American Association for Clinical Chemistry
Better health through laboratory medicine
March 2008 Clinical Laboratory News: Diagnostic Profiles

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March 2008: Volume 34, Number 3


Lower Glucose Levels May Confer CVD Risk in Women


The revised 2003 American Diabetes Association definition of impaired fasting glucose (IFG) offers little benefit over the 1997 definition in terms of predicting risk of CVD or diabetes, according to a recent study that also reveals important sex differences in the predictive powers of IFG (Journal of the American College of Cardiology 2008; 51: 264–270). Researchers from the National Heart, Lung, and Blood Institute, Boston University, and Harvard University studied participants in the Framingham Offspring Study to characterize the 2003 ADA definition of IFG—fasting plasma glucose of 100–125 mg/dL—by examining incident CVD events as compared with the 1997 definition of IFG—fasting plasma glucose of 110–125 mg/dL—as well as to assess risk of developing diabetes based on the two definitions. Researchers differentiated between CHD and CVD, defining CHD as cases of myocardial infarction, stable and unstable angina pectoris, and CHD death, while explaining that CVD included all of these diagnoses as well as stroke, transient ischemic attack, intermittent claudication, congestive heart failure, or CVD death. The team followed participants free of CVD under the 1997 definition from 1983 to 2004 and used pooled-logistic regression to calculate multivariate-adjusted odds ratios (ORs) for incident CHD or CVD. Overall, the researchers followed 4,138 individuals who had 13,273 exams for CHD, and 4,058 participants who had 12, 918 exams for CVD. Four-year CHD event rates among women with IFG of 100–109 mg/dL, 110–125 mg/dL, and diabetes were 1.3%, 2.3%, and 2.9%, respectively. For men, those rates were 2.9%, 3.0%, and 8.7%, respectively. For the 2003 IFG definition, the OR for CHD among women was 1.7 (95% CI, 1.0–3.0), while for the 1997 definition, the OR for CHD in women was 2.2 (95% CI, 1.1–4.4). The second OR was almost as high as the OR of 2.5 for women with diabetes (95% CI, 1.2–5.2). The 1997 IFG definition yielded significantly greater odds of CVD in women (OR 2.1, 95% CI, 1.2–3.6), but the 2003 definition did not. Men were not at increased odds of developing CVD or CHD by either definition. “The 2003 IFG definition does not offer substantive advantages over the 1997 definition for prediction of CVD and diabetes,” the researchers wrote, adding that sex differences in CVD and diabetes risk raise interesting questions. These include whether the differences are due to intrinsic biologic differences or differences in risk factor management, and whether researchers should develop sex-specific cut points for IFG.


Novel Cardiac Marker Deemed Potentially Useful


Lp-PLA2 values compare favorably with several traditional lipid variables, according to a recent paper (Clinical Chemistry 2008; 54: 124–130). German researchers measured Lp-PLA2 by ELISA in blood samples from 200 post-myocardial infarction patients at 6-month intervals between May 2003 and February 2004. From a total of 1,143 samples they estimated the analytical, within-individual and between-individual variation, the critical difference, and the intraclass correlation coefficient of reliability (ICC) to assess the reliability of serial Lp-PLA2 measurements. The mean plasma Lp-PLA2 measurement for study participants was 188.7μg/L, with no significant difference between men and women. The analytical CV for Lp-PLA2 was 4.4%, the within-individual biological CV was 15.0%, the between-individual CV was 22.0%, and the ICC was 0.66. An important part of the total variation in plasma Lp-PLA2 concentration was explained by the between-individual variation (as a percentage of the total variance, 66.1%), whereas the within-individual variance was 31.3%. The analytical variance was as low as 2.6%. Researchers called for further research on season and circadian variation in Lp-PLA2 concentration and long-term variation.


KIF6 Variant Carriers Respond Better to Intensive Statin Therapy


Carriers of a particular variation of the K1F6 gene receive much greater benefit—apparently due to a mechanism distinct from lower levels of CRP—from intensive statin therapy than do noncarriers, according to a recent paper (Journal of the American College of Cardiology 2008, 51: 449–455). A team of researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, Mass., and Bristol-Meyers Squibb (Princeton, N.J.) genotyped 1,778 patients with ACS in the PROVE-IT-TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22) and investigated different intensities of statin therapy in carriers of the 719Arg variant of KIF6, which codes for kinesin-like protein 6. Benefit from intensive versus moderate statin therapy was significantly greater in the 59% of the cohort who were carriers (HR 0.59, 95% CI, 0.45–0.77) than in those who were noncarriers (HR 0.94, 95% CI, 0.70–1.27 for interaction between 719Arg carrier status and treatment). Absolute risk reduction was 10.0% in carriers versus 0.8% in noncarriers. Significant benefit of intensive therapy in carriers was apparent as early as day 30 of therapy. Carriers and noncarriers did not differ in treatment LDL-C, triglyceride, or CRP levels. “The absence of significant benefit from intensive statin therapy in noncarriers does

not preclude the possibility that a portion of noncarriers do benefit from statin therapy, but it does suggest that noncarriers may be treated with standard statin therapy and also with other lipid-modifying drug or by strategies that target other risk factors such as hypertension, diabetes, or smoking,” the researchers wrote.  


Genetic Variations Linked to Prostate Cancer


Some men with low PSA levels may have an increased risk of prostate cancer if they carry one or more of five prostate single-nucleotide-polymorphisms (SNPs) associated with the disease, new research suggests (New England Journal of Medicine 2008; 358: 910–919). An international team of researchers evaluated 16 SNPs from five chromosomal regions in 2,893 Swedish subjects with prostate cancer and 1,781 controls. To assess the individual and combined association of the SNPs with prostate cancer, the researchers associated multiple SNPs in each of the five regions with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. The researchers estimated that together, the five SNPs and family history accounted for 46% of the cases of prostate cancer in the study population. The five SNPs plus family history had a cumulative association with prostate cancer. In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46, compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis. The authors called their study “only a first step toward defining a genetic association with prostate cancer in populations.”An accompanying editorial by Edward P. Gelmann, MD, of Columbia University Medical Center in New York, N.Y. notes that the findings have more mechanistic than clinical importance because the five SNPs do not distinguish between indolent and aggressive prostate cancer. However, the ability to quantify risk prior to knowing family history or identification of a tumor via rising PSA level may be important in some cases, he writes.