American Association for Clinical Chemistry
Better health through laboratory medicine
May 2007 Clinical Laboratory News: Diagnostic Profiles

May 2007: Volume 33, Number 5

Glucose Levels Predict Hospitalization
for CHF in High-Risk Patients
Fasting plasma glucose is a modest but significant independent risk factor for chronic heart failure (CHF) hospitalization in high-risk patients, according to a study published in Circulation (DOI: 10.1161/CIRCULATIONAHA.106.661405). To evaluate associations between fasting plasma glucose and risk of hospitalization for CHF, a multinational team of researchers assessed baseline fasting plasma glucose levels in 31,546 subjects with more than one coronary, peripheral, or cerebrovascular disease, or diabetes mellitus (DM) with organ damage. Sixty-nine percent of the patients were male, with a mean age of 67. They participated in two parallel trials: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trial. At baseline, 37% of subjects from both trials had known DM and 3.2% had newly diagnosed DM. The researchers compared baseline fasting plasma glucose with the adjusted CHF event rate at a mean follow-up of 2.4 years through interim analyses that were blinded for randomized treatment. Among all subjects, 668 patients were hospitalized for CHF. After adjustment for age and sex, as little as a fasting plasma glucose increase of 1 mmol/L or higher was associated with a 1.10-fold-increased risk of CHF hospitalization (95% CI, 1.08–1.12). The association persisted after further adjustment for smoking, previous myocardial infarction, hypertension, waist-to-hip ratio, creatinine, DM, and use of aspirin, ß-blockers, or statins (HR 1.05; 95% CI, 1.02 to1.08). The absence of a significant interaction between patients with and without known DM suggests that the degree of dysglycemia, and not the DM diagnosis per se, is the key determinant of the relationship, researchers wrote.
Fecal DNA Test for CRC Shows Improvement
An improved fecal DNA test for colorectal cancer (CRC) screening shows much higher sensitivity than an earlier version, according to new research published in Clinical Gastroenterology and Hepatology (2007; 5: 111–117). A study of the earlier version—which analyzed 22 gene mutations—showed it had 52% sensitivity and 94% specificity for CRC in average-risk individuals. In the current study, researchers sought to determine sensitivity and specificity of a second generation fecal DNA integrity assay (DIA), testing for the 22 mutations used in the earlier version, plus a marker for vimentin gene methylation. The researchers evaluated 162 patients, 40 with CRC and 122 with normal colonoscopies. The enhanced DIA increased sensitivity of the prototype assay to 72.5%. Vimentin gene methylation alone provided sensitivity and specificity of 72.5 % and 86.9%, respectively. The optimal combination of vimentin methylation plus DIA resulted in 87.5% sensitivity and 82% specificity and allowed researchers to detect cancers at various locations and stages.
New Polymorphism Linked to Warfarin Resistance
A newly discovered polymorphism on the VKORC1 gene confers resistance to warfarin treatment, researchers reported in Blood (2007; 109: 2477–2480). Investigators from Sheba Medical Center in Tel Hashomer, Israel, analyzed the polymorphism, AspTyr, and known CYP2C9 and VKORC1 poymorphisms in 15 warfarin-resistant patients and eight warfarin-sensitive patients. The patients received warfarin doses of 80–185 mg/week, and 7–13 mg/week, respectively. The researchers also studied 99 controls who received 8–105 mg/week. The researchers found the VKORC1 AspTyr polymorphism in seven of the 15 resistant patients, compared with none of the eight sensitive patients. Analysis showed that AspTyr patients needed much higher warfarin doses than noncarriers (80.9 versus 42.7 mg/week, respectively). Asp36Tyr was significantly associated with doses of more than 70 mg/week (OR, 13.0, 95% confidence limit, 1.3–124.2). “While the known CYP2C9 and VKORC1 markers enable classification of warfarin dose requirements as low (7–20 mg/week) or intermediate (20–70 mg/week), respectively, the AspTyr marker is specifically indicative of high-dose requirements and is dominant over the dose-reducing effect of CYP2C9*2,*3, and VKORC1*2,” the investigators wrote. They called for prospective studies in larger cohorts to determine the marker’s predictive value.
Tests for Genetic ACS Risk Factors Are Premature

Genetic associations with acute coronary syndrome (ACS) should be interpreted with caution and need extensive validation, according to a study published in JAMA (297: 1551–1561). Through a literature search, the multi-site research team identified 85 genetic variants reported to be significant susceptibility factors for artherosclerosis or ACS. Restricting analysis to white patients in order to reduce confounding data from racial mixture, the researchers studied 811 patients who presented at two Kansas City, Mo. hospitals from March 2001 through June 2003. During 2005 and 2006, the researchers genotyped these patients and 650 age and sex-matched controls for the 85 variants in order to replicate reported associations. In preliminary analysis, only 1 putative risk genotype (-455 promoter variant in α-fibrogen) was nominally statistically significant. Among the four variants that met nominal statistical thresholds, the researchers found an excess of a different variant than was previously reported among cases in the original study. Concluding that their findings could did not support the panel of gene variants as bona fide ACS risk factors, the researchers said the findings added that “such clinical genetic testing is premature and underscores the importance of robust replication studies of reported associations prior to their application to clinical care.”

LDL-C Levels Often Too High in Patients Considered Low Risk

While the majority of the U.S. population is at low 10-year cardiac risk as defined by current guidelines from the National Cholesterol Education Program Adult Treatment Panel (ATP III), a significant proportion has not met LDL-C goals, according to research published in Circulation (DOI:10.1161/CIRCULATION.AHA. 106.645473). To inform future cholesterol screening guidelines, researchers sought to quantify the number of individuals at intermediate risk who might benefit from additional testing. Using data from the 1999 to 2002 National Health and Nutrition Examination Survey (NHANES) for 7,399 individuals ages 20 to 79, researchers from the University of Wisconsin in Madison determined CHD risk, LDL-C levels, and achievement of ATP III goals through a medical condition review, risk factor summation, and Framingham Risk Score calculation. The group of individuals at intermediate risk comprised 5.4% of the population, a figure lower than previous estimates. Of those at high risk, only 23% had an LDL-C level <100 mg/dL, and only 3.1% had an LDL-C level <70 mg/dL. Of those individuals at very high risk, only 26% had an LDL-C level <100 mg/dL, and as few as 4.6% had an LDL-C level <70 mg/dL. Based on their findings, the researchers suggested a scheme that combined the full risk assessment process with LDL-C levels to determine which patients might benefit from more testing.