Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification

Myocardial infarction and stroke often occur without prior warning in asymptomatic individuals. Identifying individuals at risk is important for cost-effective use of preventive therapies. Algorithms based on risk factors statistically associated with cardiovascular events classify individuals into high-risk, intermediate-risk, or low-risk categories. However, more than one-third of adults in the U.S. are in the intermediate-risk category, and decisions regarding therapy are challenging in this subset. Testing for alterations in arterial function and structure that predate cardiovascular events may help refine cardiovascular risk assessment in the intermediate-risk group and identify candidates for aggressive therapy. Vascular ultrasonography and tonometry are promising test modalities for assessment of arterial function and structure in asymptomatic subjects. Several prospective studies have shown that measures of arterial function and structure provide prognostic information incremental to conventional risk factors. Standardization of methodology and establishment of quality control standards in the performance of these tests could facilitate their integration into clinical practice as adjuncts to existing cardiovascular risk stratification algorithms

Evidence for Positive Selection in the C-terminal Domain of the Cholesterol Metabolism Gene PCSK9 Based on Phylogenetic Analysis in 14 Primate Species

Cholesterol homeostasis is maintained through finely tuned mechanisms regulating intestinal absorption, hepatic biosynthesis and secretion as well as plasma clearance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted enzyme of the serine protease family that reduces cellular uptake of plasma low-density lipoprotein (LDL) cholesterol by promoting LDL receptor (LDL-R) degradation. Species-specific positive selection has been noted in the LDLR promoter, leading to differential expression of LDLR among primates. Whether PCSK9 experienced significant selective pressure to maintain a functional relationship with its target protein, LDL-R, is unknown.We compiled the sequences of the coding regions of PCSK9 from 14 primate species in the clade of Hominoids, Old World monkeys and New World monkeys. To detect selective pressure at the protein level, the ratios of nonsynonymous/synonymous substitution rate (d(N)/d(S)) under different evolutionary models were calculated across the phylogeny of PCSK9. Maximum likelihood analyses of d(N)/d(S) ratios for the aligned coding region sequences among 14 primate species indicated that PCSK9 was subject to a strong functional constraint (i.e., purifying selection). However, positive selection was noted in the functional carboxyl-terminal (C-terminal) domain in many branches across the phylogeny, especially in the lineage leading to the orangutan. Furthermore, at least five positively selected amino acids were detected in this lineage using the branch-site model A. In a sliding-window analysis, several d(N)/d(S) peaks in the C-terminal domain in both the human and the orangutan branches were noted.These results suggest that among primates, differential selective pressure has shaped evolutionary patterns in the functional domains of PCSK9, an important regulator of cholesterol homeostasis

A Genome-Wide Association Study of Red Blood Cell Traits Using the Electronic Medical Record

The Electronic Medical Record (EMR) is a potential source for high throughput phenotyping to conduct genome-wide association studies (GWAS), including those of medically relevant quantitative traits. We describe use of the Mayo Clinic EMR to conduct a GWAS of red blood cell (RBC) traits in a cohort of patients with peripheral arterial disease (PAD) and controls without PAD.Results for hemoglobin level, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were extracted from the EMR from January 1994 to September 2009. Out of 35,159 RBC trait values in 3,411 patients, we excluded 12,864 values in 1,165 patients that had been measured during hospitalization or in the setting of hematological disease, malignancy, or use of drugs that affect RBC traits, leaving a final genotyped sample of 3,012, 80% of whom had ≥2 measurements. The median of each RBC trait was used in the genetic analyses, which were conducted using an additive model that adjusted for age, sex, and PAD status. We identified four genomic loci that were associated (P<5 × 10(-8)) with one or more of the RBC traits (HBLS1/MYB on 6q23.3, TMPRSS6 on 22q12.3, HFE on 6p22.1, and SLC17A1 on 6p22.2). Three of these loci (HBLS1/MYB, TMPRSS6, and HFE) had been identified in recent GWAS and the allele frequencies, effect sizes, and the directions of effects of the replicated SNPs were similar to the prior studies.Our results demonstrate feasibility of using the EMR to conduct high throughput genomic studies of medically relevant quantitative traits