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The Journal of Immunology, Vol 155, Issue 6 3013-3020, Copyright © 1995 by American Association of Immunologists

ARTICLES

Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein

HO Madsen, P Garred, S Thiel, JA Kurtzhals, LU Lamm, LP Ryder and A Svejgaard
Department of Clinical Immunology, National University Hospital, Copenhagen, Denmark.

Mannan-binding protein (MBP) is a serum lectin participating in the innate immune defense by opsonizing various microorganisms for phagocytosis. Opsonization defect due to MBP deficiency and low levels of the protein can partially be explained by the dominant effect of three different mutations in the structural part of the MBP gene. Large interracial differences in the frequencies of these variants have previously been described, but they cannot explain the large interindividual variation in MBP serum concentration. We describe the existence of additional polymorphisms at positions -550 (H/L variants) and -221 (X/Y variants) in the promoter region of the gene. The promoter haplotypes, HY, LY, and LX, show associations with high, medium, and low levels of MBP serum concentrations, respectively. Moreover, this represents a genetic system with additive effect of haplotypes in which a low producing LX haplotype in the homozygous state down-regulates the basal expression of MBP as effectively as a single structural variant. Populations of pure Eskimos, Caucasoids, and black Africans show marked interethnic differences in the frequencies of promoter haplotypes regulating the expression of the normal peptide, with the HY haplotype frequency varying from 0.83 in Eskimos via 0.33 in Caucasoids to 0.08 in Africans. The LY haplotype frequency varies from 0.04 in Eskimos via 0.39 in Caucasoids to 0.23 in Africans. The LX haplotype frequency varies from 0.03 in Eskimos via 0.24 in Caucasoids to 0.23 in Africans. The effect of the promoter variants can explain almost all of the ethnic differences not explainable by the structural variants alone.


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A. Koch, M. Melbye, P. Sorensen, P. Homoe, H. O. Madsen, K. Molbak, C. H. Hansen, L. H. Andersen, G. W. Hahn, and P. Garred
Acute Respiratory Tract Infections and Mannose-Binding Lectin Insufficiency During Early Childhood
JAMA, March 14, 2001; 285(10): 1316 - 1321.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
C. T. Heise, J. R. Nicholls, C. E. Leamy, and R. Wallis
Impaired Secretion of Rat Mannose-Binding Protein Resulting from Mutations in the Collagen-Like Domain
J. Immunol., August 1, 2000; 165(3): 1403 - 1409.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
M. W. Turner, L. Dinan, S. Heatley, D. L. Jack, B. Boettcher, S. Lester, J. McCluskey, and D. Roberton
Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians
Hum. Mol. Genet., June 12, 2000; 9(10): 1481 - 1486.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
D. C. Kilpatrick
Mannan-binding lectin concentration during normal human pregnancy
Hum. Reprod., April 1, 2000; 15(4): 941 - 943.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
R. Wallis and J. Y. T. Cheng
Molecular Defects in Variant Forms of Mannose-Binding Protein Associated with Immunodeficiency
J. Immunol., November 1, 1999; 163(9): 4953 - 4959.
[Abstract] [Full Text] [PDF]

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 Hum ReprodHome page
D.C. Kilpatrick, L. Starrs, S. Moore, V. Souter, and W.A. Liston
Mannan binding lectin concentration and risk of miscarriage
Hum. Reprod., September 1, 1999; 14(9): 2379 - 2380.
[Abstract] [Full Text] [PDF]

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 Clin. Chem.Home page
R. A. Hegele, C. P. Busch, T. K. Young, P. W. Connelly, and H. Cao
Mannose-binding Lectin Gene Variation and Cardiovascular Disease in Canadian Inuit
Clin. Chem., August 1, 1999; 45(8): 1283 - 1285.
[Full Text] [PDF]

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 J. Immunol.Home page
H. O. Madsen, M. L. Satz, B. Hogh, A. Svejgaard, and P. Garred
Different Molecular Events Result in Low Protein Levels of Mannan-Binding Lectin in Populations from Southeast Africa and South America
J. Immunol., September 15, 1998; 161(6): 3169 - 3175.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
E. C. Crouch
Collectins and Pulmonary Host Defense
Am. J. Respir. Cell Mol. Biol., August 1, 1998; 19(2): 177 - 201.
[Abstract] [Full Text]

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 FASEB J.Home page
M. Roger
Influence of host genes on HIV-1 disease progression
FASEB J, June 1, 1998; 12(9): 625 - 632.
[Abstract] [Full Text]


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