Genetic Influence on Inflammation Variables in the Elderly

Abstract

Background-Inflammation variables (C-reactive protein [CRP], fibrinogen, and soluble intercellular adhesion molecule-1[sICAM-1]) have been identified as risk factors for cardiovascular disease. It is still not known how much the regulation of inflammatory risk factors is determined by genetic factors, and the aim of this study was to determine the heritability of these inflammation variables and of the acute phase regulating cytokines interleukin-6 (IL-6) and tumor necrosis factor-␣ (TNF-␣) at older ages. Methods and Results-The heritability of CRP, fibrinogen, sICAM-1, IL-6, and TNF-␣ was determined in a twin study consisting of 129 monozygotic twin pairs and 153 dizygotic same-sex twins aged 73 to 94 years who participated in the Longitudinal Study of Aging of Danish Twins. Furthermore, we determined the influence of selected genetic polymorphisms on the plasma level variations. Genetic factors accounted for 20% to 55% of the variation in plasma levels of the inflammation variables. The highest heritability was found for sICAM-1. The genetic polymorphisms we studied explained only a small, insignificant part of the heritability. Conclusions-This study in elderly twins provides evidence for a substantial genetic component of inflammatory cardiovascular risk factors among the elderly.

Genetic Architecture of the Pro-Inflammatory State in an Extended Twin-Family Design

“…Furthermore, we show a significant effect of non-additive factors on TNF-␣. Four smaller twin studies of TNF-␣ and IL-6 values in healthy unchallenged subjects are consistent with our findings, as the MZ correlations found in those studies were about twice as high as the DZ correlations in elderly subjects (de Maat et al, 2004), young adults (Grunnet et al, 2006), and middle-aged twins (Su et al, , 2009b. In their sample of young adult subjects, Grunnet and colleagues (2006) even found the MZ correlations for TNF-␣ to be more than twice as high as the DZ correlations.…”

“…Results replicate the importance of genetic factors in pro-inflammation observed before (de Lange et al, 2001(de Lange et al, , 2006de Maat et al, 2004;Grunnet Note: Abbreviations: df = degrees of freedom; Model = specification of the model that is tested; -2LL = minus twice the logarithm of the likelihood; vs = the model against which this submodel is tested; 2 = model fit statistic: difference in -2LL of two nested models; df = difference in the number of parameters between the models, p = p-value (was regarded significant when <.01), a 2 , d 2 , c 2 , e 2 = proportions of variance explained by additive, non-additive, shared, and unique environmental effects. The 95% confidence intervals are depicted within parentheses.…”

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

“…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.…”

“…[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).…”

“…[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.…”