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An analysis of genetic variation across the MBL2 locus in Dutch Caucasians indicates that 3′ haplotypes could modify circulating levels of mannose-binding lectin

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Abstract

Mannose-binding protein (MBL) is a critical component of innate immunity and provides first-line protection against pathogens. Both circulating MBL serum levels and functional activity have been correlated with common genetic variants in the MBL2 gene. Associations between MBL deficiency and severe infections have been reported in immuno-incompetent patients and for autoimmune disorders; however, measured MBL serum levels do not fully correlate with the ‘secretor haplotypes’. Previously, the MBL2 locus was resequenced and determined that a recombination hotspot divides MBL2 into two haplotype blocks. It was sought to investigate whether additional variants, in either block structure could associate with MBL serum levels. Therefore, 31 common variants were analysed across the locus in 212 DNA samples of healthy Caucasian individuals with known MBL serum concentrations. The additional 5′ variants were in strong linkage to the elements of the ‘secretor haplotypes’; functional alleles B, C and D also lie on restricted haplotypes. Four variants in the 3′ block (Ex4-1483T>C, Ex4-1067G>A, Ex4-901G>A and Ex4-710G>A) are components of a distinct haplotype block. The results of this study suggest that additional 5′ variants as well as markers of distinct 3′ haplotype blocks in MBL2 may contribute to circulating protein levels, but further studies are required to confirm these observations. Last, there could be a selective advantage for diversification of the 3′ region of the gene.

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Acknowledgments

The authors are grateful to S. Berndt for her helpful assistance in the computation of the haplotype association tests. We thank E. Tarazona-Santos, M. Yeager, B. Staats, B. Packer, S. Savage, J.G. Taylor VI. and H.C. Erickson for discussion of the data; M. Kiley, E. Schatzkin, M. Brown, A. Eckert, A. Crenshaw and D. Kressley for their excellent technical assistance. We also want to thank the two anonymous reviewers for their critical comments.

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Authors and Affiliations

  1. Section on Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-4605, USA

    Toralf Bernig & Stephen Chanock

  2. Emma Children’s Hospital, Academic Medical Centre, University of Amsterdam, 1105, Amsterdam, The Netherlands

    Willemijn Breunis & Taco Kuijpers

  3. Sanquin Research Institute at the Central Laboratory of the Blood Transfusion Service, University of Amsterdam, 1066, Amsterdam, The Netherlands

    Nannette Brouwer & Dirk Roos

  4. Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892-4605, USA

    Amy Hutchinson & Robert Welch

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  1. Toralf Bernig
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  2. Willemijn Breunis
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  4. Amy Hutchinson
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  8. Stephen Chanock
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Correspondence to Stephen Chanock.

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Bernig, T., Breunis, W., Brouwer, N. et al. An analysis of genetic variation across the MBL2 locus in Dutch Caucasians indicates that 3′ haplotypes could modify circulating levels of mannose-binding lectin. Hum Genet 118, 404–415 (2005). https://doi.org/10.1007/s00439-005-0053-5

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