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

Inga Thorsen Vengen,Carl Platou,Vibeke Videm,Lars Vatten,Hans O Madsen,Peter Garred,Nikolaos Frangogiannis

doi:10.1371/journal.pone.0042113

Abstract

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.

Highlights

Accumulating evidence suggests that atherosclerosis is an inflammatory disease where the innate immune system plays a crucial part in the pathophysiology [1]
The latter is initiated by mannose-binding lectin (MBL) or by proteins of the ficolin family [3]
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]

Summary

Introduction

Accumulating evidence suggests that atherosclerosis is an inflammatory disease where the innate immune system plays a crucial part in the pathophysiology [1]. The complement system is activated through three possible pathways, denoted as the classic, alternative or lectin pathway The latter is initiated by mannose-binding lectin (MBL) or by proteins of the ficolin family [3]. 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]. There were higher frequencies of variant haplotypes causing MBL deficiency among cases, compared to controls (p = 0.025, alpha level by permutations = 0.028). Frequencies of MBL2 and ficolin alleles are available as supporting information (Table S2 and Table S3)

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Conclusion