The CRP genotype, serum levels and lung function in men: the Caerphilly Prospective Study.

Systemic CRP (C-reactive protein) has been associated with impaired lung function. A causal relationship would increase the value of CRP as both a diagnostic and therapeutic tool. We assessed the association between lung function parameters, circulating CRP and CRP polymorphisms using Mendelian randomization in efforts to attribute causality to known associations. Spirometric parameters of FEV1 (forced expiratory volume in 1 s) and FVC (forced vital capacity) were determined in 2173 men participating in the Caerphilly Prospective Study. Lung function measures on 1021 participants were available at follow-up (mean, 16.8 years later). Serum CRP levels were measured at baseline, and three CRP polymorphisms were analysed. Haplotype analysis was performed. Serum CRP levels at baseline were inversely associated with contemporaneous FEV1 and FVC as well as at follow-up (P<0.001) even after adjustment for conventional confounders. Serum CRP was associated with FEV1 decline (P=0.04). All three CRP polymorphisms (rs1800947, rs1130864 and rs1205) predicted serum CRP; however, there were no clear associations of the polymorphisms or haplotypes with lung function or with lung function decline. In conclusion, serum CRP was associated with lung function cross-sectionally; however, CRP polymorphisms were not associated with lung function or decline, suggesting that the CRP-lung function relationship is due to reverse causality, an unmeasured confounding factor or only has a modest causal effect.

Association between C-reactive protein genotype, circulating levels, and aortic pulse wave velocity.

Circulating C-reactive protein (CRP) level is associated with cardiovascular disease. Whether this relationship is causal has been subject of debate, especially as a potential therapeutic target. Previous studies have demonstrated an association between circulating CRP levels and arterial pulse wave velocity, an accepted measure of arterial stiffness. We investigated the association between circulating CRP levels, CRP genotype, and aortic pulse wave velocity by examining data on 790 healthy male participants of the Caerphilly study. Circulating CRP levels were associated with aortic pulse wave velocity after adjustment for cardiovascular risk factors and other potential confounders (P=0.001). Three single nucleotide polymorphisms in the CRP gene (rs1130864, rs1800947, and rs1205) were associated with differences in circulating CRP levels (ratio of geometric means: 1.12, 95% CI 1.03 to 1.21, P=0.005; 0.76, 95% CI 0.66 to 0.87, P<0.001; 0.88, 95% CI 0.81 to 0.95, P=0.001, respectively). However, there was no relationship between any of the genotypes and aortic pulse wave velocity (regression coefficient for C:G/G:G versus C:C genotypes for single nucleotide polymorphism rs1800947 beta=0.005; 95% CI, -0.57 to 0.58; P=0.99). These results suggest that although circulating CRP levels are associated with aortic pulse wave velocity, CRP does not have a causal role in the development of arterial stiffness. CRP may simply act as a marker of vascular damage (ie, reverse causality), or the association reflects residual confounding. Further studies are needed to confirm these findings, particularly in view of the central role CRP has played in cardiovascular disease so far.

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.

OBJECTIVE: The influence of the degree of resection on survival in patients with glioblastoma multiforme is still under discussion. The highly controlled 5-aminolevulinic acid study provided a unique platform for addressing this question as a result of the high frequency of "complete" resections, as revealed by postoperative magnetic resonance imaging scans achieved by fluorescence-guided resection and homogeneous patient characteristics. METHODS: Two hundred forty-three patients with glioblastoma multiforme per protocol from the 5-aminolevulinic acid study were analyzed. Patients with complete and incomplete resections as revealed by early magnetic resonance imaging scans were compared. Prognostic factors that might cause bias regarding resection and influence survival (e.g., tumor size, edema, midline shift, location, age, Karnofsky Performance Scale score, National Institutes of Health Stroke Scale score) were used for analysis of overall survival. Time to reintervention (chemotherapy, reoperation) was analyzed further to exclude bias regarding second-line therapies. RESULTS: Treatment bias was identified in patients with complete (n = 122) compared with incomplete resection (n = 121), i.e., younger age and less frequent eloquent tumor location. Other factors, foremost preoperative tumor size, were identical. Patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001). In multivariate analysis, only residual tumor, age, and Karnofsky Performance Scale score were significantly prognostic. To account for distribution bias, patients were stratified for age (>60 or