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Carcinogenesis Advance Access originally published online on October 27, 2006
Carcinogenesis 2007 28(4):828-836; doi:10.1093/carcin/bgl198
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Published by Oxford University Press 2006

The mannose-binding lectin (MBL2) haplotype and breast cancer: an association study in African-American and Caucasian women

Toralf Bernig1, Brenda J. Boersma2, Tiffany M. Howe2, Robert Welch3, Sunita Yadavalli3, Brian Staats3, Leah E. Mechanic2, Stephen J. Chanock1 and Stefan Ambs2,*

1 Section on Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH) Bethesda, MD, USA
2 Laboratory of Human Carcinogenesis, CCR NCI, NIH, Bethesda, MD, USA
3 Core Genotyping Facility, NCI NIH, Bethesda, MD, USA

*To whom correspondence should be addressed at: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37/Room 3050B, Bethesda, MD 20892-4258, USA. Tel: +1 301 496 4668; Fax: +1 301 496 0497; Email: ambss{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Common genetic variants in cancer-related genes contribute to breast cancer. The innate immune system plays a crucial role in the immune surveillance against malignancies, thus it is plausible that genetic variations in key genes of the innate immunity such as the mannose-binding lectin (MBL), MBL2, could influence the risk for breast cancer. We investigated the association of MBL2 genotypes with breast cancer and conducted a comprehensive genotype and haplotype analysis of 26 MBL2 single nucleotide polymorphisms (SNPs) in a case–control study of breast cancer [166 African-American (AA) case patients versus 180 controls and 127 Caucasian (CAU) case patients versus 137 controls]. We observed that the A allele of the 3'-UTR SNP Ex4-1067 (NCBI SNP ID: rs10824792) was significantly associated with a decreased disease risk in AA women [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.27–0.81]. Haplotype analysis of MBL2 showed that the frequency of the corresponding 3' haplotype TATAAC (Ex4-1483, Ex4-1067, Ex4-1047, Ex4-901, Ex4-710, 3238bp 3' STP) was lower in cases than controls among AA women (0.15 versus 0.21; P = 0.02) suggesting a protective effect after adjusting for covariates (OR = 0.51, 95% CI = 0.29–0.88, P = 0.018). In conclusion, this study presents preliminary evidence that common genetic variants in the 3'-UTR of MBL2 might influence the risk for breast cancer in AA women, probably in interaction with the 5' secretor haplotypes that are associated with high concentrations of MBL.

Abbreviations: AA, African-American; CAU, Caucasian; MBL, mannose-binding lectin; SNP, single nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The incidence of breast cancer has increased in recent decades, and about one of every eight women in the United States develops breast cancer during her lifetime (1). Hormonal, environmental and genetic factors have been implicated in the causation and progression of breast cancer (2). The evidence for a genetic predisposition to breast cancer is strong, and experiments with inbred mice point to the importance of allelic diversity in the host genetic background for breast cancer (3–5). Epidemiological studies also suggest that low-penetrance alleles in genes of cancer-related pathways contribute to the onset and progression of breast cancer (6–9).

Recently, a probable relationship between inflammation, innate immunity and breast cancer has been described (10,11). The contribution of tumor-infiltrating monocytes to breast cancer progression is well documented (12). Cytokines regulate angiogenesis of breast tumors and persistent oxidative stress increases the invasive potential of mammary epithelial cells (13,14). Moreover, mice lacking the inducible nitric oxide synthase, a pro-inflammatory enzyme, have a delayed onset of breast cancer (15). Together, these results support the hypothesis that inflammation is part of the initiation and progression of breast cancer.

Both the adaptive and innate immunity regulate survival and migration of tumor cells, and provide important protection against malignancies (10,16,17). Complement activation is a central mechanism in innate immune response and leads to the formation and liberation of pro-inflammatory factors as well as activation of inflammatory cells, which in turn, contribute to tumorigenesis (18–20). The lectin activation of complement is driven by the mannose-binding lectin (MBL) (21–23). Non-synonymous variants in exon 1 of the encoding MBL2 gene, known as the D-, B- and C-allele, alter the functional properties and circulating levels of the MBL protein (24–26). They create, together with three linked 5' polymorphisms (aka –550, –221 and +4; also known as H/L, Y/X and P/Q), seven well-characterized secretor haplotypes (HYPA, LYPA, LYQA, LXPA, HYPD, LYPB and LYQC), which strongly correlate with alterations in complement activation and altered circulating levels of MBL (27–29). In numerous studies, associations between variant MBL2 alleles and susceptibility to infectious and auto-immune diseases have been reported (30–33). There is also emerging evidence that MBL2 variants are risk factors in human cancer (34).

In this report, we evaluated the association between 26 pre-ascertained haplotype-tagging single nucleotide polymorphisms (SNPs) in the MBL2 gene, which include the tagging SNPs for the secretor haplotypes, and breast cancer incidence in African-American (AA) and Caucasian (CAU) women. We performed the analysis of MBL2 genotypes and haplotypes based on the recently described genomic structure of the gene (35).


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population
The subjects were recruited between 1993 and 2003 and resided in the greater Baltimore area at the time of recruitment. Cases and hospital-based controls were recruited at the following hospitals in Baltimore, MD: University of Maryland Medical Center, Baltimore Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital. Case patients (n = 293) were selected from a group of 361 breast cancer patients, who had pathologically confirmed incident breast cancer and had, by self-report, no previous history of the disease. The controls were frequency-matched to cases by race and age and had, by self-report, no history of breast cancer. They were either hospital-based (n = 230) or population-based (n = 87). Population-based controls were identified from Maryland Vehicle Administration records and contacted by mail and then by telephone. The participation rate was 88% among eligible hospital-based controls and 90% among eligible population-based controls. Inclusion criteria included being self-identified AA or CAU and born in the United States. Subjects were excluded if they were known HIV, HCV or HBV carriers, were IV-drug users, were institutionalized, or were physically or mentally unable to sign consent and complete the questionnaire.

Fresh-frozen breast tissue, if available, and blood samples were collected from cases and controls. Breast reduction specimens were obtained from 94 hospital-based controls. The blood collection was performed at the subjects' convenience but mostly at the conclusion of the interview. The subjects signed an informed consent form and were administered an epidemiology questionnaire. The questionnaire evaluated the medical, reproductive, family, and occupational history of the subjects. The Institutional Review Boards at all participating institutions have approved the study.

Serum MBL concentration
Blood samples to measure MBL serum concentrations were available for 81 AA case patients. MBL concentrations were determined with a ligand-lectin solid-phase enzyme-linked immunoassay (Human MBL ELISA Kit HK323, Cell Sciences, Canton, MA, USA). Serum was added to mannan-coated microtiter wells. We analyzed duplicates of each sample. Hundred µl of serum, undiluted or diluted from 1:1 to 1:200 depending on MBL concentrations, were incubated with buffer-activated mannan. After a washing step, a biotinylated anti-human MBL antibody was added to the wells. The MBL–antibody complex was further conjugated with streptavidin-peroxidase and incubated with tetramethylbenzidine. After stopping the enzyme-catalyzed color reaction by addition of citric acid, the absorbance was measured at 450 nm. MBL serum concentrations were calculated using a standard curve ranging from 0.4 to 100 ng ml–1, as described in the manufacturer-provided protocol.

Genotype and haplotype analysis
Genomic DNA was isolated from blood and tissue samples as described (36). The isolated DNA was quality-tested and genotyped at the NCI Genotyping Core Facility. All genotype assays contained negative and positive controls, and 10% blinded duplicates. The overall genotype concordance among sample duplicates was 98% (discordance range per genotype: 0–4%). Haplotype tagging SNPs across the 10 kb locus that includes the MBL2 gene (NT_008583 [GenBank] , NCBI build 35, locus ID 4153) were selected on the basis of a previous re-sequencing analysis of this genomic region in samples of 102 healthy and unrelated individuals from four different ethnic groups (http://snp500cancer.nci.nih.gov) by use of the tagSNP program (35,37,38). The six markers of the secretor haplotypes were pre-assigned as tagging SNPs. SNPs in strong linkage to the secretor haplotypes and also to variants that capture the two gene conversion elements in MBL2 were included in the analysis. Overall, a total of 26 SNPs across the entire locus were genotyped by TaqmanTM assays in both study populations (Applied Biosystems, Inc., Foster City, CA, USA). Assays were validated and optimized as described in the SNP500 Cancer website (http://snp500cancer.nci.nih.gov) (39). Internal laboratory quality controls showed >99% concordance for each assay. The position of the analyzed SNPs are in accordance with the nomenclature that has been recommended by Dunnen and Antonakaris (40).

Haplotype blocks were inferred separately for the AA and CAU populations, using unphased genotype data of SNPs with minor allele frequency >1%. The default modus for a haplotype block definition that is implemented in the Haploview software was applied (http://www.broad.mit.edu/personal/jcbarret/haploview) (41,42). Two haplotype blocks were considered as separate blocks only if the multiallelic D' between both was <0.90.

To assess the association of inferred haplotypes with the risk of breast cancer and MBL serum concentrations, analytical approaches implemented in the software package Haplo.stats (version 1.1.1 written for R 1.7.1.) were used (43). The software uses an expectation-maximization (EM) algorithm to infer haplotypes from genetic markers with an unknown linkage phase. To account for haplotype ambiguity, the probability for each haplotype pair is assigned per individual, which is used to model the individual phenotypes as a function of the estimated probability. The statistical significance of the performed global and haplotype-specific tests (haplo.score) is expressed as a permutation P-value (minimal simulations: 5000, significance level <0.05), as described previously (44). Odds ratios (OR) and 95% confidence intervals (CIs), adjusted for age, family history of breast cancer and menopause, were calculated for each haplotype using a generalized linear model (haplo.glm) (45,46).

Descriptive statistical analyses were performed with SAS software (version 8.2; SAS Institute Inc., Cary, NC, USA). Deviations of the observed genotype frequencies from the Hardy-Weinberg equilibrium (HWE) were evaluated separately in the AA and CAU controls. Because of partially low genotype frequencies, an exact test was applied at all loci using a significance level P < 0.05 (Institute of Human Genetics, Technical University Munich, Germany; http://ihg.gsf.de) (47–49).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Study population and MBL2 genotype analysis
The race-stratified distribution of the demographic characteristics in the study population is shown in Table I. There were no significant differences in age at diagnosis, body mass index (BMI) and the menopausal status between cases and controls. In both study populations, cases had a significantly greater proportion of individuals with a family history of breast cancer.


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  		Table I Demographic characteristics of cases and controls stratified by race/ethnicity

 
Twenty-six haplotype tagging SNPs were genotyped in the AA and CAU study population (Table II), with an average success rate of 98% in AA (cases 99%, controls 96%) and 98% in CAU (cases 99%, controls 97%). Seven individuals (5 AA controls, 2 CAU controls) could not be successfully genotyped. No significant deviations from HWE were observed in the CAU control population and only the SNP at –1101 did not fit HWE in the AA controls. The observed differences in genotype frequencies by race, including the frequencies of the SNPs in the secretor haplotypes (aka –550, L/H; aka –221, Y/X; aka +4, P/Q; D-, B- and C-allele), were in agreement with previously reported genotype frequencies (28,35,50). Because of the different genotype frequencies in AA and CAU, all further genotype and haplotype analyses were performed stratified by race to avoid false-positive findings that are attributable to population admixture (51–53).


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  		Table II Features of the 26 MBL2 htSNPs

 
MBL2 SNPs and breast cancer
Table III shows the crude ORs for the risk to develop breast cancer associated with the 26 MBL2 SNPs. Significant crude associations between several MBL2 SNPs and breast cancer were observed in AA women. After adjusting for age at diagnosis, family history, and menopausal status, only the association between SNP Ex4-1067 and breast cancer remained statistically significant. The variant Ex4-1067A allele (A/G or A/A) was associated with a significantly decreased incidence of breast cancer among AA women when compared with carriers of the common G/G genotype (OR = 0.47, 95% CI = 0.27–0.81, P = 0.01).


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  		Table III MBL2 SNPs and risk for developing breast cancer

 
Linkage disequilibrium pattern and inferred haplotypes
Figure 1 shows the inferred haplotype blocks for the two study populations on the basis of pair-wise linkage disequilibrium tests. There are four blocks in AA, but blocks I and II can be considered as one haplotype block because of the high multiallelic D' value of 0.98 between these two blocks. The observed block structure is consistent with the previously detected haplotype pattern in this genomic region for AA using the same set of tagging SNPs. Block I and II (16 SNPs) can be referred to the extended 5' block and contains the secretor SNPs, whereas block III (3 SNPs) covers the conversion element and block IV (6 SNPs) spans the 3'-UTR and the 3' flanking region (35). For the CAU population, the entire MBL2 locus can be regarded as one haplotype block based on the limited diversification between the 5' and 3' region of the gene in this population, and because of the high interblock D' value.


Figure 1
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  		Fig. 1 Map of typed SNPs across the entire MBL2 locus. (A) Map of all genotyped 26 htSNPs with their position on the contig (NM_0000242, NCBI build 35, locus ID 4153). The six SNPs that contribute to the secretor haplotypes (HYPA, HYPD, LXPA, LYPA, LYPB, LYQA and LYQC) are designed with H/L, Y/X, P/Q, D, B and C. (B) Haplotype block pattern across the MBL2 locus in African American (AA) and Caucasian (CAU) populations (cases and controls). Haplotype blocks were inferred from unphased genotype data by D' confidence limits (upper confidence limit > 0.97, lower confidence limit > 0.70, fraction of informative pairs in strong LD: 0.95) using Haploview software. Between the blocks, value of multiallelic D' is shown as a measure of recombination between adjacent haplotype blocks (haplotype frequency ≥ 0.005)

 
MBL2 haplotypes and breast cancer
We analyzed differences in MBL2 haplotype frequencies between cases and controls using only those inferred haplotypes that had a frequency of >0.5% in our study population. The adjusted global score statistic with age at diagnosis, family history and menopausal status as covariates did not reveal a significantly different haplotype distribution between cases and controls in the AA and CAU populations for any of the examined haplotype blocks (data not shown). Furthermore, no haplotype-specific association was observed in the AA population for haplotypes in the extended 5' block and block III, and for the inferred haplotypes across the entire locus in the CAU population. Additionally, there were no significant differences in the distribution of the secretor haplotypes between cases and controls in both study populations.

Despite the absence of an association between haplotypes of the extended 5' block and block III and breast cancer in our population, the analysis of block IV haplotypes indicated a statistically significant association between the TATAAC haplotype and breast cancer in AA women (haplotype-specific score –2.258, P = 0.023); notably, this common block IV haplotype carries the breast cancer-associated variant at Ex4-1067. To further evaluate the risk modifying effect of haplotype TATAAC, a regression model (haplo.glm) with adjustments for age, family history and menopausal status was applied (Table IV). Using the most frequent haplotype in block IV as the reference, a significant association between the TATAAC haplotype and a decreased risk for breast cancer was observed in those AA women who carried at least one copy of this haplotype (OR = 0.51, 95% CI = 0.29–0.88, P = 0.018). Although the disease association of TATAAC did not reach significance at the 0.05 level in a model using all other haplotypes as reference, the similar point estimates for the disease risk supports the suggested protective effect by this haplotype (OR = 0.61, 95% CI = 0.32–1.18, P = 0.14).


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  		Table 4 MBL2 3' haplotypes and risk for developing breast cancer in African-American women

 
Serum MBL levels and 3' haplotypes
Because one 3' haplotype, TATAAC, was associated with breast cancer in AA women, we investigated the relationship between the four most common 3' haplotypes (CGTGGT, TGTAAC, TATAAC and TGGAGC) and MBL serum concentrations in AA subjects. Serum was available for 81 AA case patients. The mean MBL level of these patients was 1652 ng ml–1 (median 861 ng ml–1). When we reconstructed individual haplotype pairs for the 81 case patients, a trend for higher MBL serum levels among carriers of the TATAAC haplotype was observed that was borderline significant (Kruskal–Wallis test, P = 0.066). Individuals with at least one copy of this 3' haplotype had higher MBL serum concentrations (mean 2166 ng ml–1, median 1300 ng ml–1) than individuals with other haplotypes (mean 1483 ng ml–1, median 601 ng ml–1).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Infections and inflammation promote the development of human cancer (10,54). MBL2 is a key regulator of the innate immune response and a prime candidate for genetic association studies in cancer because of its genomic heterogeneity that causes low and high expression phenotypes. Functional relationships between MBL2 secretor haplotypes and alterations in complement activation have been demonstrated (27–29,55,56).

We evaluated the association of 26 genetic variants in the MBL2 gene with breast cancer in AA and CAU women. The tagging SNPs had been pre-ascertained on the basis of the previously published haplotype block structure for the MBL2 gene (35). Our analyses revealed a moderate but statistically significant association between the variant allele Ex4-1067A and a reduced breast cancer risk in AA women. The corresponding haplotype TATAAC was also significantly less frequent in AA case patients than in matched controls, pointing to a possible protective effect of this haplotype against breast cancer in AA women. We did not observe an association between MBL2 genetic variants and breast cancer in CAU women.

Haplotype-based association studies are a rational approach to exploit linkage disequilibrium between common genetic variants. The approach is effective for determining a non-random association of alleles with a disease using surrogate markers, even if the causal marker is unknown (57–59). SNP Ex4-1067 may represent such a surrogate marker; however, it is possible that this variant in the 3'-UTR of MBL2 is selected among cancer patients because of its effect on MBL serum levels. We previously reported an association between the Ex4-1067A and high serum levels of MBL (60), which is consistent with the findings in the present study. We also observed that the corresponding 3' haplotype was linked to secretor haplotypes encoding for high protein serum concentrations (i.e. HYPA and LYQA). These data indicate a possible epistatic interaction between distinct 5' located secretor haplotypes and 3' haplotype blocks in MBL2 that may favor high MBL serum levels. Our analysis of serum MBL in 81 AA case patients provided more evidence of an association among the Ex4-1067A genotype and the corresponding TATAAC haplotype and MBL protein levels. The detected MBL serum concentrations were higher in individuals with at least one copy of 3' haplotype TATAAC than in individuals with other 3' haplotypes. Then again, serum samples were only available for a subset of the AA case patients, and the association between the TATAAC haplotype and serum MBL was only borderline significant and did not reach statistical significance at the P < 0.05 level.

It is plausible that higher MBL serum levels enhance the immunosurveillance against epithelial malignancies such as breast cancer, which, in turn, provides protection against the onset of a clinical disease. Several studies have shown that MBL recognizes unusual carbohydrate structures on the surface of tumor cells and inhibits tumor progression by a MBL-dependent cell-mediated cytotoxicity (61–63). The protection should be strongest for individuals who harbor MBL2 genotypes associated with a high serum concentration of the protein. We did not observe that the known secretor haplotypes are associated with breast cancer, but others found an association between the HYD haplotype, which encodes both a functionally impaired MBL protein and a lower protein serum level, and the risk to develop stomach cancer in a case–control study in Warzaw, Poland (34). The authors of this study did not evaluate the Ex4-1067 SNP, however, their findings suggest that genetic variations in MBL2 and consequential phenotypic changes of the encoded protein may be involved in the tumorigenesis of epithelial malignancies.

We did not observe the same protection in CAU and AA women in our study. Although numerous studies have shown that MBL concentrations adequately correlate with the secretor haplotypes of MBL2 in different human populations, one would expect a similar functional effect of MBL serum levels in tumor surveillance in different ethnic groups. MBL could interact with additional risk factors that are more common in the AA population. In this regard, it is noteworthy that the combination of the HYD MBL2 haplotype and an at-risk IL-1B genotypes (CT or TT at location –511) was associated with an increased risk for stomach cancer in CAUs, possibly through modulation of the immune responses (34). Moreover, the detected differences in the LD structure between both study populations could also cause a differential disease association. Such relationships have been observed for other genomic regions in the past (41,64,65). Therefore, future studies are required to corroborate our findings, although other studies have already shown that certain 3' variants in other genes are functional and alter mRNA stability and translation (66–70).

We have analyzed multiple SNPs, which were required to fully cover the MBL2 locus. The inclusion of 26 SNPs creates the possibility of a type-I error and false-positive discoveries. Different approaches for preventing a type-I error have been discussed in the literature, but these approaches may also result in a loss of valid information because of overcorrection (71–76). The application of a stringent Bonferroni adjustment in our study would be too conservative because the studied SNPs are not independent as shown by our haplotype analysis. Moreover, the probability of a false-positive discovery not only depends on the observed P-value, but also on the prior probability that the association between the genetic variant and the disease is real (75,77). This prior probability is high for MBL2 genotypes because of the previously demonstrated role of MBL2 haplotypes in the tumorigenesis of an epithelial malignancy (34). It should also be noted that we reduced the likelihood of a false-positive finding by performing permutation testing in the haplotype analysis (43,76).

In conclusion, we observed that the variant allele Ex4-1067A in the 3'-UTR and the corresponding 3' haplotype, TATAAC, were associated with a lower breast cancer incidence in AA women. These are preliminary findings and future studies in larger datasets are required to corroborate the relationship between the 3'-UTR haplotype of MBL2 and breast cancer. Finally, more functional studies are warranted to define the implication of several 3' haplotypes on gene expression, mRNA stability and protein function of MBL2 (75,78–80).


   Acknowledgments
 
The authors are grateful to E. Tarazona-Santos, M. Yeager, B. Packer, S. Savage and J.G.Taylor VI for discussion of the data; the team members of the Core Genotyping Facility, NCI, for their excellent technical assistance. We would like to thank Raymond Jones, Audrey Salabes, John Cottrell, Leoni Leondaridis, Glennwood Trivers, Elise Bowman and personnel at the University of Maryland and the Baltimore Veteran Administration, and the Surgery and Pathology Departments at the University of Maryland Medical Center, Baltimore Veterans Affairs Medical Center, Union Memorial Hospital, Mercy Medical Center, and Sinai Hospital for their contributions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received May 20, 2006; revised October 10, 2006; accepted October 11, 2006.


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