American Association of Immunologists

Fine Mapping of IGAD1 in IgA Deficiency and Common Variable Immunodeficiency: Identification and Characterization of Haplotypes Shared by Affected Members of 101 Multiple-Case Families1,2

Igor Vorechovsky*,{dagger}, Michael Cullen{ddagger}, Mary Carrington{ddagger}, Lennart Hammarström* and A. David B. Webster{dagger}

* Department of Biosciences at NOVUM, Karolinska Institute, Huddinge, Sweden; {dagger} Medical Research Council Immunodeficiency Research Group, Department of Clinical Immunology, University College London Medical School, London, United Kingdom; and {ddagger} Biological Carcinogenesis and Development Program, National Cancer Institute-Frederick Cancer Research and Development Program, Frederick, MD 21702


   Abstract
Top
 Abstract
References
 
To limit the region containing a mutation predisposing to selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID), 554 informative members of 101 multiple-case families were haplotyped at the IGAD1 candidate locus in the MHC. Microsatellite markers were placed onto the physical map of IGAD1 to establish their order and permit rapid haplotype analyses. Linkage analysis of this extended family set provided additional support for a strong susceptibility locus at IGAD1 with a maximum multipoint nonparametric linkage score in excess of 3. Although the transmission of maternal IGAD1 haplotypes from unaffected heterozygous parents to the affected offspring was in excess, this was not apparent in multiple-case families with a predominance of affected mothers, suggesting that this parental bias is influenced by the affection status of transmitting parents and supporting a maternal effect in disease susceptibility. Of 110 haplotypes shared by 258 affected family members, a single haplotype (H1) was found in 44 pairs of affected relatives, accounting for the majority of the IGAD1 contribution to the development of IgAD/CVID in our families. The H1 allelic variability was higher in the telomeric part of the class III region than in the distal part of the class II region in both single- and multiple-case families. Incomplete H1 haplotypes had most variant alleles in the telomeric part of the analyzed region in homozygous IgAD/CVID patients, whereas this was not observed in unaffected homozygotes. These data suggest that a telomeric part of the class II region or centromeric part of the class III region is the most likely location of IGAD1.


   Acknowledgments
 
We thank J. Björkander, T. Español, C. M. Farber, L. Gomez, S. Koskinen, M. D. Laycock, J. Litzman, J. Lokaj, L. Luo, N. Matamoros, C. Mullighan, R. Paganelli, E. Parízková, A. Plebani, I. Quinti, A. Ryan, O. Sanal, H. Siwinska-Golebiowska, M. N. Voniatis, C. M. R. Weemaes, and P. L. Yap for referring families with IgAD/CVID or technical help.

Received for publication December 3, 1999. Accepted for publication February 11, 2000.


   References
Top
 Abstract
 References
 

  1. Burrows, P. D., M. D. Cooper. 1997. IgA deficiency. Adv. Immunol. 65:245.[Medline]
  2. Schaffer, F. M., J. Palermos, Z. B. Zhu, B. O. Barger, M. D. Cooper, J. E. Volanakis. 1989. Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Proc. Natl. Acad. Sci. USA 86:8015.[Abstract/Free Full Text]
  3. Volanakis, J. E., Z.-B. Zhu, F. M. Schaffer, K. J. Macon, J. Palermos, B. O. Berger, R. Go, R. D. Campbell, H. W. J. Schroeder, M. D. Cooper. 1992. Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J. Clin. Invest. 89:1914.
  4. Voechovsky, I., A. D. B. Webster, A. Plebani, L. Hammarström. 1999. Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences and the role of anti-IgA antibodies in disease predisposition. Am. J. Hum. Genet. 64:1096.[Medline]
  5. Ambrus, M., E. Hernadi, G. Bajtai. 1977. Prevalence of HLA-A1 and HLA-B8 antigens in selective IgA deficiency. Clin. Immunol. Immunopathol. 7:311.[Medline]
  6. Hammarström, L., C. I. Smith. 1983. HLA-A, B, C and DR antigens in immunoglobulin A deficiency. Tissue Antigens 21:75.[Medline]
  7. Cobain, T. J., M. A. French, F. T. Christiansen, R. L. Dawkins. 1983. Association of IgA deficiency with HLA A28 and B14. Tissue Antigens 22:151.[Medline]
  8. Olerup, O., C. I. Smith, J. Björkander, L. Hammarström. 1992. Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc. Natl. Acad. Sci. USA 89:10653.[Abstract/Free Full Text]
  9. Fiore, M., C. Pera, L. Delfino, I. Scotese, G. B. Ferrara, C. Pignata. 1995. DNA typing of DQ and DR alleles in IgA-deficient subjects. Eur. J. Immunogenet. 22:403.[Medline]
  10. Mullighan, C. G., G. C. Fanning, H. M. Chapel, K. I. Welsh. 1997. TNF and lymphotoxin-{alpha} polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J. Immunol. 159:6236.[Abstract]
  11. Reil, A., G. Bein, H. K. G. Machulla, B. Sternberg, M. Seyfarth. 1997. High-resolution DNA typing in immunoglobulin A deficiency confirms a positive association with DRB1*0301, DQB1*02 haplotypes. Tissue Antigens 50:501.[Medline]
  12. Howe, H. S., A. K. L. So, J. Farrant, A. D. B. Webster. 1991. Common variable immunodeficiency is associated with polymorphic markers in the human major histocompatibility complex. Clin. Exp. Immunol. 83:387.[Medline]
  13. Schaid, D. J., S. S. Sommer. 1994. Comparison of statistics for candidate-gene association studies using cases and parents. Am. J. Hum. Genet. 55:402.[Medline]
  14. Cucca, F., Z. B. Zhu, A. Khanna, F. Cossu, M. Congia, M. Badiali, R. Lampis, F. Frau, S. De Virgiliis, A. Cao, et al 1998. Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region. Clin. Exp. Immunol. 111:76.[Medline]
  15. Wilton, A. N., T. J. Cobain, R. L. Dawkins. 1985. Family studies of IgA deficiency. Immunogenetics 21:333.[Medline]
  16. Jr Schroeder, H. W., Z. B. Zhu, R. E. March, R. D. Campbell, S. M. Berney, S. A. Nedospasov, R. L. Turetskaya, T. P. Atkinson, R. C. Go, M. D. Cooper, J. E. Volanakis. 1998. Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes. Mol. Med. 4:72.[Medline]
  17. Hsieh, S.-L., R. March, A. Khanna, S. J. Cross, R. D. Campbell. 1997. Mapping of 10 novel microsatellites in the MHC class III region: application to the study of autoimmune disease. J. Rheumatol. 24:220.[Medline]
  18. French, M. A., R. L. Dawkins. 1990. Central MHC genes, IgA deficiency and autoimmune disease. Immunol. Today 11:271.[Medline]
  19. Olerup, O., C. I. Smith, L. Hammarström. 1991. Is selective IgA deficiency associated with central HLA genes or alleles of the DR-DQ region?. Immunol. Today 12:134.[Medline]
  20. French, M., R. Dawkins, F. T. Christiansen, W. Zhang, M. A. Degli-Esposti, G. Saueracker. 1991. Is selective IgA deficiency associated with central HLA genes or alleles of the DR-DQ region? Reply. Immunol. Today 12:135.
  21. Consortium. 1999. Complete sequence and gene map of a human major histocompatibility complex. Nature 401:921.
  22. Voechovsky, I., H. Zetterquist, R. Paganelli, S. Koskinen, A. D. Webster, J. Björkander, C. I. Smith, L. Hammarström. 1995. Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin. Immunol. Immunopathol. 77:185.[Medline]
  23. Cullen, M., J. Noble, H. Erlich, K. Thorpe, S. Beck, W. Klitz, J. Trowsdale, M. Carrington. 1997. Characterization of recombinants in the HLA class II region. Am. J. Hum. Genet. 60:397.[Medline]
  24. Macaubas, C., J. Hallmayer, J. Kalili, A. Kimura, S. Yasunaga, F. C. Grumet, E. Mignot. 1995. Extensive polymorphism of a (CA)n microsatellite located in the HLA-DQA1/DQB1 class II region. Hum. Immunol. 42:209.[Medline]
  25. Cullen, M., H. Erlich, W. Klitz, M. Carrington. 1995. Molecular mapping of a recombination hotspot located in the second intron of the human TAP2 locus. Am. J. Hum. Genet. 56:1350.[Medline]
  26. Dib, C., S. Faure, C. Fizames, D. Samson, N. Drouot, P. V. A., S. Millasseau, J. Marc, E. Hazan, M. Seboun, M. Lathrop, et al 1996. A comprehensive genetic map of the human genome based on 5264 microsatellites. Nature 380:152.[Medline]
  27. Martin, M. P., A. Harding, R. Chadwick, M. Kronick, M. Cullen, L. Lin, E. Mignot, M. Carrington. 1998. Characterization of 12 microsatellite loci of the human MHC in a panel of reference cell lines. Immunogenetics 47:131.[Medline]
  28. Kruglyak, L., M. J. Daly, M. P. Reeve-Daly, E. S. Lander. 1996. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58:1347.[Medline]
  29. Olerup, O., C. I. Smith, L. Hammarström. 1990. Different amino acids at position 57 of the HLA-DQ ß chain associated with susceptibility and resistance to IgA deficiency. Nature 347:289.[Medline]
  30. De La Concha, E. G., M. Fernandez-Arquero, A. Martinez, F. Vidal, P. Vigil, L. Conejero, M. C. Garcia-Rodriguez, G. Fontan. 1999. HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID). Clin. Exp. Immunol. 116:516.[Medline]
  31. Mitchell, L. E.. 1998. Differentiating between fetal and maternal genotypic effects using transmission test for linkage disequilibrium. Am. J. Hum. Genet. 60:1006.
  32. Kong, A., N. J. Cox. 1997. Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61:1179.[Medline]
  33. Beck, S., S. Abdulla, R. P. Alderton, R. J. Glynne, I. G. Gut, L. K. Hosking, A. Jackson, A. Kelly, W. R. Newell, P. Sanseau, et al 1996. Evolutionary dynamics of non-coding sequences within the class II region of the human MHC. J. Mol. Biol. 255:1.[Medline]
  34. Beck, S., A. Kelly, E. Radley, F. Khurshid, R. P. Alderton, J. Trowsdale. 1992. DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing. J. Mol. Biol. 228:433.[Medline]
  35. Carrington, M., M. Dean. 1994. A polymorphic dinucleotide repeat in the third intron of TAP1. Hum. Mol. Genet. 3:218.[Free Full Text]
  36. Lin, L., L. Jin, A. Kimura, M. Carrington, E. Mignot. 1997. DQ microsatellite association studies in three ethnic groups. Tissue Antigens 50:507.[Medline]
  37. Colonna, M., G. B. Ferrara, J. Strominger, T. Spies. 1991. Hypervariable microsatellites in the central MHC class III region. K. Tsuji, and M. Aizawa, and T. Sasazuki, eds. HLA 1991 179. Oxford University Press, Oxford.
  38. Udalova, I. A., S. A. Nedospasov, G. C. Webb, D. D. Chaplin, R. L. Turetskaya. 1993. Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics 16:180.[Medline]
  39. Ulgiati, D., G. Grimsley, C. Leelayuwat, L. J. Abraham. 1996. Analysis of the major histocompatibility complex microsatellite CL1 in different human haplotypes. Eur. J. Immunogenet. 23:205.[Medline]



This article has been cited by other articles:


Home page
 BloodHome page
U. Salzer, C. Bacchelli, S. Buckridge, Q. Pan-Hammarstrom, S. Jennings, V. Lougaris, A. Bergbreiter, T. Hagena, J. Birmelin, A. Plebani, et al.
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes
Blood, February 26, 2009; 113(9): 1967 - 1976.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Sekine, R. C. Ferreira, Q. Pan-Hammarstrom, R. R. Graham, B. Ziemba, S. S. de Vries, J. Liu, K. Hippen, T. Koeuth, W. Ortmann, et al.
Role for Msh5 in the regulation of Ig class switch recombination
PNAS, April 24, 2007; 104(17): 7193 - 7198.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
I R Korponay-Szabo, I Dahlbom, K Laurila, S Koskinen, N Woolley, J Partanen, J B Kovacs, M Maki, and T Hansson
Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency
Gut, November 1, 2003; 52(11): 1567 - 1571.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Kralovicova, L. Hammarstrom, A. Plebani, A. D. B. Webster, and I. Vorechovsky
Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency
J. Immunol., March 1, 2003; 170(5): 2765 - 2775.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. G. De la Concha, M. Fernandez-Arquero, L. Gual, P. Vigil, A. Martinez, E. Urcelay, A. Ferreira, M. C. Garcia-Rodriguez, and G. Fontan
MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes
J. Immunol., October 15, 2002; 169(8): 4637 - 4643.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vorechovsky, I.
Right arrow Articles by Webster, A. D. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vorechovsky, I.
Right arrow Articles by Webster, A. D. B.
Right arrowPubmed/NCBI databases
*OMIM

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS