Carita Eklund

Chapter 5 Proinflammatory cytokines in CRP baseline regulation

Low-grade inflammation, a minor elevation in the baseline concentration of inflammatory markers such as C-reactive protein (CRP), is nowadays recognized as an important underlying condition in many common diseases. Concentrations of CRP under 10 mg/1 are called low-grade inflammation and values above that are considered as clinically significant inflammatory states. Epidemiological studies have revealed demographic and socioeconomic factors that associate with CRP concentration; these include age, sex, birth weight, ethnicity, socioeconomic status, body mass index (BMI), fiber consumption, alcohol intake, and dietary fatty acids. At the molecular level, production of CRP is induced by proinflammatory cytokines IL-1, IL-6, and IL-17 in the liver, although extra hepatic production most likely contributes to systemic concentrations. The cytokines are produced in response to, for example, steroid hormones, thrombin, C5a, bradykinin, other cytokines, UV-light, neuropeptides and bacterial components, such as lipopolysaccharide. Cytokines exert their biological effects on CRP by signaling through their receptors on hepatic cells and activating different kinases and phosphatases leading to translocation of various transcription factors on CRP gene promoter and production of CRP protein. Genetic polymorphisms in the interleukin genes as well as in CRP gene have been associated with minor elevation in CRP. As minor elevation in CRP is associated with both inflammatory and noninflammatory conditions, it should be noticed that the elevation might just reflect distressed or injured cells homeostasis maintenance in everyday life, rather than inflammation with classical symptoms of redness, swelling, heat, and pain.

Childhood Environmental and Genetic Predictors of Adulthood Obesity: The Cardiovascular Risk in Young Finns Study

CONTEXT Obesity from childhood to adulthood is associated with adverse health later in life. Increased youth BMI is a risk factor for later obesity, but it is unknown whether identification of other risk factors, including recently discovered genetic markers, would help to identify children at risk of developing adult obesity. OBJECTIVES Our objective was to examine the childhood environmental and genetic predictors of adult obesity. DESIGN, SETTING, AND PARTICIPANTS We followed 2119 individuals of the Cardiovascular Risk in Young Finns Study for up to 27 yr since baseline (1980, age 3-18 yr). MAIN OUTCOME MEASURE We evaluated adult obesity [body mass index (BMI) ≥ 30 kg/m(2)]. RESULTS The independent predictors (P < 0.05) of adult obesity included childhood BMI, C-reactive protein (CRP), family income (inverse), mothers BMI, and polymorphisms near genes TFAP2B, LRRN6C, and FLJ35579. A risk assessment based on childhood BMI, mothers BMI, and family income was superior in predicting obesity compared with the approach using data only on BMI (C-statistics 0.751 vs. 0.772, P = 0.0015). Inclusion of data on childhood CRP and novel genetic variants for BMI did not incrementally improve C-value (0.779, P = 0.16). A nonlaboratory risk score (childhood BMI, mothers BMI, and family income) predicted adult obesity in all age groups between 3-18 yr (P always <0.001). CONCLUSIONS Childhood BMI, CRP, family income (inversely), mothers BMI, and polymorphisms near genes FLJ35779, TFAP2B, and LRRN6C are independently related to adulthood obesity. However, because genetic risk markers and CRP only marginally improve the prediction, our results indicate that children at high risk of adult obesity can be identified using a simple non-laboratory-based risk assessment.

Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians.

Objective  Apolipoprotein E (APOE) genotype is a regulator of hepatic lipoprotein metabolisms and has been linked with longevity. The relationship between APOE genotype and plasma C‐reactive protein (CRP), which is produced by the liver during inflammation, has not been studied in nonagenarians. The aim of the present study was to establish whether APOE genotype is related to plasma concentrations of CRP and lipids, or longevity among nonagenarians.

Mendelian Randomization Suggests No Causal Association Between C-reactive Protein and Carotid Intima-media Thickness in the Young Finns Study

To the Editor: It is unclear whether C-reactive protein (CRP), a nonspecific marker of acute phase inflammatory response, is causally related to arterial intima-media thickness (IMT), a risk factor for coronary heart disease (CHD). Previous evidence from conventional observational studies is inconsistent and suggests that the association may be biased or confounded.1 According to the Mendelian randomization approach, the genetic variants in the CRP gene ( CRP ) may represent good instruments for CRP levels that are largely free from reverse causation bias and confounding.1 If the association between CRP and IMT is causal, then genetic variants in CRP should be related to IMT to the extent predicted by the magnitude of their association with average CRP levels. …

Epistatic effect of C-reactive protein (CRP) single nucleotide polymorphism (SNP) +1059 and interleukin-1B SNP +3954 on CRP concentration in healthy male blood donors

Baseline C‐reactive protein (CRP) concentrations are indicative of persons prone to cardiovascular diseases and are about 40–50% heritable. We have previously shown that interleukin (IL)‐1B +3954 allele T is associated with lower CRP concentration. In this study, we aimed to examine the effect of this polymorphism together with the CRP +1059 gene polymorphism on baseline CRP concentrations, and genotyped 336 healthy blood donors for CRP +1059 (G→C) and IL‐1B +3954 (C→T) polymorphisms. In men, the carriers of the CRP +1059 C‐allele had significantly lower CRP values than GG homozygotes (0.66 versus 0.43 mg l−1, up to −35%, P = 0.009). No significant difference was found in women. When the data were stratified for both of these polymorphisms in men, CRP +1059 GG homozygotes had low CRP concentrations only if they were allele‐T carriers of IL‐1B +3954 simultaneously (0.93 versus 0.50 mg l−1, P = 0.013). Genotype CRP +1059 GG/IL‐1B +3954 CC was associated with an almost 3‐fold risk of a higher baseline CRP value [odds ratio (OR) 2.84 (CI 1.03–6.07)]. Thus, both IL‐1B +3954 (C→T) and CRP +1059 (G→C) polymorphisms influence baseline CRP values and act independently of each other in male subjects. These polymorphisms might be predictive markers of persons prone to cardiovascular diseases.

Epistatic Effect of TLR4 and IL4 Genes on the Risk of Asthma in Females

Background: Many studies have demonstrated a connection between asthma and T-cell cytokine genes, such as genes coding for interleukin-4 (IL4) and IL-13, which are involved in the regulation of the TH1/TH2 balance. The toll-like receptor 4 (TLR4), the principal receptor for bacterial endotoxin, has attracted attention as a potential risk factor for asthma. We examined whether the polymorphisms of the TLR4 (A/G at +896) and IL4 (C/T at –590) showed an epistatic effect on the risk of asthma or atopy. Methods: Gene polymorphism analyses and skin prick tests were performed on asthmatic and nonasthmatic adult subjects of a Finnish population-based case-control study. The phenotype studied was persistent asthma. Results: The results showed that genotypes of neither the TLR4 SNP at +896 nor IL4 SNP at –590 were separately found to be associated with asthma. However, the female carriers of allele G (i.e. genotype AG or GG) of TLR4 and allele T (genotype CT or TT) of IL4 had a significantly increased risk for asthma. No association of these genes and atopy was found. Conclusions: Our results indicate that in females the TLR4 and IL4 genes show an epistatic effect on the risk of asthma. The low LPS-responsive allele G of TLR4 and high IgE production allele T of IL4 were found to be the predisposing combination. However, there was no epistatic effect on the risk of atopy.

Serum amyloid A is independently associated with metabolic risk factors but not with early atherosclerosis: the Cardiovascular Risk in Young Finns Study

Background.  Serum amyloid A (SAA) is a sensitive marker of inflammation and its elevation has been implicated in obesity and in cardiovascular disease, yet data on its regulation in young adults or on its role in early atherosclerosis is scarce. We investigated which factors explain the variation in SAA and analysed whether SAA could be associated with preclinical atherosclerosis.

Genetic Variants and Their Interactions in the Prediction of Increased Pre-Clinical Carotid Atherosclerosis: The Cardiovascular Risk in Young Finns Study

The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach—in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population—can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the “gray zone” of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.

Association of C-reactive protein (CRP) gene allelic variants with serum CRP levels and hypertension in Turkish adults

OBJECTIVE Serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease and metabolic syndrome (MetS). The aim of this study was to analyze the CRP gene allelic variations in the Turkish adult risk factor (TARF) study and relate them with serum CRP levels as well as MetS and its components. METHODS We analyzed CRP gene polymorphisms (-286C>T>A [rs3091244], +1444C>T [rs1130864], +1059G>C [rs1800947], and +1846G>A [rs1205]) as well as their haplotypes, in addition to measuring CRP levels (n=1138) and collecting risk factor data from 1987 adults (mean age 54.3+/-11.9 years, 51.3% women) participating in the TARF Study. MetS was defined by using the criteria of the National Cholesterol Education Program modified for pre-diabetes and in men for abdominal obesity. RESULTS After adjustment for the major cardiovascular risk factors, four CRP SNPs (-286C>T>A, +1059G>C, +1444C>T, and +1846G>A) were significantly associated with serum CRP levels in women (p<0.05), whereas the -286C>T>A and +1444C>T polymorphisms were associated with CRP levels in men (p<0.05). The haplotype analyses revealed four common CRP haplotypes. The haplotype 1 (CGCA) in women and the haplotype 3 (TGTG) in men were associated with serum CRP levels and hypertension (p<0.05). However, no haplotype association was observed for MetS or its components. CONCLUSION CRP gene allelic variation is associated with serum CRP levels as well as hypertension in Turkish adults.

Complement factor H 402His variant confers an increased mortality risk in Finnish nonagenarians: The Vitality 90+ Study

Ageing is characterized by chronic low-grade inflammation and the expected lifespan may be affected by several immunological and inflammatory mediators. In this study, we investigated whether the functional Tyr402His polymorphism (rs1061170) on complement factor H (CFH) gene, which is a key inflammatory downregulator, modulates the longevity of 491 nonagenarians in the Vitality 90+ study. Logistic regression analysis and Kaplan-Meier method with the log rank test were used to examine the effect of the CFH Tyr402His polymorphism on 4-year mortality. After follow-up, we observed that risk factor-adjusted mortality was significantly higher among the carriers of CFH 402His allele compared to non-carriers (OR 1.78, 95% CI 1.19-2.67, p=0.005) and that the survival curves of CFH 402His carriers and non-carriers deviated significantly (p=0.016). We propose that the increased mortality is inflammation-related and mediated by aberrant complement regulation by the CFH 402His variant.