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BACKGROUND/AIM: The aim of the present study was to compare fecal immunochemical tests (FITs) for colorectal cancer (CRC) screening with the traditional guaiac-based FOB tests (gFOBT). MATERIALS AND METHODS: A cohort of 368 colonoscopy-referral patients were evaluated by i) the new-generation FIT: ColonView quick test (CV; Biohit Oyj, Finland) and ii) a conventional gFOBT HemoccultSENSA (HS; Beckman Coulter, USA). Three fecal samples were requested for both assays, and all subjects underwent diagnostic colonoscopy with biopsy confirmation. Sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under curve (AUC) were calculated for both tests using three endpoints: adenoma (A), advanced adenoma (AA) and adenocarcinoma (AC). RESULTS: Colonoscopy and biopsies disclosed normal mucosa in 90/378 (24.5%) subjects, early A in 108/368 (29.3%) cases, AA in 48/368 (13.0%) and AC in 37/368 (10.1%), and non-neoplastic conditions in the remaining 85 (30.3%). For the AC endpoint, the CV (Hb/Hp) test had 94.6% SE and 65.1% SP (AUC=0.799), while the HS test had SE of 75.7% and SP of 84.3% (AUC=0.800). For the A endpoint, the difference between CV and HS was even more pronounced; SE of 44.2% and 19.2%, respectively (p<0.0001). Hb and Hb/Hp complex of the CV test showed equal performance for all endpoints. CONCLUSION: Sensitivity (94.6%) of the ColonView quick test for the most reproducible endpoint (invasive CRC) far exceeded the pooled sensitivity (79%) estimated in a recent meta-analysis for 8 common FIT brands. As shown in a previous study, ColonView quick test is superior in SE to HemoccultSENSA test, making CV a perfect FIT for organized CRC screening.

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BACKGROUND/AIM: Because of the major health problems and annual economic burden caused by cigarette smoking, effective new tools for smoking intervention are urgently needed. Our previous randomized controlled trial (RCT) provided promising results on the efficacy of slow-release L-cysteine lozenge in smoking intervention, but the study was not adequately powered. To confirm in an adequately-powered study the results of the previous RCT implicating that effective elimination of acetaldehyde in saliva by slow-release L-cysteine (Acetium® lozenge, Biohit Oyj, Helsinki), would assist in smoking cessation by reducing acetaldehyde-enhanced nicotine addiction. On this matter, we undertook a double-blind, randomized, placebo-controlled trial comparing Acetium® lozenge and placebo in smoking intervention. MATERIALS AND METHODS: A cohort of 1,998 cigarette smokers were randomly allocated to intervention (n=996) and placebo arms (n=1,002). At baseline, smoking history was recorded by a questionnaire, with nicotine dependence testing according to the Fagerström scale (FTND). The subjects used smoking diary recording the daily numbers of cigarettes, lozenges and subjective sensations of smoking. The data were analysed separately for point prevalence of abstinence (PPA) and prolonged abstinence (PA) endpoints. RESULTS: Altogether, 753 study subjects completed the trial per protocol (PP), 944 with violations (mITT), and the rest (n=301) were lost to follow-up (LTF). During the 6-month intervention, 331 subjects stopped smoking; 181 (18.2%) in the intervention arm and 150 (15.0%) in the placebo arm (OR=1.43; 95%CI=1.09-1.88); p=0.010). In the PP group, 170 (45.3%) quitted smoking in the intervention arm compared to 134 (35.4%) in the placebo arm (OR=1.51, 95%CI=1.12-2.02; p=0.006). In multivariate (Poisson regression) model, decreased level of smoking pleasure (p=0.010) and "smoking sensations changed" were powerful independent predictors of quit events (IRR=12.01; 95%CI=1.5-95.6). CONCLUSION: Acetium® lozenge, herein confirmed in an adequately powered study to be an effective means to aid smoking quit, represents a major breakthrough in the development of smoking intervention methods, because slow-release L-cysteine is non-toxic, with no side-effects or limitations of use.

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BACKGROUND/AIM: Russian Federation is among the high-incidence countries for gastric cancer (GC), with the incidence being projected to continue increasing. Using a non-invasive blood test with four stomach-specific biomarkers (pepsinogen-I (PG-I) and -II (PG-II), amidated gastrin-17 (G-17) and Helicobacter pylori (HP) IgG antibodies) in a hospital-based screening setting, we aimed to determine the prevalence of GC risk conditions: HP-infection and atrophic gastritis (AG). PATIENTS AND METHODS: A population-derived cohort of 918 asymptomatic subjects (646 women and 272 men) with a mean age of 51.8 years (range=26-83) was examined with the GastroPanel® (GP) test. GP results were verified by gastroscopy and biopsies (the Updated Sydney System (USS) classification for all test-positive AG cases and for random 5% test-negatives (n=263) to correct for the verification bias. RESULTS: Of the 918 subjects, only 199 (21.7%) tested completely normal, while 76.7% (704/918) had HP-infection. Altogether, in 99 subjects (10.8%), GP suggested AG: atrophic gastritis in the antrum (AGA) (n=21), atrophic gastritis in the corpus (AGC) (n=69) or atrophic pangastritis (AGpan) (n=9). The overall concordance between GP and USS classification was 82.5% (217/263) with weighted kappa intra-class correlation coefficient (ICC)=0.875 (95% confidence interval (CI)=0.840-0.901). The sensitivity/specificity balance in receiver operating characteristic (ROC) analysis for PG-I as a marker of moderate/severe AGC (AGC2+) had area under the curve (AUC)=0.895 (95%CI=0.837-0.953). Using the AGC2+ end-point, verification bias-corrected specificity of PGI reached 96.4% (95%CI=94.7-97.9) and that of PGI/PGII ratio 94.6% (95%CI=92.6-96.3), with inevitable erosion in sensitivities. CONCLUSION: While capable of detecting the subjects at risk for GC (HP and/or AG), GP should be the cost-effective means to break the current ominous trend in GC incidence in Russian Federation.

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BACKGROUND/AIM: Harmans are condensation products of acetaldehyde and biogenic amines in saliva. Like other monoamine oxidase inhibitors, harmans help maintain behavioral sensitization to nicotine and mediate the addictive potential of cigarette smoke-derived acetaldehyde. The aim of this study was to test the hypothesis that effective elimination of acetaldehyde in saliva by slow-release L-cysteine (Acetium™ lozenge; Biohit Oyj, Helsinki, Finland) blocks the formation of harmans and eliminates acetaldehyde-enhanced nicotine addiction in smokers. STUDY DESIGN: A double-blind, randomized, placebo-controlled trial comparing Acetium lozenges and placebo in smoking intervention was undertaken. MATERIALS AND METHODS: A cohort of 423 cigarette smokers were randomly allocated to intervention (n=212) and placebo arms (n=211). Smoking-related data were recorded by questionnaires, together with nicotine dependence testing by Fagerström scale. The participants used a smoking diary to record the daily number of cigarettes, test lozenges and sensations of smoking. The data were analyzed separately for point prevalence of abstinence and prolonged abstinence endpoints. RESULTS: Altogether, 110 study participants completed the trial per protocol, 234 had minor violations, and the rest (n=79) were lost to follow-up. During the 6-month trial, 65 participants quit smoking; 38 (17.9%) in the intervention arm and 27 (12.8%) in the placebo arm [odds ratio (OR)=1.48; 95% confidence intervals (CI)=0.87-2.54; p=0.143]. Success in the per protocol group was better (42.9% vs. 31.1%, respectively; OR=1.65, 95% CI=0.75-3.62; p=0.205) than in the modified intention-to-treat group: 13.5% vs. 7.4% (p=0.128). CONCLUSION: If the efficacy of Acetium lozenge can be confirmed in an adequately powered study, this new approach would represent a major breakthrough in smoking quit intervention because slow-release L-cysteine is non-toxic with no side-effects or limitations of use.

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AIM: To compare a new-generation fecal immunochemical test (FIT) with the leading guaiac-based test in detection of fecal occult blood (FOB) in colonoscopy-referral patients. PATIENTS AND METHODS: A cohort of 300 patients referred for colonoscopy was examined by two different tests for FOB: ColonView quick test (CV) (FIT test for haemoglobin (Hb) and haemoglobin/haptoglobin (Hb/Hp) complex) and HemoccultSENSA (HS) (quaiac test for Hb). Three fecal samples were tested and all subjects were examined by diagnostic colonoscopy with biopsy verification. The test was interpreted positive if any of the three samples tested positive for Hb (HS test) and either Hb or Hb/Hp complex (CV test). The performance indicators (sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC)) were calculated for both tests using three endpoints (adenoma (A), adenoma/carcinoma (A/AC) and carcinoma (AC)), collectively and were stratified according to tumor site. The two tests were compared regarding their sensitivity/specificity balance (AUC), using the receiver operating characteristics (ROC) comparison test. RESULTS: Colonoscopy (and biopsies) disclosed normal results in 85 (27.2%) subjects, A in 91 cases (30.3%) and AC in 95 (31.7%) patients. For the combined A+AC endpoint, the HS test had SE of 58.3% and SP of 96.5% (AUC=0.774), while the CV test had 97.2% SE and 85.8% SP (AUC=0.916) (p=0.0001). For the A endpoint, the difference between HS and CV was even more significant, AUC=0.637 and AUC=0.898, respectively (p=0.0001). In CV test, the Hb/Hp complex was 15% (93% vs. 78%) and 8% (96% vs. 88%) more sensitive than Hb alone, for the A and A+AC endpoints, respectively. Being more stable than Hb in the feces, the Hb/Hp complex detected 100% of the tumors in the proximal colon, as contrasted to only 41.2% and 52.9% by the Hb of HS and CV test, respectively (p=0.0001). CONCLUSIONS: With its 100% SE and 95.3% SP for proximal colon neoplasia, as well as 98.2% SE and 95.3% SP for the distal neoplasia, ColonView is superior to current FIT tests on the market, recently shown to exhibit pooled SE of 79% and pooled SP of 94% for colorectal cancer (CRC) in a comprehensive meta-analysis. With these exceptional performance indicators, ColonView quick test should be the test-of-choice for CRC screening.

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UNLABELLED: Indoleamine 2,3-dioxygenase (IDO) activity and expression is increased in many hematological malignancies, but has not been previously studied in chronic lymphocytic leukemia (CLL). We determined IDO activity and expression in 49 patients with CLL. We found that IDO activity is increased in CLL. This may have some influence on CLL progression. BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in the catabolism of tryptophan, suppressing T-cell activity. IDO activity and expression are increased in many malignant diseases, including hematological malignancies. IDO expression can mediate immunotolerance to tumors. IDO activity and expression have not previously been studied in chronic lymphocytic leukemia (CLL). METHODS: We measured IDO activity by calculating the kynurenine-tryptophan (kyn-trp) ratio. IDO and IDO2 gene expression was determined by using real-time polymerase chain reaction (PCR). RESULTS: In patients with CLL, the serum kyn-trp ratio--reflecting increased IDO activity--was significantly higher compared with controls, but in peripheral blood mononuclear cells (PBMCs)--mainly representing malignant B cells--the expression of genes encoding IDO and IDO2 enzymes was reduced. CONCLUSIONS: Increased IDO activity in patients with CLL may affect disease progression, although it originates from cells other than malignant B cells.

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BACKGROUND: Old age is associated with increased levels of circulating pro-inflammatory cytokines, a phenomenon termed inflamm-aging. Elevated levels of pro-inflammatory cytokines have been associated with several age-associated diseases and with a shortened lifespan. Indoleamine 2,3-dioxygenase (IDO) has immunomodulatory properties and its activity is elevated in inflammation, autoimmune disorders and malignancies. We have previously shown that IDO activity is increased in nonagenarians compared to young individuals and that high IDO activity is associated with mortality at old age. FINDINGS: In this study our aim was to assess whether this difference in IDO activity in the plasma was due to the differential expression of either the IDO1 or IDO2 gene in peripheral blood mononuclear cells. Our results show that IDO1 and IDO2 are not differently expressed in nonagenarians compared to controls and that the expression of IDO genes is not associated with the level of IDO activity in the plasma. CONCLUSION: The level of IDO activity in the plasma is not regulated through the expression of IDO1 or IDO2 in the peripheral blood mononuclear cells.

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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), mother's BMI, and polymorphisms near genes TFAP2B, LRRN6C, and FLJ35579. A risk assessment based on childhood BMI, mother's 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, mother's 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), mother's 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.

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BACKGROUND: C-reactive protein (CRP) is an inflammatory protein that may play a role in the pathogenesis of cardiovascular disease (CVD). However, its status as a causal risk factor is still controversial. CRP gene single nucleotide polymorphisms (SNPs) have been shown to associate with CRP concentration, but not convincingly with early atherosclerotic changes. OBJECTIVE: We assessed whether CRP genotypes or their haplotypes associate with plasma CRP levels or carotid artery intima-media thickness (IMT) or carotid artery elasticity (CAE) in a Finnish middle-aged study population. METHODS: We genotyped CRP gene polymorphisms -717A>G (rs2794521), -286C>T>A (rs3091244), +1059G>C (rs1800947), +1444C>T (rs1130864) and +1846G>A (rs1205) and measured CRP concentration in a sub-population (N=1332, mean age 58.2 ± 8.0, women n=727 and men n=605) of a large Finnish cross-sectional health examination survey, The Health 2000 Study, carried out in 2000-2001. Results. Significant association (both sexes p<0.0001, women p=0.015 and men p=0.029) was found between CRP rs1800947 genotype and CRP concentration. Multivariate analysis showed an independent effect of the genotype on CRP concentration after adjustment for risk factors (women p=0.036 and men p=0.009). Similar associations were seen at the haplotype level in haplotype ACCCA where +1059 C-carriers had lower median CRP values than non-carriers (p=0.008). One CRP genotype (rs1130864) was associated with one CAE parameter in men but no association was observed between CRP genotypes and carotid artery IMT. CONCLUSIONS: CRP gene allelic variation is associated with CRP levels in both sexes and with one CAE parameter (SI) in men in a population-based Finnish cohort of middle-aged subjects.

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BACKGROUND: Increased levels of C-reactive protein (CRP) and serum amyloid A (SAA) are associated with an increased risk of cardiovascular disease. It is hypothesized that dysregulation of the autonomic nervous system (ANS) leads to increased inflammation via the cholinergic anti-inflammatory pathway. Heart rate variability (HRV) is a marker of ANS function. HRV has been shown to be associated with CRP levels. Currently, there are no studies addressing the relationship between HRV and SAA. DESIGN: The purpose of this study was to compare the associations between HRV, CRP and SAA in healthy young adults. CRP and SAA concentrations and short-term HRV indices [high frequency (HF), low frequency (LF), total spectral component of HRV, root mean square differences of successive R-R intervals, the standard deviation of all R-R intervals and ratio between LF and HF) were measured in 1601 men and women aged 24-39 taking part in the Cardiovascular Risk in Young Finns study. RESULTS: A significant inverse correlation (P < 0·05) between HRV indices and inflammatory markers was observed. However, in linear regression analyses, only inverse association between HRV indices and CRP levels remained significant (P < 0·05), while association between HRV indices and SAA levels was attenuated to the null (P > 0·05) after adjusting for age, sex, body mass index, cholesterol levels, leptin and other common traditional cardiovascular risk factors. CONCLUSIONS: Reduced HRV indices are independently associated with increased CRP levels, but not with SAA levels. This association supports the hypothesis that dysregulation of the ANS may lead to increased inflammation early in adulthood.

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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.

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The human immune system, especially the adaptive branch, substantially declines with ageing. Several distinct immunosenescent events have already been described, yet data regarding to age-associated baseline alterations in immune cell function is limited. Therefore, by using the TaqMan Human Immune Arrays we conducted a preliminary gene expression profiling of immune-related genes in the peripheral blood mononuclear cells of young individuals (aged 22­37 years, n = 13) and nonagenarians (n = 12), the latter being part of the Vitality 90+ Study. We also analysed the correlations between significantly regulated genes. The results revealed a significantly decreased expression of CCR7, CD19, CD28, CD40LG, ICOS, IL4, IL6 and LTA as well as significantly increased expression of FN1 in the nonagenarians as compared to the controls. Significant direct correlations were observed between the expression of CCR7 and CD19, CCR7 and ICOS, ICOS and CD19, ICOS and CD40LG, as well as CD40LG and CD28 in the nonagenarians but not in the controls. These results suggest that the key players of adaptive immunity i.e. the factors required for full lymphocyte activation are markedly and coordinately down-modulated in the very old individuals. Further research is, however, required to establish the relationship between these changes and the mechanisms of immunosenescence.

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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.

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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.

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Nitric oxide (NO) as a vasoactive substance is a crucial element in the pathogenesis of sepsis. Endothelial NO synthase (eNOS) is, in turn, a key regulator of vascular NO production. The eNOS gene polymorphism at position 894 (G>T, Glu298Asp) resulting in T allele has been studied in the context of vascular diseases, but its role in sepsis has not yet been explored. We here studied the effect of eNOS Glu298Asp polymorphism on the clinical course of the disease in patients with bacteremia. The study comprised 147 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococci, or Escherichia coli. Laboratory findings and clinical data were registered on admission and during 6 consecutive days. The polymorphism of eNOS gene, G894T, was genotyped. Carriage of the T allele was associated with low MAP (P = 0.004) and high Sequential Organ Failure Assessment score (P = 0.001) in patients with E. coli bacteremia. The effect on blood pressure was most prominent in the early stage of the disease (MAP on admission = 52 mmHg in T-allele carriers vs. 91 mmHg in noncarriers; P < 0.001). However, the same was not detected in bacteremia caused by a gram-positive organism (S. aureus, S. pneumoniae, or beta-hemolytic streptococci). The Glu298Asp polymorphism had no effect on case fatality in any pathogen. Carriage of the T allele of the eNOS gene is a risk factor for hypotension in patients with E. coli bacteremia but not in bacteremia caused by a gram-positive organism.

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BACKGROUND: Use of combined oral contraceptives (COCs) is known to increase concentrations of C-reactive protein (CRP), an important predictor of cardiovascular disease. The inflammatory nature of the disease is well acknowledged. The aim of this study was to find out whether the metabolic, lifestyle and genetic determinants of CRP differ between women who use COCs and those who do not use any hormonal contraceptives (non-users). MATERIAL AND METHODS: A total of 1,257 women (24-39 years) participated in the ongoing Cardiovascular Risk in Young Finns Study, a population based cross-sectional follow-up study. Use of hormonal contraceptives was determined by questionnaire. Plasma CRP and other cardiovascular risk factors were measured; five CRP gene polymorphisms were genotyped (-717A>G, -286C>T>A, +1059G>C, +1444C>T and +1846G>A) and CRP haplotypes were constructed. RESULTS: Multivariate regression analysis revealed that BMI and leptin were the main determinants of CRP in non-users, whereas in COC users the main determinants were BMI, leptin and triglycerides. The median CRP and triglyceride values were significantly higher in COC users than in non-users. The correlations between triglyceride and CRP were tested separately in different COC users in accordance with progestagen content and dosage, the analysis revealing significant association only in women using a high dosage of progestagen or cyproterone. The haplotypes of CRP gene had no significant association with CRP concentration in COC users, while independent effects on CRP were found in non-users. CONCLUSION: Our study suggests that use of COCs alters the metabolic determinants and genetic regulation of CRP.

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CONTEXT: Leptin and C-reactive protein (CRP) concentrations are increased in inflammation, and both have been linked to increased risk for cardiovascular diseases. OBJECTIVE: The objective of the study was to explore in a population-based sample whether the relation between leptin and CRP is independent of obesity level and whether genetic causes of CRP elevation contribute to leptin levels. DESIGN: This was a population-based study including 1862 young adults (971 women; 891 men) aged 24-39 yr. SETTING: The study was conducted at five centers in Finland. MAIN OUTCOME MEASURES: Associations between leptin and CRP adjusted for obesity indices, risk factors, genetic variables, and lifestyle variables were measured. RESULTS: Women had 3.0-fold higher median concentrations of leptin (12.5 vs. 4.1 ng/ml) and 1.3-fold higher median concentrations of CRP (0.75 vs. 0.56 mg/liter) than men (P < 0.0001 in both comparisons). In univariate analyses, CRP and leptin were significantly intercorrelated (r = 0.47, P < 0.0001 for women; r = 0.46, P < 0.0001 for men). In multiple regression analysis including age, body mass index, waist circumference, insulin, lipids, systolic and diastolic blood pressures, smoking status, and use of oral contraceptives in women, leptin was the main determinant of CRP in men (P < 0.0001) and the second most important determinant in women (P < 0.0001). A Mendelian randomization test based on genetic variants in the CRP gene (five single nucleotide polymorphisms) provided no support for CRP as a causal agent for leptin. CONCLUSIONS: Leptin, obesity, and oral contraceptive use in women were the main factors related to CRP. The relation between leptin and CRP was independent of obesity and cardiovascular risk factors.

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Genetic association studies have used variants in the C-reactive protein (CRP) gene to estimate causal effects of lifelong circulating CRP levels on disease endpoints. However, the extent to which the genetic variants are actually associated with lifelong circulating CRP levels has not been demonstrated empirically. In a population-based prospective cohort study (1980-2001) of 1,609 young Finns (768 men and 841 women), the authors genotyped five single nucleotide polymorphisms in the CRP gene (-717A/G, -286C/T/A, +1059G/C, +1444T/C, and +1846G/A) and assessed circulating CRP levels at ages 3-18 years and 24-39 years. The haplotypes from the five single nucleotide polymorphisms were associated with circulating CRP levels in childhood and adulthood, with the strongest effect being found for average CRP level across these two measures taken at two time points in the life course. In combination, the haplotype pairs accounted for 3.9%, 3.3%, and 5.0% of the variation in circulating CRP levels in childhood, in adulthood, and for the mean of CRP levels at both time points, respectively. These findings support the assumption that the above genetic variants define groups with long-term differences in circulating CRP levels.

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C-reactive protein (CRP) is an important molecule in the defence against bacterial infections. To discover if variation in the CRP gene is associated with clinical outcome of bacteraemia, we investigated 147 microbiologically verified bacteraemia patients (mean age 59 y, range 19-93 y) and determined whether CRP -717A>G, +1059G>C or +1444C>T single nucleotide polymorphisms (SNPs) were associated with clinical outcome of bacteraemia and/or CRP concentration caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-haemolytic streptococci or Escherichia coli. The patients were genotyped for CRP gene polymorphisms, CRP was measured and clinical outcomes were recorded. The CRP -717A>G, a promoter region polymorphism was strongly associated with mortality from Streptococcus pneumoniae but did not correlate with plasma CRP concentration. These results suggest that mortality from Streptococcus pneumoniae may be associated with polymorphism of the promoter region of the CRP gene.

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