Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study

doi:10.1016/S0140-6736(02)09093-1

The Lancet

Volume 359, Issue 9324, 22 June 2002, Pages 2159-2163

https://doi.org/10.1016/S0140-6736(02)09093-1 Get rights and content

Summary

Background

Macrophage inhibitory cytokine-1 (MIC-1) is part of the TGF-β superfamily. Raised concentrations of MIC-1 in serum arise in several disease states, can be detected in normal individuals, and can partly be genetically determined. We aimed to investigate whether MIC-1 has a role in atherothrombosis.

Methods

We did a prospective, nested, case-control study in 27 628 initially healthy women. Of these women, we established baseline concentrations of MIC-1 in 257 who subsequently had myocardial infarction, stroke, or died from a cardiovascular event (cases) and in 257 matched for age and smoking status, who did not report cardiovascular disease during 4-year follow-up (controls). We also assessed polymorphisms in the MIC-1 gene (MIC-1 H and MIC-1 D) in all 514 women.

Findings

MIC-1 concentrations were higher at baseline in women who subsequently had cardiovascular events than in those who did not (618 vs 538 pg/mL, p=0·0002). Concentrations above the 90th percentile (>856 pg/mL) were associated with a 2·7-fold increase in risk (95% CI 1·6–4·9, p=0·001). This effect was independent of traditional cardiovascular risk factors and at least additive to that of C-reactive protein. There was no significant association between MIC-1 polymorphism and vascular events.

Interpretation

MIC-1 could be a novel target for cardiovascular disease prevention.

Introduction

macrophage inhibitory cytokine 1 (MIC-1) is part of the transforming growth factor-β (tgf-β) superfamily, and it was first cloned on the basis of its increased mRNA expression associated with macrophage activation.¹ Although MIC-1 is not expressed in resting macrophages, stimulation of these macrophages by several biological mediators, including tumour necrosis factor α, interleukin 1, and macrophage-colony stimulating factor, induce its expression. Because of its induction by many proinflammatory cytokines, but failure of direct induction by lipopolysaccharide and interferon γ, researchers have postulated that MIC-1 could be an autocrine downregulator of macrophage activation.¹

Although originally identified in activated macrophages, MIC-1 can be expressed in several tissues.2, 3, 4, 5 Results of northern-blot analysis of human tissues show presence of small amounts of MIC-1 mRNA in kidney, pancreas, and prostate, but large amounts in placenta.2, 4 Large amounts of MIC-1 have also been detected by immunohistochemistry in biopsy specimens of breast, colon, and prostate cancer,⁵ but MIC-1 cannot be detected within normal epithelial cells of these organs.⁵ This fact, together with induction of MIC-1 expression by p53, and data showing that MIC can induce apoptosis of some epithelial tumour cell lines,6, 7, 8 also suggests a role for MIC-1 in epithelial neoplasms.

Shortly after cloning of MIC-1 cDNA, two allelic forms of this gene—due to one nucleotide polymorphism—were identified. This polymorphism causes an alteration of a histidine (H) to an aspartic acid (D) residue at position 6 of MIC-1.⁹ The homozygous D allele is present in about 5% of normal individuals.¹⁰ Because properties of these aminoacids differ from each other, this polymorphism could alter function of MIC-1.

While doing epitope-mapping studies of a series of monoclonal and polyclonal antibodies against MIC-1, it became apparent that one of these antibodies could discriminate between H and D alleles of MIC-1,⁹ a property that facilitates deduction of genotype from phenotype of MIC-1 present in serum.¹⁰ These antibodies have also enabled development of a sensitive immunoassay capable of quantification of MIC-1 in normal and pathological sera.²

Because MIC-1 is a product of activated macrophages, its concentration in serum or plasma could be useful in diagnosis of atherosclerosis. Results of studies have suggested that activated macrophages are implicated in pathogenesis of atherosclerosis and in vascular occlusion, which is often the ultimate endpoint of this process.11, 12 There are also strong epidemiological data linking measurement of inflammatory markers such as C-reactive protein and interleukin 6 with risk of vascular occlusive events.13, 14

We therefore postulated that the increased inflammatory response present within atherosclerotic vessel walls is associated with increased secretion and release of MIC-1, and that this increase in baseline concentration might be associated with increased risk of future cardiovascular events. We also aimed to assess whether any effect of plasma MIC-1 concentration on vascular risk might be modified by the H/D variation within MIC-1.

Section snippets

Participants

We did a prospective, nested, case-control study in apparently healthy women participating in the Women's Health Study (WHS), a continuing primary prevention trial of aspirin and vitamin E being done in 27 628 American women aged 45 years and older, who have no previous evidence of cardiovascular disease or cancer.¹⁵ Every study participant provided a baseline plasma and buffy-coat sample, which was stored on liquid nitrogen until time of analysis. Methods used for collection, storage, and

Results

Of 257 incident cardiovascular events assessed, 111 were myocardial infarction, 113 thromboembolic stroke, and 33 death from cardiovascular event. Women who subsequently developed these events during follow-up (cases) were more likely than their matched controls to have a history of hyperlipidaemia, hypertension, obesity, or diabetes. Use of hormone replacement therapy did not differ between groups. Because of the study design, cases and controls were almost identical in terms of age and

Discussion

Our results show that baseline concentrations of MIC-1 were raised in participants at increased risk of developing future cardiovascular events. Women with the highest concentrations of MIC-1 at entry had a risk of future myocardial infarction, thromboembolic stroke, or cardiovascular death nearly three times higher than that of women with lower concentrations. Although MIC-1 concentrations correlated with both interleukin 6 and C-reactive protein (two other inflammatory biomarkers known to

GLOSSARY

macrophage inhibitory cytokine 1: A member of the transforming growth factor-β (TGF-β) superfamily.
transforming growth factor-β (tgf-β) superfamily: Consists of several dimeric proteins having a conserved cysteine knot structure. These cytokines are typically involved in embryogenesis, regulation of growth and inflammation, and wound and fracture healing. This superfamily contains proteins such as TGF-β, bone morphogenetic proteins, inhibins, and glial-derived neurotrophic factors.
p21: A universal

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Biochemistry
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The study comprised 160 participants in total, of whom 88 had lung cancer, 31 had pneumonia, and 41 were control subjects. Among the 88 patients with lung cancer, 64 were willing to participate in follow-up chemotherapy-related studies and meet the inclusion criteria. The serum GDF15 concentration in 288 samples (31 cases, pneumonia group samples; 41 cases, control samples; 88 cases, lung cancer group samples; 64 cases, after 1 chemotherapy cycle; and 64 cases, after 2 chemotherapy cycles) with advanced lung cancer were detected by ELISA. The possible correlations between serum GDF15 level and sex, age, height, weight, body mass index, smoking history, diabetes status, and laboratory findings (hemoglobin, prealbumin, and lactate dehydrogenase) were analyzed using parametric and nonparametric tests. Thereafter, the sensitivity of GDF15 in diagnosing lung cancer was calculated. The serum levels of GDF15, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA) 21-1 were determined in 64 patients with lung cancer, before and after chemotherapy reception. For the evaluation of the efficacy of chemotherapy, receiver operating characteristic curves were plotted.
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Mechanisms of DiseaseConcentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Results

Discussion

GLOSSARY

J Biol Chem

FEBS Lett

Trends Cardiovasc

MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily

Proc Natl Acad Sci USA

The transforming growth factor-beta superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women

J Clin Endocrinol Metab

Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues

Cell Tissue Res

MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation

J Leukoc Biol

Macrophage inhibitory cytokine-1 (MIC-1) in epithelial neoplasia

J Leukoc Biol

PTGF-beta, a type beta transforming growth factor (TGF-beta) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-beta signalling pathway

Proc Natl Acad Sci USA

Epitope mapping of the transforming growth factor-beta superfamily protein, macrophage inhibitory cytokine-1 (MIC-1): identification of at least five distinct epitope specificities

Biochemistry

Mechanisms of Disease
Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study