Published online before print January 19, 2004, doi: 10.1161/01.CIR.0000109757.95461.10
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(Circulation. 2004;109:471-475.)
© 2004 American Heart Association, Inc.
Clinical Investigation and Reports |
Prospective Analysis of Mannose-Binding Lectin Genotypes and Coronary Artery Disease in American Indians
The Strong Heart Study
From Missouri Breaks Industries Research Inc (L.G.B.), Timber Lake, SD; Medstar Research Institute (M.D., B.V.H.), Washington, DC; University of North Carolina (K.E.N.), Chapel Hill, NC; Southwest Foundation for Biomedical Research (J.W.M.), San Antonio, Tex; University of Oklahoma Health Sciences Center (Y.Z., E.T.L.), Oklahoma City, Okla; and University of Pittsburgh (S.D., R.E.F.), Pittsburgh, Pa.
Reprint requests to Lyle Best, MD, #1 Airport Rd, RR1, Box 88, Rolette, ND 58366. E-mail sbest{at}utma.com
Received June 16, 2003; de novo received September 18, 2003; accepted October 23, 2003.
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Abstract |
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Background— Mannose-binding lectin (MBL) is a circulating immune factor responsible for opsonization of pathogens and directly activating complement. Common variations in the MBL gene are responsible for an opsonic deficiency that affects 5% to 7% of whites and are associated with increased susceptibility to infections. After a preliminary report associating these variations with coronary artery disease (CAD), we determined MBL genotypes in 3 American Indian communities experiencing an increased mortality and morbidity from CAD.
Methods and Results— We examined DNA from 434 participants in a population-based cohort, the Strong Heart Study. Genotypes for 3 common MBL coding variations and 1 promoter polymorphism were determined. The frequency of a composite genotype that conferred low MBL levels was 20.7% in 217 cases and 11.1% in matched controls without CAD. A conditional logistic regression model indicated a univariate OR for CAD of 2.3 (95% CI 1.3 to 4.2, P=0.005) for the variant genotypes. After adjustment for demographic and CAD risk factors, including type 2 diabetes mellitus, fibrinogen, triglycerides, and hypertension, the OR was 3.2 (95% CI 1.5 to 7.0, P=0.004).
Conclusions— Variant MBL genotypes coding for markedly diminished levels of MBL are predictive of CAD. After adjustment for multiple traditional risk factors for ischemic heart disease, this association remains significant. A high prevalence of variant MBL alleles and CAD in this population suggests that potentially important public health benefits may accrue from future interventions based on these genotypes.
Key Words: coronary disease • genetics • inflammation • immune system • epidemiology
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Introduction |
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There is recent evidence that the pathogenesis of atherosclerosis involves the altered control of inflammation by innate immune defenses that include pattern-recognition molecules such as toll-like receptors and possibly mannose-binding lectin (MBL).1–3 The latter serum protein opsonizes a variety of pathogenic microorganisms by binding mannose moieties on their surface and activating complement via the lectin pathway before antibody formation.4 Major decreases in opsonization detected in 5% to 7% of whites5 and commonly among other populations result from markedly decreased levels of MBL related to variations of both structural and promoter portions of this gene.5–8 In both children and adults, an increased risk of certain infectious conditions has been associated with low levels of MBL or genotypes predictive of low levels.9–12
Deficiencies in MBL can be caused by 3 single nucleotide polymorphisms within exon 1 of the MBL gene on chromosome 10: allele B at codon 54 (G54D), allele C at codon 57 (G57E), and allele D at codon 52 (R52C), with the most common codon at these loci designated allele A.4 This effect is substantially modulated by at least 4 promoter polymorphisms, including the H/L and X/Y systems, which show reductions of MBL up to 85% among individuals homozygous for the LX ("low") promoters.8 The structural variations have typically been labeled "O" alleles in contrast to the most common "A" allele. Thus, the OO genotype could represent, for example, BB, BC, or CD genotypes, and an AO individual is heterozygous for the common allele and 1 of the 3 structural variations. Those with an OO genotype have virtually undetectable levels of MBL regardless of promoter genotype. The presence of a heterozygous genotype (AO) results in an approximate 8-fold reduction of MBL levels, but there is considerable overlap in the distribution of MBL levels in those with AA and AO genotypes.6,7,13,14 The frequency of MBL alleles (rather than MBL concentration) has been a preferred measurement of effect, because no clear cutoff of MBL concentration defines deficiency.15 There is some disparity in the limited reports examining direct associations of MBL with CAD.3,16–18
Coronary artery disease (CAD) accounts for a large proportion of mortality and morbidity in American Indian communities.19 The Strong Heart Study (SHS) is a longitudinal cohort study of CAD and its risk factors in American Indians of different ethnicity living in 3 different locations. We sought to investigate prospectively whether the genotypes previously associated with low MBL levels were independent predictors of incident CAD among this population.
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Methods |
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The American Indian communities participating in SHS and the study design, survey methods, and laboratory techniques have been described previously.20,21 Approval was obtained from relevant Institutional Review Boards and tribes, and all participants gave informed consent. The present study genotyped 434 participants selected as cases or controls from among the 4549 individuals originally enrolled at age 45 to 74 years in the SHS between July 1989 and January 1992. At enrollment and at 2 subsequent times, a physical examination was conducted along with a fasting venipuncture, standardized blood pressure measurements, and ECGs, recorded and coded as described previously.20,21 American Diabetes Association criteria were used to classify participant diabetic status.22 Participants were considered hypertensive if they were taking antihypertensive medications and had a systolic blood pressure >140 mm Hg or a diastolic blood pressure greater than 90 mm Hg. Covariate measurements are from the examination just before the defining event.
Ascertainment of fatal and nonfatal cardiovascular events occurring between examinations was accomplished by medical record review and/or yearly participant contact.23 Trained medical record abstractors reviewed medical records for all potential CAD events or interventions, including procedures diagnostic of CAD (eg, treadmill test and coronary angiography). Using information from these medical records, death certificates, and standard criteria, physician reviewers determined the specific CAD diagnosis. After an initial review, a second physician independently abstracted records with a diagnostic concordance rate >90%. Discordant conclusions were adjudicated by additional review and discussion.
Cases were identified by evidence of definite myocardial infarction (MI), definite CAD without MI, definite evidence of MI by Minnesota ECG coding,23 or mortality codes indicating either definite MI, sudden death due to coronary heart disease, or definite coronary heart disease occurring after initial enrollment and DNA collection through December 31, 1999.20 Participants with only a diagnosis of possible CAD, "other cardiovascular disease," stroke, congestive heart failure, or peripheral vascular disease were excluded. Controls were those individuals without any of the above diagnoses.
DNA Analysis and Assignment of Genotype Status
DNA was genotyped for the presence of the B, C, or D structural variations and 1 promoter polymorphism, the G/C polymorphism at -550 bp (the H and L alleles)7 of the MBL gene. MBL genotypes were determined by the oligonucleotide ligation assay as described by Nickerson and colleagues.24 Genotypes of quality-control samples were determined by direct DNA sequencing. Genotyping was done in a manner that was blinded to case-control status. The structural variations were assumed to occur on opposing chromosomes. A number of promoter variants and structural alleles have been found to be in complete linkage disequilibrium. The B and C structural and X promoter alleles are always associated with the L promoter, whereas the D structural allele is invariably linked with the H promoter.8 Inferred haplotypes were developed from these known relationships.
Individuals were considered exposed to the effects of MBL-deficient genotype (LOW_1) in the primary analysis if they had either 2 structural variations (OO) or an inferred LA/O genotype. In a supplementary analysis, exposure to the LOW_2 composite genotype (OO or LA/O or LA/LA) was considered. These risk genotypes were compared with reference genotypes categorized as ALL_1 or ALL_2 (all genotypes not included in either LOW_1 or LOW_2, respectively) or HIGH (either HA/HA or HA/LA). There is ample documentation of the biological effect of these various genotypes on basal MBL levels,8 although unidentified background genetic influences in unique populations are always possible.
Statistical Analysis
Cases (n=217) were individually matched with controls for SHS center, gender, and age (within 5 years) by a computer algorithm. Descriptive statistics of cardiovascular covariates used paired t test, McNemar’s 
2 test, and sign rank test for comparisons. The covariates included hypertension (HTN; yes/no), cigarette smoking status (current or ex-smoker versus nonsmoker), type 2 diabetes mellitus (DM2) status, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, body mass index, self-reported American Indian heritage (%), albuminuria, and fibrinogen. Those with normal glucose tolerance and impaired glucose tolerance were categorized as nondiabetic, and the presence of either microalbuminuria (urinary albumin/creatinine ratio 
30 mg/g) or macroalbuminuria was combined for analysis.
McNemar’s test was used to compare numbers of discordant pairs. Conditional logistic regression models (SAS/STAT 8.1 by SAS Institute Inc) were also used to evaluate the relation between MBL genotypes and CAD, with adjustment for covariates known to influence the risk of CAD. Models were conditioned on the original matched variables, and additional covariates were reduced by forward selection if covariates were found insignificant at the P>0.05 level. In analyses with HIGH as the referent genotype, indicator variables were used to create 3 composite genotypes, LOW, HIGH, and "other." Results were not statistically significant for "other" genotypes and are not shown.
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Results |
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Characteristics of the 217 matched pairs are summarized in Table 1. Among cases, 66 were defined by mortal events, 28 by a single morbid event, and the remaining 123 by multiple morbid events. Cardiovascular risk factors such as HTN, total cholesterol, low HDL cholesterol, triglycerides, DM2, fibrinogen, and albuminuria were increased in cases compared with controls. Table 2 shows that the prevalence of OO genotypes among both cases and controls (4.6%) was similar to that reported for both northern Europeans3 (3%) and indigenous groups (2% to 4%) in Greenland12,14 and Canada.25 Among both cases and controls, the LL genotype frequency in the present study (14.3%) was midway between that reported for European (38%) and Eskimo (3%) populations.8 Heterozygous AO and HL individuals made up 28.8% and 41.5% of total cases and controls, respectively. Table 3 indicates the proportion of various inferred haplotypes and combined genotypes in cases and controls, with significant differences between cases and controls of HA/LA, LA/LA, and LOW_2 composite genotypes. Control population genotypes showed no significant deviation from expected Hardy-Weinberg distributions (data not shown).
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Table 4 shows a univariate analysis of differences in discordant case-control pairs. Significant differences in discordant pairs were seen in comparison of LOW_2 and both reference genotypes, but LOW_1 genotype was only significant compared with the HIGH group. Results of conditional logistic regression models that tested associations between the outcome of CAD and both genotypic risk groups are found in Table 5. Unadjusted, the LOW_1 genotype compared with the HIGH reference group was marginally significant as a predictor of CAD, with an OR of 1.8 (95% CI 0.98 to 3.24, P=0.057), but when adjusted for the significant covariates of DM2, fibrinogen, triglycerides, and HTN, the OR was 3.3 (95% CI 1.4 to 7.7, P=0.005). The LOW_2 risk genotype showed highly significant predictive value compared with either the HIGH or ALL_2 reference groups, in both univariate and adjusted models (Table 5).
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Discussion |
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The present study is the first of prospective design and shows a strong, independent association between variant MBL genotypes predictive of lower MBL levels and incident CAD. This is particularly remarkable in this population of American Indians given the marked presence of other CAD risk factors such as DM2, HTN, and albuminuria, for which we were able to adjust in our analysis. These results suggest that MBL variant alleles are determinants of CAD for a subset of individuals, independent of other risk factors.
The initial report of an association between MBL genotypes and CAD from Norway indicated that the prevalence of homozygous structural (but not heterozygous) genotypes predicting low levels of MBL was increased among those with prior coronary artery bypass procedures compared with normal blood donors, although other risk factors for cardiovascular disease were not reported.3 Other attempts to explore possible relationships between CAD and MBL function have yielded somewhat conflicting results either because of the absence of control for other cardiovascular risk factors in small study samples or the use of less specific outcomes. These include the association of MBL variants with a slightly higher mean area of plaque detected in the carotid artery in whites at high risk for CAD, although the more common parameter of carotid atherosclerosis, arterial wall thickness, was not reported.16 In another study of US physicians, no relationship was noted between MBL levels and self-reported peripheral arterial disease.17 Most recently, a significant association between persistent infection with Chlamydia pneumoniae and CAD was reported, but only in the context of OO or AO structural MBL genotypes.18 In contrast, the present study showed a strong association of the MBL variant structural and promoter alleles directly with CAD.
The theoretical basis of an increased risk of CAD due to low levels of MBL is that inflammation can initiate atherosclerosis1 and insufficient MBL can increase the risk and duration of inflammatory infections.9–12 Paradoxically, elevated levels of MBL may enhance tissue damage during acute injury, because its inhibition with monoclonal antibody limited myocardial complement deposition and ischemic injury in an experimental model of reperfusion injury.26
Differences in MBL expression have been recognized as common and important immune modulating effects on the human response to infectious agents.5,9,10,12,27 A possible example of these interactions may be the high prevalence of the HYA haplotype in the Eskimo population of Greenland and the very low prevalence of this haplotype in African populations.8 Thus, the nonconcordant studies of MBL and CAD to date may reflect different population prevalence rates of infectious agents, as well as host responses. Our inability to observe an association between heterozygous variant MBL structural alleles and CAD, consistent with the original report by Madsen et al,3 may reflect differing thresholds for the influence of MBL on the various outcomes of CAD versus clinical infections, as previously suggested.27 Alternatively, the dynamic response of promoter alleles to infectious exposures may be more important than the presumably static effect of structural variants on basal MBL levels. Although the prevalence of MBL genotypes among the Canadian Inuit and the relationship of MBL genotypes to acute infections among the Inuit of Greenland have been established, little is known about the prevalence of MBL polymorphisms and their potential relationship to CAD in other indigenous populations.12,25
The strengths of the present study include its prospective design; a large, population-based sample; the systematic adjudication of CAD events; a high probability of ascertainment of all events; and adjustment for multiple known CAD risk factors. Analyses of the additional affects of the 3 remaining promoter MBL variations that were not assayed may have been useful. Future studies should examine whether genotype is associated with CAD in younger individuals or with exposure to various infectious agents.
In the present study, a prevalence of at least 11% for MBL genotypes, which confers an adjusted OR of 3.2 for CAD, suggests that future interventions guided by MBL genotypes that predict deficiencies in this innate immune defense may offer important public health benefits for this and possibly other populations. Much additional work needs to be done, however, to confirm the relationship between MBL and CAD, determine proper screening methods, and explore potential modulators of MBL action.
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Acknowledgments |
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This work was supported by cooperative agreement grants U01-HL65520, U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65521, and R01HL62233 from the National Heart, Lung, and Blood Institute, Bethesda, Md. We thank the SHS participants, Indian Health Service facilities, and participating tribal communities for their extraordinary cooperation and involvement, which has contributed to the success of the Strong Heart Study. Lyle Best, Michael Davidson, Kari North, and Ying Zhang were responsible for study design, data analysis, and manuscript preparation. Robert Ferrell and Susan DeCroo were responsible for laboratory test design and analysis. Jean MacCluer, Elisa Lee, and Barbara Howard contributed to manuscript preparation.
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Footnotes |
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The views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service.
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References |
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