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*
Department of Clinical Immunology, National University Hospital, Copenhagen, Denmark;
State Serum Institute, Copenhagen, Denmark; and
Laboratory of Immunogenetics, University of Buenos Aires, Buenos Aires, Argentina
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MBL deficiency and low levels of serum MBL are the basis for a common opsonic deficiency (6) and are associated with recurrent infections in infancy (7, 8) and adult life (9), with an increased susceptibility to sexually transmitted HIV-1 infection (10), and with autoimmune diseases such as systemic lupus erythematosus (11, 12, 13) and rheumatoid arthritis (14). In contrast, it has been suggested that high serum concentrations of MBL may be disadvantageous by facilitating the entrance or increasing the pathogenecity of certain pathogens, especially intracellular microorganisms (15, 16, 17, 18, 19).
MBL is a multichain molecule of up to six subunits; each subunit
consists of three identical 32-kDa polypeptide chains that contain a
cysteine-rich region, a collagenous region, a "neck" region, and a
carbohydrate-binding domain (20). MBL deficiency and low levels of
serum MBL are strongly associated with the presence of variant
MBL alleles that encode three different structural variants,
B, C, and D (codons 54, 57, and 52,
respectively) (7, 21, 22), of the MBL polypeptide. The normal allele is
known as A. Each variant is the result of a single point
mutation that disrupts the collagen-like structure of the MBL
polypeptide. This leads to a reduction of functional MBL to 
10% in
individuals that are heterozygous for defective alleles compared with
the functional MBL found in individuals with two functional alleles
(7). The variant alleles are quite frequent in normal, healthy
populations of African, Caucasian, Asian, and Eskimo origin, in that
they are present in 20 to 50% of such individuals (15, 21, 22, 23, 24, 25).
Other variants (H, L, X, and Y) that are found upstream of the gene also have a dramatic effect on serum MBL levels, and different frequencies of both types of variants account for the large interracial differences in MBL serum levels (25). Initially, three promoter haplotypes were identified and subjected to investigation (HY, LY, and LX) (25). However, further division of the haplotypes is possible when a polymorphism (P/Q) located in the 5'-untranslated portion of the gene (position +4) is taken into account (22).
In this study, we have analyzed populations from two different continents on the southern hemisphere, namely black Africans from Mozambique and two South American populations of native Indians from different parts of Argentina, to elucidate whether selective forces may have influenced the genetics of MBL and thereby the MBL serum levels. Moreover, we looked for additional polymorphisms in the MBL gene.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood samples were randomly selected from a nonselected black African population of children (n = 154) from a suburban area of Maputo in Mozambique in Southeast Africa that were participating in a prospective malaria study (26) and also from two different Indian tribes from different parts of Argentina in South America (i.e., the Chiriguanos Indians (n = 43) from Northern Argentina and the Mapuche Indians (n = 25) from Southern Argentina) (27). All individuals were unrelated. In addition, a previously analyzed population of healthy and unrelated Danes comprising 42 laboratory staff members and 81 blood donors (22, 25) was expanded to include 60 laboratory staff members and 190 blood donors (i.e., a total of 250 individuals). Plasma was stored at -80°C, and genomic DNA was isolated from whole blood, granulocytes, or mononuclear cells according to a standard procedure (28).
Genomic PCR
PCRs were performed in 10 to 50 µl volumes that contained 100 to 500 ng of genomic DNA, 0.1 to 0.25 mM of specific primers in the presence of 1.5 mM MgCl2, 0.2 mM of deoxynucleotide triphosphate, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 0.001% (w/v) gelatin, and 0.5 to 2 U of Taq DNA polymerase (Life Technologies, Gaithersburg, MD) or AmpliTaq DNA polymerase (Perkin-Elmer, Norwalk, CT), including TaqStart Ab (Clonetech, Palo Alto, CA) to prevent unspecific amplification. DNA was amplified by general PCR, by PCR using sequence-specific priming (SSP), and by site-directed mutagenesis (SDM)-PCR (22).
All PCRs were initiated by a 2-min denaturation step at 94°C and completed by a 5-min extension step at 72°C. The temperature cycles for the different types of PCRs were as follows: general PCR: 35 cycles of 30 s at 94°C, 60 s at 58°C, and 120 s at 72°C; SDM-PCR: 35 cycles of 30 s at 94°C, 30 s at 55°C, and 60 s at 72°C; PCR-SSP: 10 cycles of 10 s at 94°C and 60 s at 65°C followed by 20 cycles of 10 s at 94°C, 50 s at 61°C, and 30 s at 72°C.
Polymerase chain reaction-restriction fragment length polymorphism
The B and C alleles were detected by BanI and MboII restriction enzyme digestions of the 685-base pair (bp) product that had been amplified by the MBL exon 1 PCR primers (upstream primer: 5'-AGTCGACCCAGATTGTAGGACAGAG-3'; downstream primer: 5'-AGTTGTTGTTCTCCTGTCCAG-3'), followed by a 2% agarose gel electrophoresis. The PCR product contained one nonpolymorphic BanI site, which served as internal control of the enzyme digestion and gave rise to two fragments of 116 bp and 569 bp. The latter fragment was cleaved into two fragments of 308 bp and 261 bp in the A, C, and D genotypes; it remains uncleaved in the B genotype. The PCR product also contained two nonpolymorphic MboII sites, giving rise to three fragments of 83 bp, 94 bp, and 508 bp. The latter fragment was cleaved into two fragments of 280 bp and 228 bp in the C genotype but remained uncleaved in the A, B, and D genotypes. The D allele was detected by RFLP that was performed on SDM-PCR products; these products were produced under nonstringent primer annealing conditions (55°C) using a mutated 5'-primer (upstream primer: 5'-CATCAACGGCTTCCCAGGCAAAGACGCG-3'; downstream primer: 5'-AGGATCCAGGCAGTTTCCTCTGGAAGG-3'). The MluI restriction enzyme cleaved the 125-bp PCR product that was specific for the D allele into two fragments of 100 bp and 25 bp, while the HhaI restriction enzyme cleaves the A, B, and C alleles. SDM-PCR restriction fragments were separated by 4% MetaPhor (FMC, Rockland, ME) agarose gel electrophoresis.
MBL haplotyping
The cis/trans-location of the promoter variants L, X, and Y relative to the structural variants B, C, and D was determined by a nested PCR, initiated by PCR-SSP, and succeeded by a general PCR using MBL exon 1 primers (B and C variants) or by an SDM-PCR using allele D primers (D variant) (25). An RFLP analysis of the PCR products was subsequently performed using the relevant restriction enzymes (BanI and MboII for the B and C variants and MluI and HhaI for the D variant). For the P and Q variants, an RFLP analysis was performed directly on the PCR-SSP product when determining the cis/trans-location to the B and C alleles. In an analogy, the cis/trans-location of the promoter variant L relative to the X and Y variants is determined by PCR-SSP using the MBL cis-LX and MBL cis-LY primer pairs; these pairs combine a downstream specificity for the L allele with upstream specificities for the X and Y alleles, respectively. The sequences of the PCR primers are listed in Reference 25.
Sequence-specific oligonucleotide (SSO) hybridization
The genotyping of the H, L, X, Y, P, and Q alleles was performed by a dot-blot hybridization of SSO probes to the PCR product essentially as described previously (25). The SSO probe that is specific for the H allele was previously mistyped (25), and the correct sequence is as follows: 5'-AAGCCTGTGTAAAACACC-3'.
Direct sequence analysis
A DNA sequence analysis was performed by conventional manual sequencing according to the dideoxy-termination method (29) using Sequenase version 2.0 DNA polymerase (United States Biochemical, Cleveland, OH) and [35S]deoxyATP (Amersham, Bucks, U.K.). The sequencing was performed directly on a biotinylated ssPCR product that had been isolated by the binding of the biotin to superparamagnetic, streptavidin-coupled M-280 Dynabeads (Dynal, Oslo, Norway) and followed by a magnetic separation (30). The sequencing was performed on a mixture of at least four independent PCR products in each case to avoid the detection of mutations that were artificially produced by PCR. Some PCR primers and sequencing primers are listed in Reference 25; the rest were deduced from the genomic sequence of the MBL gene (20, 31).
Assay for MBL
MBL serum concentrations were measured in a double enzyme immunoassay that was based on an anti-MBL mAb (clone HYB-131) against a repeating epitope in the MBL molecule (State Serum Institute, Copenhagen, Denmark) essentially as described previously (15, 32).
Statistical analysis
Mann-Whitney and Kruskal-Wallis tests for unpaired group comparisons were used to compare the LYPA/LYQA haplotypes in the African population. All analyses were two-tailed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MBL genotyping was performed on samples from a
Mozambique population and from the Chiriguanos and Mapuche tribes by
combining various PCR-based methods (e.g., PCR-RFLP, PCR-SSP, and
PCR-SSO hybridization (25)). Haplotyping was performed on unselected
subpopulations and did not reveal any deviation from the previously
determined haplotype patterns (25). Therefore, the major part of the
haplotyping was deduced on the bases of the strong linkage
disequilibrium found between the different genotypes. The frequencies
of the haplotypes were compared with those of other previously typed
populations (25), including an expanded (n = 250)
population of healthy, unrelated Danes (Table I
). All four populations obeyed the
Hardy-Weinberg expectations with respect to the distribution of MBL
haplotypes (data not shown). Of particular interest was the finding
that the allele frequency of the B allele was as high as
0.42 and 0.46 in the two South American Indian populations, 0.11 in the
Caucasian population, and absent from the Mozambique population. By
contrast, the C allele was frequent in Mozambique (0.24) and
of low frequency in the Caucasians and the South American Indians (0.03
and 0.01, respectively). The variant D allele was only
observed in the Caucasian population (0.06). The frequencies of
individuals that were homozygous for defective alleles were quite
different: High frequencies were seen in the African and South American
populations (0.06–0.16) compared with the low frequencies in the
Caucasian and Eskimo populations (0.03). In addition, the different
populations were dominated by different functional haplotypes.
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The previously identified MBL haplotypes (25) were
based on the sequencing of the promoter region and exon 1 of the
MBL gene and on other PCR-based methods defining the
cis/trans-localization of the variant sites. To achieve a
more complete description of the known MBL haplotypes, we
chose to sequence the promoter region and all of the protein-coding
portion of the MBL gene. This analysis was performed on DNA
from individuals that were homozygous for each of the known haplotypes
as judged by PCR-based typing methods. The different MBL
haplotypes are shown in Figure 1. Most
interestingly, the sequencing of MBL genes from individuals
that were homozygous for the LYQ haplotypes (i.e.,
LYQA and LYQC) revealed five additional base
substitutions/deletions in the promoter region when compared with the
known MBL haplotypes (Figs. 1 and 2). To search for possible haplotypes
that are intermediary to the LYPA and LYQA
haplotypes, we sequenced the regions including the new mutations in
randomly selected individuals that were homozygous for LYPA
(n = 7) and LYQA (n = 12)
and were from ethnically different backgrounds. This analysis
did not reveal any "hybrids" between these haplotypes.
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An isolated comparison of the influence of the P
variant vs the Q variant on serum MBL levels is not
meaningful, because the P variant is part of both high- and
low-expressing haplotypes. The only means of studying this influence is
by comparing the serum MBL levels in individuals with the functional
haplotypes LYPA and LYQA. This comparison
was not possible previously because of the skewed frequency of the
LYPA and LYQA haplotypes in the populations
investigated. However, a high frequency of both haplotypes in the
Mozambique population allowed this comparison. Serum samples were
available in 136 of the 154 individuals analyzed for MBL
genotypes, and MBL concentrations were measured in these cases. A total
of 15 and 9 individuals were homozygous for LYPA and
LYQA, respectively, and 28 were heterozygous for
LYPA/LYQA. The median MBL serum concentrations in
LYPA homozygous individuals, LYPA/LYQA
heterozygous individuals, and LYQA homozygous individuals
were 1072 µg/L, 1472 µg/L, and 2896 µg/L, respectively
(Kruskal-Wallis, p = 0.009) (Fig. 3 and Table III). Although not significant, a similar
trend was observed when we tested the functional promoter haplotype
LYQA (n = 21) against the likewise
functional haplotype LYPA (n = 12) in
individuals that were otherwise heterozygous for the structural
mutation C (median serum concentrations: 330 and 180 µg/L,
respectively; Mann-Whitney, p = 0.16, Table III).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As would be expected based on the previous population studies performed on African populations (21, 25), the Mozambique population had a high frequency of defective MBL haplotypes (0.24) and a high frequency of individuals that were homozygous for defective MBL alleles (0.06). The Mozambique population was very homogenous for the MBL genotypes/haplotypes when compared with a previously typed population from Kenya and was dominated by the functional haplotypes LYQA and LYPA. The only defective allele found was the typical African MBL variant C allele (codon 57 variant) that is located on the LYQC haplotype.
The two native Indian tribes from Argentina were quite similar with respect to MBL haplotype distribution; they were dominated by of the functional haplotype HYPA and the defective haplotype LYPB. The presence of the LYQC haplotype in 2 of 25 individuals of the Mapuche tribe may indicate some ethnic admixture with settlers of Old World origin, and this possibility is in agreement with the 6% Old World origin admixture that was estimated previously in this population by the use of blood genetic markers (27).
The haplotypes found in these original South American populations are
essentially the same as those found in Eskimos from Eastern Greenland
(Table I
and 25 and those found in populations of Asian origin
(our unpublished observations). This observation is in agreement
with the well-established population migration theories that postulate
a primary migration of the Eskimos from Siberia to Eastern Canada and
Greenland that was followed later on by a secondary wave of migration
through North to South America. Accordingly, although the migrations of
Eskimos and the South American populations were probably not
contemporary, they all appear to descend from populations carrying the
HYPA and LYPB haplotypes. Although a
"bottle-neck effect" can never be excluded as the cause of the
different haplotype distributions in the Eskimos and the South American
Indians, the high frequencies of the defective haplotype
LYPB that are found in both of these populations could very
well be due to a selection pressure favoring low serum MBL in this
region, especially since the same phenomenon seems to have occurred in
subSaharan Africa through the C allele.
When serum MBL levels were compared in subpopulations of the
Chiriguanos and Mozambique populations, we found no difference in the
levels expressed by the different haplotypes. This observation is
somehow surprising, because the South American Indians are highly
dominated by the high-producing haplotype, HYPA, while the
Africans are dominated by lower-producing haplotypes (Table I).
However, the MBL levels of the HYPA haplotype were
significantly lower in the South American Indians than in other
populations (e.g., the Eskimos). This could indicate that the MBL serum
levels of the South American Indians may have been lowered by
consumption of the protein. Alternatively, it cannot be excluded that
other down-regulating variants exist outside of the region of the
Indian HYPA haplotype that we have analyzed.
In addition to the evidence of a selective advantage of low serum MBL, this study revealed the existence of at least seven MBL haplotypes: Three were defective haplotypes (LYPB, LYQC, and HYPD), and five were functional haplotypes with different expression levels (i.e., a low-producing LXPA haplotype, two LYA haplotypes consisting of a high-producing LYQA haplotype and an intermediate-producing LYPA haplotype, and finally a high-producing HYPA haplotype).
A difference in MBL expression of the LYPA and LYQA haplotypes was found when the MBL levels of these haplotypes were compared in the Mozambique population. This finding means that each of the identified promoter haplotypes has different influences on the MBL level. The evolution of the MBL gene seems to have passed through steps that have given rise to both higher- (HYPA and LYQA) as well as lower- (LYPA and LXPA) expressing variants in addition to the structural variants with the massive down-regulating effect on the MBL serum levels.
Previously, we have proposed a model for the evolution of the
MBL gene based on the MBL haplotypes (25). With
the finding of five additional mutations in the LYQA and
LYQC haplotypes this model must now be slightly modified
(Fig. 4).
We still propose that a high-producing haplotype may be the original
haplotype, but based on the findings of the new mutations, we find that
the known haplotypes more likely have evolved from an ancestral
haplotype positioned in the large "mutational gap" of the
evolutionary tree between the LYQA and LYPA
haplotypes and not from the HYPA or the LYPA
haplotype as indicated previously (25). Perhaps the original haplotype
has been lost from present populations, because our analysis did not
indicate the existence of any haplotypes that were intermediate to the
LYPA and LYQA haplotypes. Thus, the ancestral
gene may originate somewhere in between the present day haplotypes.
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Consequently, we still propose in our revised model that a high-producing haplotype may be the original haplotype, and that this haplotype subsequently evolved into lower-producing haplotypes by the introduction of both structural and regulatory mutations.
In conclusion, this study has revealed that the MBL genetic system is even more complex than suggested previously. In addition, the high frequencies of two different variant alleles that are associated with low MBL concentrations on different continents support the assumption that such high frequencies may have evolved in response to the deleterious effects of certain types of infections.
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Acknowledgments |
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Footnotes |
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2 M. Leonardo Satz died on October 10, 1997.
3 Address correspondence and reprint requests to Dr. H. O. Madsen, Department of Clinical Immunology, National University Hospital, DK-2200 Copenhagen, Denmark. E-mail address:
4 Abbreviations used in this paper: MBL, mannan-binding lectin; SSP, sequence-specific priming; SDM, site-directed mutagenesis; SSO, sequence-specific oligonucleotide.
Received for publication March 10, 1998. Accepted for publication May 12, 1998.
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D. Pirulli, M. Boniotto, L. Vatta, S. Crovella, A. Spano, M. Morgutti, S. Zezlina, L. Bertola, D. Roccatello, F. Scolari, et al. Polymorphisms in the promoter region and at codon 54 of the MBL2 gene are not associated with IgA nephropathy Nephrol. Dial. Transplant., April 1, 2001; 16(4): 759 - 764. [Abstract] [Full Text] [PDF]
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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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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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