Genetically Determined Serum Levels of Mannose-Binding Lectin Correlate Negatively with Common Carotid Intima-Media Thickness in Systemic Lupus Erythematosus

Troelsen, Lone N.; Garred, Peter; Christiansen, Buris; Torp‐Pedersen, Christian; Jacobsen, Søren

doi:10.3899/jrheum.100158

Cited by 17 publications

(16 citation statements)

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“…The MBL gene ( MBL2 ) has several polymorphic sites [4], and the combined genetic profile corresponds to normal , intermediate or deficient serum concentrations of the protein [5]. After the original study by Madsen et al in 1998, where MBL deficiency was associated with increased risk for severe atherosclerosis in relatively young patients [6], polymorphisms in MBL2 and serum concentrations of the protein have been linked to both increased and reduced risk of atherosclerosis and coronary artery disease in different populations [7], [8], [9], [10], [11]. Furthermore, a study in knockout mice demonstrated increased atherosclerotic lesions when the lectin pathway was inhibited [12].…”

Section: Introductionmentioning

confidence: 99%

Mannose-Binding Lectin Deficiency Is Associated with Myocardial Infarction: The HUNT2 Study in Norway

et al. 2012

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ObjectivesMannose-binding lectin (MBL) and ficolins activate the complement cascade, which is involved in atherogenesis. Based on a pilot study, we hypothesized that functional polymorphisms in the MBL gene (MBL2) leading to dysfunctional protein are related to development of myocardial infarction (MI). The aim of the present study was to study polymorphisms in MBL2 and ficolin genes in relation to the risk of MI.Methods and ResultsUsing the population-based HUNT Study in Norway, 57133 persons were followed up for a first-time MI from 1995–1997 until the end of 2008. The 370 youngest MI patients were matched by age (range 29–62 years) and gender to 370 controls. A younger population was selected because disease in this group might be less dependent on non-genetic risk factors. The study size was based on power calculation. Polymorphisms in MBL2 and in the genes of ficolin-1, ficolin-2 and ficolin-3 were genotyped by pyrosequencing and related to the risk of MI, estimated as odds ratios (OR). Functional haplotypes were analyzed and stringent alpha levels of significance were set by permutation testing. Variant MBL2 haplotypes causing MBL deficiency were associated with a two-fold higher risk of MI (OR 2.04, 95%CI 1.29–3.24). Adjustments for conventional cardiovascular risk factors did not substantially influence the association. The ficolins were not associated with MI risk.ConclusionIn a young to middle aged and relatively healthy Caucasian population, MBL2 variants related to functional MBL deficiency were associated with a doubling of the risk for MI, independent of conventional risk factors. This supports that MBL deficiency may lead to increased atherosclerosis or development of vulnerable plaques.

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Section: Introductionmentioning

confidence: 99%

Mannose-Binding Lectin Deficiency Is Associated with Myocardial Infarction: The HUNT2 Study in Norway

et al. 2012

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“…16 In line with our current findings, a smaller study in systemic lupus erythematosus patients who had MBL concentrations comparable with our study participants also reported that high plasma MBL was associated with lower cIMT. 26 In our study, participants with high plasma MBL appeared less likely to develop CVD and CVE. The same was observed for those with the wild-type genotype, but these latter associations were nonsignificant.…”

Section: Discussionmentioning

confidence: 71%

“…Previous studies on cIMT were cross-sectional, substantially smaller, and conducted in selected populations. 16,26 We observed that high plasma MBL may protect against intimal-medial thickening, whereas the association of MBL with low-grade inflammation appeared to be nonlinear. This suggests that high MBL can have protective, as well as harmful, effects in the vasculature, which might explain why previous large studies on MBL and incident CVD have to some extent reported contradictory findings.…”

Section: Discussionmentioning

confidence: 83%

“…This confirms a previously reported beneficial role of MBL in vascular integrity in a large study. 26 cIMT reflects pathological changes in the vessel wall that may result from early atherosclerosis and also from aging of the vessel wall. [22][23][24] High MBL may protect from intimalmedial thickening via its beneficial role in vascular clearup processes and tissue turnover.…”

Section: Discussionmentioning

confidence: 99%

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Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

Hertle

Arts

Kallen

et al. 2016

ATVB

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12associations with future CVD. When the effect of MBL on complications of established CVD was investigated, low MBL was in fact protective in most studies. [13][14][15] Thus, considerable discrepancy remains in the literature on whether MBL has beneficial or adverse effects in CVD.This reported discrepancy might be explained by a dual role of MBL in different etiologic aspects of CVD. Objective-Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima-media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD. Approach and Results-In a prospective cohort (n=574; age 60±7 years; 7-year follow-up), we investigated longitudinal associations of plasma MBL, MASP-1, MASP-2, MASP-3, and MAp44 with biomarker scores that reflect low-grade inflammation and endothelial dysfunction, respectively, and with cIMT. We also investigated their associations with incident CVD (n=73). In adjusted analyses, low-grade inflammation was lowest in the middle tertile (T Middle )

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“…While not as extensively studied as in patients with rheumatoid arthritis in larger scale studies [7–10], genetic polymorphisms potentially contributing to cardiovascular disease in patients with SLE have increasingly been identified in a number of lupus cohorts [11–16]. Thus far, genetic polymorphisms associated with premature atherosclerosis and cardiovascular disease in patients with SLE have been convincingly found in the interferon regulatory factor 8 (IRF8) [11], matrix metalloproteinase-2 (MMP-2) functional promoter [12], plasminogen activator inhibitor 1 (PAI-1) promoter [13], mannose-binding lectin-2 (MBL-2) [14], stromelysin promoter [15], and C-reactive protein (CRP) genes [16]. With the ever-increasing knowledge in the pathogenesis of atherogenesis in SLE, more genetic polymorphisms related to CVD in patients with SLE are expected to be identified.…”

Section: Introductionmentioning

confidence: 99%

Imbalance between Endothelial Damage and Repair: A Gateway to Cardiovascular Disease in Systemic Lupus Erythematosus

Mak

Kow

2014

BioMed Research International

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Atherosclerosis is accelerated in patients with systemic lupus erythematosus (SLE) and it leads to excessive cardiovascular complications in these patients. Despite the improved awareness of cardiovascular disease and advent of clinical diagnostics, the process of atherogenesis in most patients remains clinically silent until symptoms and signs of cardiovascular complications develop. As evidence has demonstrated that vascular damage is already occurring before clinically overt cardiovascular disease develops in lupus patients, intervention at the preclinical stage of atherogenesis would be plausible. Indeed, endothelial dysfunction, one of the earliest steps of atherogenesis, has been demonstrated to occur in lupus patients even when they are naïve for cardiovascular disease. Currently known “endothelium-toxic” factors including type 1 interferon, proinflammatory cytokines, inflammatory cells, immune complexes, costimulatory molecules, neutrophils extracellular traps, lupus-related autoantibodies, oxidative stress, and dyslipidemia, coupled with the aberrant functions of the endothelial progenitor cells (EPC) which are crucial to vascular repair, likely tip the balance towards endothelial dysfunction and propensity to develop cardiovascular disease in lupus patients. In this review, altered physiology of the endothelium, factors leading to perturbed vascular repair contributed by lupus EPC and the impact of proatherogenic factors on the endothelium which potentially lead to atherosclerosis in lupus patients will be discussed.

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Genetically Determined Serum Levels of Mannose-Binding Lectin Correlate Negatively with Common Carotid Intima-Media Thickness in Systemic Lupus Erythematosus

Abstract: In this group of SLE patients, MBL2 low-expressing genotypes and low serum levels of MBL were correlated with ccIMT, independent of the effects of traditional and nontraditional cardiovascular risk modifiers.

Cited by 17 publications

References 55 publications

Mannose-Binding Lectin Deficiency Is Associated with Myocardial Infarction: The HUNT2 Study in Norway

Mannose-Binding Lectin Deficiency Is Associated with Myocardial Infarction: The HUNT2 Study in Norway

Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

Imbalance between Endothelial Damage and Repair: A Gateway to Cardiovascular Disease in Systemic Lupus Erythematosus

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