Obesity Is an Important Determinant of Baseline Serum C-Reactive Protein Concentration in Monozygotic Twins, Independent of Genetic Influences

Greenfield, Jerry R.; Samaras, Katherine; Jenkins, A. B.; Kelly, Paul; Spector, Tim D.; Gallimore, J. Ruth; Pepys, Mark B.; Campbell, Lesley V.

doi:10.1161/01.cir.0000130640.77501.79

Cited by 171 publications

(133 citation statements)

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“…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.…”

supporting

confidence: 89%

“…24,39,[57][58][59][60] Khaodhiar et al 61 reported that in morbid obesity IL-6 may be secreted in an endocrine (systemic) manner in proportion to the expansion of fat mass particularly in the abdominal region with a corresponding increase in hepatic CRP production. Greenfield et al 43 examined the relationship between CRP and obesity in 194 healthy female twins and it seemed that obesity and adipose tissue are important determinants of baseline plasma CRP concentrations independent of genetic influences. Together with our findings of only a moderate genetic control of plasma CRP levels in corresponding with the opinion of Retterstol et al, 17 we suggested that a major part of the previously described CRP heritability was mediated by adipose tissue and the BMI.…”

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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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confidence: 99%

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

et al. 2006

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“…At the basic level, obesity is always due to greater energy intake than is expended, but the interaction of genetic and environmental factors that regulate both accumulation and distribution of body fat is complex. Recent studies of twins from our cohort, 2 and others, 3,4 have shown that total and central fat mass are responsible for most of the additional circulating inflammatory markers and cytokines that lead to increased heart disease. Determinants of fat accumulation include basal and sleeping metabolic rate, thermogenesis and the thermic effect of food, physical activity, efficiency of nutrient absorption by the gut and hormonal status, 5 which are all regulated differently depending on genetic make-up.…”

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confidence: 59%

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

et al. 2006

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Obesity is a multifactorial disorder with a complex phenotype. It is a significant risk factor for diabetes and hypertension. We assessed obesity-related traits in a large cohort of twins and performed a genome-wide linkage scan and positional candidate analysis to identify genes that play a role in regulating fat mass and distribution in women. Dizygous female twin pairs from 1094 pedigrees were studied (mean age 47.0711.5 years (range 18 -79 years)). Nonparametric multipoint linkage analyses showed linkage for central fat mass to 12q24 (141 cM) with LOD 2.2 and body mass index to 8q11 (67 cM) with LOD 1.3, supporting previously established linkage data. Novel areas of suggestive linkage were for total fat percentage at 6q12 (LOD 2.4) and for total lean mass at 2q37 (LOD 2.4). Data from follow-up fine mapping in an expanded cohort of 1243 twin pairs reinforced the linkage for central fat mass to 12q24 (LOD 2.6; 143 cM) and narrowed the -1 LOD support interval to 22 cM. In all, 45 single-nucleotide polymorphisms (SNPs) from 26 positional candidate genes within the 12q24 interval were then tested for association in a cohort of 1102 twins. Single-point Monks -Kaplan analysis provided evidence of association between central fat mass and SNPs in two genes -PLA2G1B (P ¼ 0.0067) and P2RX4 (P ¼ 0.017). These data provide replication and refinement of the 12q24 obesity locus and suggest that genes involved in phospholipase and purinoreceptor pathways may regulate fat accumulation and distribution.

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“…Those studies which adjusted for visceral adiposity, as measured by WHR or waist circumference, showed weaker associations than those that did not. Visceral adipose tissue, compared with subcutaneous fat, is known to produce more pro-inflammatory cytokines [37] and is associated with CRP levels [38], suggesting that visceral adiposity could be an additional important confounding factor that was not considered in all studies.…”

Section: Discussionmentioning

confidence: 99%

Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis

et al. 2009

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Aims/hypothesis We examined the association between serum C-reactive protein (CRP) and incident diabetes in a prospective study, and added these data to a literature-based meta-analysis to explore potential sources of heterogeneity between studies. Methods We analysed a case-control study nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, including 293 incident diabetes cases and 708 controls. We combined 16 published studies on CRP and incident diabetes in a random-effect meta-analysis. Results In the EPIC-Norfolk cohort, serum CRP was associated with a higher risk of diabetes after adjusting for age, sex, BMI, family history of diabetes, smoking and physical activity (OR 1.49, comparing the extreme thirds of CRP distribution [95% CI 1.03-2.15], p=0.03). However, the association was completely attenuated after further adjustment for WHR, serum γ-glutamyltransferase and serum adiponectin (OR 1.00; 95% CI 0.66-1.51, p=1.0). In a meta-analysis of 16 published studies with 3,920 incident diabetes cases and 24,914 controls, the RR was 1.72 (95% CI 1.54-1.92), comparing the extreme thirds of CRP distribution, with substantial heterogeneity between studies (I 2 =52.8%, p=0.007). Conclusions/interpretation Initial evidence of association between CRP and incident diabetes was confounded by central adiposity, markers of liver dysfunction and adiponectin in the primary analysis. Despite an overall positive association in the meta-analysis, considerable heterogeneity existed between studies. The degree of adjustment for central adiposity and baseline glycaemia explained some of this heterogeneity and suggests that CRP may not be an independent risk factor for type 2 diabetes.

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Obesity Is an Important Determinant of Baseline Serum C-Reactive Protein Concentration in Monozygotic Twins, Independent of Genetic Influences

Cited by 171 publications

References 65 publications

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

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

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis

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