Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6

Wood, Alice; Brull, David; Humphries, Steve E.; Montgomery, Hugh

doi:10.1053/euhj.1999.2207

Cited by 207 publications

(145 citation statements)

References 104 publications

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“…An association between IL-6 and BP level is biologically plausible. IL-6 stimulates the synthesis of many acute-phase reaction proteins, including CRP, 23 and counter-regulates TNF-a and interleukin-1 b levels. 24 A common functional polymorphism of the IL-6 gene promoter region (-174 G4C) has been shown to influence levels of circulating IL-6 in vivo.…”

Section: Discussionmentioning

confidence: 99%

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

et al. 2004

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High blood pressure (HBP) has been associated with elevated C-reactive protein (CRP), a marker of chronic mild inflammation. However, the association between HBP and other inflammatory markers, particularly interleukin 6 (IL-6) and tumour necrosis alpha (TNF-a), has not been evaluated in well-controlled studies. We examined the cross-sectional relationship between IL-6, TNF-a, and CRP and HBP in a random sample of 196 healthy subjects. All markers were measured in duplicate with high-sensitivity ELISA tests. Three blood pressure (BP) measurments were averaged for the analysis, and subjects with systolic BP X140 and/or diastolic BP X90 mmHg were considered hypertensive. Log binomial regression was used to estimate multivariate-adjusted prevalence ratios (PR) of HBP. Of the subjects, 40% (79) were hypertensive (mean age: 44 years; range 30-64). After adjustment for age, sex, body mass index, family history of HBP, and the level of the other inflammatory markers, subjects in the second (PR: 3.10, P ¼ 0.003), third (PR: 2.32; P ¼ 0.031), and fourth quartiles (PR: 2.30; P ¼ 0.036) of IL-6 were more than twice as likely to be hypertensive than those in the first quartile. Corresponding PR estimates for TNF-a levels were 1.41 (P ¼ 0.014) for the second; 1.59 (P ¼ 0.001) for the third; and 1.61 (P ¼ 0.025) for the fourth quartile. The CRP-HBP association was not statistically significant. Our results suggest that TNF-a and IL-6 could be independent risk factors for HBP in apparently healthy subjects. Nevertheless, the temporal relationship between elevated inflammation markers and HBP should be ascertained in prospective cohort studies.

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Section: Discussionmentioning

confidence: 99%

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

et al. 2004

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“…[28][29][30] Thus, some authors proposed IL-6 as a useful prognostic marker of CVD outcome [31][32][33][34][35][36][37] and suggested a central role for IL-6 in the pathogenesis of CHD. [38][39][40] However, the estimated heritability for IL-6 ranged between 0.17 and 0.57 in the literature 16,41,42 and previous studies concerning the heritability of CRP and IL-6 have to be interpreted carefully (Table 1). The design and exact analysis differed (twin to general family studies, VogelMotulsky heritability to other variance composition methods) and the correction for possible confounders varied greatly between the studies (different confounders considered, different methods).…”

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confidence: 96%

“…31 Some authors even proposed that elevated plasma IL-6 levels are a stronger predictor of cardiovascular mortality than CRP 63 and IL-6 seems to be the main circulating cytokine in systemic inflammation. 39,40 In accordance with previous studies, 16,47,64 we could demonstrate that plasma IL-6 levels were not influenced by age, BMI, sex, Family study CRP ++ + / / Vickers et al 13 Family study CRP ++ + + À Austin et al 15 Family study CRP + + + + Greenfield et al 43 Female twins CRP À + À / MacGregor et al 18 Female twins CRP ++ + / / Berger et al 44 Angiographic patients CRP / / + + Best et al 14 CHD patients CRP ++ / / / Latkovskis et al 45 CHD patients CRP / + À / Pantsulaia et al 41 Family study IL-6 + À + À Fishman et al 46 Healthy people IL-6 / / / / de Craen et al 42 Twin study IL-6 ++ / / / Posthuma et al 47 Twin study IL-6 ++ / À À Dupuis et al 48 Family study CRP/IL-6 +/+ / / / de Maat et al 16 Twin study CRP/IL-6 +/+ +/À À /+ / Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRP, C-reactive protein; IL, interleukin.Owing to different statistical methods and partial lack of adjustment, we only reflect the opinion of the above-mentioned authors concerning the CRP/IL-6 heritability. Heritability: À: no heritability, +: slight heritability, ++: strong heritability, /: no statement.…”

mentioning

confidence: 99%

“…In previous studies, plasma CRP levels strongly correlated with those of IL-6, suggesting that measuring CRP may also have been indirectly measuring plasma IL-6 levels. 35,40,62 It was demonstrated that healthy subjects with increased plasma IL-6 levels have a twofold risk of death and CVD events, 32,33 independent of traditional cardiovascular risk factors but additive to that for CRP. 31 Some authors even proposed that elevated plasma IL-6 levels are a stronger predictor of cardiovascular mortality than CRP 63 and IL-6 seems to be the main circulating cytokine in systemic inflammation.…”

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confidence: 99%

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Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels – a study in twins

et al. 2006

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Elevated baseline levels of acute-phase proteins such as C-reactive protein (CRP) or cytokines like interleukin-6 (IL-6) are known risk factors for atherosclerosis and cardiovascular disease (CVD) events. However, until today, there is only controversial information about the contribution of genetic and environmental factors. Therefore, we performed an open prospective study in 108 monozygotic (MZ) and 60 same-sex dizygotic (DZ) twin pairs to analyse the genetic and environmental contributions to plasma CRP and IL-6 levels. Heritability of IL-6 was 0.61, indicating that plasma IL-6 levels are to a major part influenced by genetic determinants; however, for CRP, heritability was only 0.22, pointing to a moderate genetic influence. Plasma CRP levels were strongly influenced by female gender, older age and especially the body mass index. Our data underline the central role of IL-6 in low-grade inflammation contributing to atherosclerosis and CVD. Genes and Immunity (2006) Keywords: twin pairs; heritability; interleukin-6; C-reactive protein; body mass index Low-grade inflammation is thought to play an essential role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD) events. 1,2 As a highly sensitive C-reactive protein (CRP) measurement is possible, several large epidemiological studies have demonstrated association between elevated plasma CRP levels reflecting low-grade inflammation and the development of CVD events such as coronary heart disease (CHD), stroke or peripheral arterial disease. 3-7 CRP represents not only a sensitive marker for systemic inflammation, but also contributes to the complex interaction occurring between endothelial dysfunction, lipid accumulation, cell activation and inflammatory response in the pathogenesis of atherosclerosis. [8][9][10][11] Family studies have suggested that 35-45% of the variations in plasma baseline CRP levels are genetically determined [12][13][14][15] and twin studies revealed a heritability of 20-52% for CRP. [16][17][18] In addition, it is known that (environmental) factors such as obesity, older age, female gender, smoking, diabetes mellitus, chronic infections, lower socio-economic status, greater alcohol consumption and medications such as oral contraceptives are involved in a low-grade inflammatory response with elevated plasma CRP levels. 6,[19][20][21][22][23][24][25][26] An aim of determining plasma CRP levels could be related to polymorphisms in upstream cytokines such as interleukin (IL)-6. 13,27 IL-6 induces CRP production in hepatocytes and it is the only cytokine that can stimulate the synthesis of all other acute-phase proteins. [28][29][30] Thus, some authors proposed IL-6 as a useful prognostic marker of CVD outcome 31-37 and suggested a central role for IL-6 in the pathogenesis of CHD. [38][39][40] However, the estimated heritability for IL-6 ranged between 0.17 and 0.57 in the literature 16,41,42 and previous studies concerning the heritability of CRP and IL-6 have to be interpreted carefully (Table 1). The design and exact an...

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“…Полученные нами результаты подтвержда-ют данные других авторов, свидетельствующие о том, что при НС и остром инфаркте миокарда наблюдается гиперэкспрессия провоспалитель-ных цитокинов [7,13,18]. Повышение спонтан-ной и индуцированной продукции IL-1β и IL-6 больных НС по сравнению со здоровыми лица-ми свидетельствует об активации циркулирую-щих клеток крови и выраженном усилении их способности секретировать провоспалительные цитокины.…”

Section: Discussionunclassified

Features of Cytokine Production in Patients With Unstable Angina: Dependence on Ethnicity in the Republic of Sakha (Yakutia)

Гольдерова¹,

Nikolaeva²,

Тарасова³

et al. 2014

Med. immunol.

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Резюме. В работе исследовали уровень спонтанной и митоген-индуцированной продукции ци-токинов (IL-1β, IL-4, IL-6, IL-10 и IFNγ) клетками крови 24 мужчин с нестабильной стенокардией (НС), относящихся к коренному (n = 12, якуты) и пришлому населению Республики Саха (n = 12, русские). В целом по группе больных НС была выявлена активация воспалительных реакций, что проявлялось усилением спонтанной и индуцированной продукции провоспалительных цитокинов IL-1β, IL-6 и индуцированной продукции IFNγ. По сравнению со здоровыми лицами у больных НС была снижена спонтанная и митоген-индуцированная продукция противовоспалительного IL-4, а индуцированная продукция IL-10 была повышена. Можно предположить, что при НС развивается проатерогенный Th1-иммунный ответ, при одновременном подавлении Th2-клеток. Различия, вы-явленные в этнических группах, дают основание полагать, что тяжесть и распространенность атеро-склеротического поражения, чаще наблюдаемая у больных некоренной национальности ассоцииру-ется с повышением продукции провоспалительных цитокинов IL-1β и IL-6. Ключевые слова: цитокины, атеросклероз, нестабильная стенокардия. Golderova A.S., Nikolaeva I.N., Tarasova V.E., Kozlov V.A. FEATURES OF CYTOKINE PRODUCTION IN PATIENTS WITH UNSTABLE ANGINA: DEPENDENCE ON ETHNICITY IN THE REPUBLIC OF SAKHA (YAKUTIA)Abstract. We investigated levels of spontaneous and mitogen-induced cytokine production (IL-1β, IL-4, IL-6, IL-10 and IFNγ) by peripheral blood cells of 24 men with unstable angina (UA), including indigenous population (n = 12, Yakuts), and a group of Russian migrants to the Republic of Sakha (n = 12). Activation of inflammatory response was revealed in the total group of patients with UA, manifesting by increase of spontaneous and induced production of the pro-inflammatory IL-1β, IL-6 cytokines, and mitogen-induced production of IFNγ. As compared with healthy individuals, spontaneous and induced production of antiinflammatory IL-4 was decreased in UA patients, whereas the mitogen-induced production of IL-10 proved to be enhanced. Therefore, it is highly possible that a pro-atherogenic Th1-immune response is developing during UA, along with suppression of Th2-driving response. The differences revealed for different ethnic groups suggest that severity and prevalence of atherosclerotic disease, which is more common in the non-native patients, is associated with increased production of pro-inflammatory IL-1β and IL-6 cytokines.

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Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6

Cited by 207 publications

References 104 publications

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension

Genetic and environmental contributions to plasma C-reactive protein and interleukin-6 levels – a study in twins

Features of Cytokine Production in Patients With Unstable Angina: Dependence on Ethnicity in the Republic of Sakha (Yakutia)

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