American Association for Clinical Chemistry
Better health through laboratory medicine
November 2010 Clinical Laboratory News: Diagnostic Profiles

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November 2010: Volume 36, Number 11

CRP Genetic Variants May Have Prognostic Value in Chronic Inflammation

A recent study found that common genetic variants of C-reactive protein (CRP) may influence acute-phase CRP significantly enough to have a clinically relevant impact on assessment of inflammatory disease activity (Plos Medicine 2010; 7:e10000341). The authors suggest that genetically adjusted CRP measurements might improve the accuracy and utility of clinical algorithms that incorporate CRP to diagnose and monitor infectious and inflammatory diseases.

The study involved two independent sets of patients with chronic inflammation due to rheumatoid arthritis, with >40% of the combined groups having CRP >10 mg/L. The authors were interested in exploring the effect of CRP genetic variants in chronic inflammation because most of the existing literature addressing this issue measured CRP rise after a single event, such as myocardial infarction or coronary artery bypass surgery.

The researchers genotyped the respective patient sets and employed linear modeling to explore the relationship between genotype and serum CRP. They used erythrocyte sedimentation rate as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients.

The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets, translating into an approximate 3.5-fold change in expected serum CRP levels between carriers of two common variants. Applying this outcome to a common rheumatoid arthritis disease activity score algorithm, the authors calculated that a patient with genetically determined low CRP would be required to have considerably worse scores of joint tenderness and swelling to be considered for the same treatment as an individual with a higher genetically determined CRP level. Based on these findings, the authors suggest that if technology advances to the point of rapid genetic testing, then a personalized, genetically adjusted CRP level may prove to be a useful diagnostic and predictive marker. 

Baseline PSA Reliably Predicts Prostate Cancer Death

Using data from the Duke Prostate Center, investigators found that baseline prostate-specific antigen (PSA) level is a reliable and independent predictor of death from prostate cancer (Cancer 2010;DOI:10.1002/cncr.25447). The results may diffuse the controversy over the benefits of PSA screening, according to the authors.

Although the PSA test has been adopted widely as a screening tool, evidence about its benefits versus harms has been mixed. Conflicting interim results from two major clinical trials released in 2009 only added to the debate; however, PSA levels have been proven useful in numerous risk stratification models. This led the authors to hypothesize that baseline PSA measurements could stratify and predict risk of death from prostate cancer and all cause mortality.

Out of the approximately 35,000 subjects in the Duke Prostate Center database, the researchers included data from 4,568 individuals who had a follow-up time ≥6 months after baseline PSA measurement and were ultimately diagnosed with prostate cancer. After multivariate statistical analyses, they found the overall rate of death from prostate cancer was 3.5%, and that baseline PSA (either as a continuous or categoric variable), age at baseline PSA, and race were all predictors of death from prostate cancer. Subjects with baseline PSA between 4.0–9.9 ng/mL and ≥10 ng/mL were three and 11.5 times, respectively, more likely to die from prostate cancer than those with baseline PSA <2.5 ng/mL. African Americans and advanced age at the time of baseline PSA also were associated with a higher rate of death from the disease. The area under the receiver operator characteristic curve for baseline PSA as a continuous variable in predicting death from prostate cancer was 0.839.

Scoring Model Stratifies VTE Risk in Cancer Patients

Austrian researchers confirmed the utility of a previously developed risk scoring model for predicting venous thromboembolism (VTE) in cancer patients, and they reported that adding two biomarkers to the scoring model significantly improved risk stratification in this population (doi:10.1182/blood-2010-02-270116). The findings have implications for better identifying cancer patients at highest risk for VTE, so that clinicians can implement primary thromboprophylaxis appropriately.

To better stratify the risk of VTE in cancer patients, another team of researchers proposed a risk scoring model in 2008 to predict chemotherapy-associated thrombosis in ambulatory cancer patients. This model, which incorporated the site of cancer, platelet count, hemoglobin levels, use of erythropoiesis-stimulating agents, leukocyte count, and body mass index, had not been validated independently. This led investigators at the Medical University of Austria to evaluate the risk model in a prospective cohort study of 819 patients with newly diagnosed cancer or progression of disease who had not received chemotherapy, radiotherapy, or surgery recently.

Using the previously published model, the researchers found that in comparison to patients with risk scores of 0, hazard ratios for patients with risk scores of 1, 2 and ≥3 were 2.7, 5.5 and 9.5, respectively. Adding two biomarkers—sP-selectin and D-dimer—to this model significantly improved the risk stratification. Compared to patients with a risk score of 0, hazard ratios for patients with highest risk scores ≥5 was 25.9. The hazard ratios declined with declining risk score from 15.6 for patients with scores of 4 to 3.7 for those with scores of 1. 

Hypertriglyceridemic-Waist Phenotype Identifies Patients at Risk for CAD

New research indicates that increased waist circumference and elevated triglyceride levels are associated with increased risk of coronary artery disease among both men and women (CMAJ 2010; 182:1427–1432). While the authors emphasize that these findings should not supplant use of the National Cholesterol Education Program clinical criteria for diagnosing metabolic syndrome, they suggest that the hypertriglyceridemic-waist phenotype is a simple and inexpensive way to help identify patients with intra-abdominal as opposed to subcutaneous abdominal obesity. Such individuals have a deteriorated cardiometabolic risk profile and are therefore at risk of coronary artery disease.

The research involved participants in the European Prospective Investigation into Cancer and Nutrition-Norfolk study, a 10-country collaborative designed to investigate diet and other determinants of cancer. At baseline, measurements were taken of the subjects’ body mass index, waist circumference, and waist-hip ratio, along with various serum markers, including triglycerides. Mean follow-up was 9.8 years. Researchers defined the hypertriglyceridemic-waist phenotype in men as waist circumference ≥90 cm and triglyceride level ≥2.0 mmol/L, and in women as waist circumference ≥85 cm and triglyceride level ≥1.5 mmol/L.

The researchers found increased risk of coronary artery disease in both women and men who had an enlarged waist circumference even without elevated triglyceride levels and vice versa. However, having both enlarged waist circumference and high triglycerides conveyed the highest risk. The unadjusted hazard ratio for future coronary artery disease in men with the hypertriglyceridemic-waist phenotype was 2.40 compared with men who did not have the phenotype, and 3.84 in women with the phenotype compared with those without it.