Kevin R. Viel

Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in Percutaneous Coronary Intervention

Several definitions have been used to assess rates of contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). Whether the definition influences observed rates of CIN is unclear. The Oxilan Registry was the first-ever prospective analysis of the efficacy and safety of ioxilan (low-osmolar and low-viscosity contrast medium), including rates of CIN assessed by multiple definitions, in PCI. From July 2006 to June 2007, consecutive patients undergoing PCI using ioxilan were enrolled. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were assessed at baseline and 3 to 5 days after PCI. CIN was defined as SCr increase >or=0.5 mg/dl, eGFR decrease >or=25%, SCr increase >or=25%, or the composite. Of 400 patients (age 62 +/- 11 years), 19% were women, 37% were diabetic, 22% were anemic, and 8% had a history of congestive heart failure. Baseline SCr was 1.12 +/- 0.3 mg/dl and 24% had an eGFR <60 ml/min. CIN rates were 3.3% (SCr increase >or=0.5 mg/dl), 7.6% (eGFR decrease >or=25%), 10.2% (SCr increase >or=25%), and 10.5% (composite). Hospitalization was prolonged in 3.4% of patients with CIN and none required dialysis. There were no deaths or severe allergic reactions. Non-ST-elevation myocardial infarction and repeat revascularization each occurred in 0.8%. In conclusion, in this unselected population undergoing PCI, CIN ranged in frequency from 3.3% to 10.5% depending on the definition used and was not associated with in-hospital mortality or substantial morbidity, such as dialysis. The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition.

Genetic determinants of normal variation in coagulation factor (F) IX levels: Genome-wide scan and examination of the FIX structural gene

Summary.  Background: High‐normal and elevated plasma FIX activity (FIX:C) levels are associated with increased risk for venous‐ and possibly arterial‐thrombosis. Objective: Because the broad normal range for FIX:C involves a substantial unknown genetic component, we sought to identify quantitative‐trait loci (QTLs) for this medically important hemostasis trait. Methods: We performed a genome‐wide screen and a resequencing‐based variation scan of the known functional regions of every distinct FIX gene (F9) in the genetic analysis of idiopathic thrombophilia project (GAIT), a collection of 398 Spanish‐Caucasians from 21 pedigrees. Results: We found no evidence for linkage (LOD scores <1.5) despite genotyping more than 540 uniformly‐spaced microsatellites. We identified 27 candidate F9 polymorphisms, including three in cis‐elements responsible for the increase in FIX:C that occurs with aging, but found no significant genotype‐specific differences in mean FIX:C levels (P‐values ≥ 0.11) despite evaluating every polymorphism in GAIT by marginal multicovariate measured‐genotype association analysis. Conclusions: The heritable component of interindividual FIX:C variability likely involves a collection of QTLs with modest effects that may reside in genes other than F9. Nevertheless, because the alleles of these 27 polymorphisms exhibited a low overall degree of linkage disequilibrium, we are currently defining their haplotypes to interrogate several highly‐conserved non‐exonic sequences and other F9 segments not examined here.

Observations regarding the immunogenicity of BDD-rFVIII derived from a mechanistic personalized medicine perspective

Author(s): Sauna, ZE; Ameri, A; Kim, B; Yanover, C; Viel, KR; Rajalingam, R; Cole, SA; Howard, TE

A linkage analysis of cigarette and alcohol consumption in an unselected Mexican American population.

The use of alcohol and tobacco is highly prevalent. Studying the rate of consumption in a non‐selected population could contribute to the elucidation of pathways involved in addiction or to the development of prevention programs. The San Antonio Family Heart Study has approximately 1,400 members with longitudinal data and did not select the proband with regard to exposure status. The goal of this study was to perform genome‐wide linkage analysis of the rate of alcohol and cigarette consumption in a “normal” population. We used SOLAR to perform variance‐components based analysis of the transformed maximal rate of consumption. Despite estimated heritabilities of 0.52 (P < 0.001) for cigarette and 0.39 (P < 0.001) for alcohol consumption, univariate linkage analyses produced only suggestive LOD scores, however the second suggestive linkage peak for the alcohol phenotype was present at 148 cM on chromosome 10, in the exact vicinity of the peak for the cigarette phenotype. In a bivariate analyses, the environmental correlation between alcohol and cigarette consumption was not significantly different from zero (ρe = −0.15, P = 0.18) and the overall genetic correlation was not different from zero (ρg = 0.16, P = 0.34). The results from the bivariate linkage analysis found a maximum LOD score of 3.82 (genome‐wide P = 0.0054) at 151 cM on chromosome 10, at the location of the overlapping peaks from the univariate analyses.

A comparison of discrete versus continuous environment in a variance components-based linkage analysis of the COGA data

BackgroundThe information content of a continuous variable exceeds that of its categorical counterpart. The parameterization of a model may diminish the benefit of using a continuous variable. We explored the use of continuous versus discrete environment in variance components based analyses examining gene × environment interaction in the electrophysiological phenotypes from the Collaborative Study on the Genetics of Alcoholism.ResultsThe parameterization using the continuous environment produced a greater number of significant gene × environment interactions and lower AICs (Akaikes information criterion). In these cases, the genetic variance increased with increasing cigarette pack-years, the continuous environment of interest. This did not, however, result in enhanced LOD scores when linkage analyses incorporated the gene × continuous environment interaction.ConclusionAlternative parameterizations may better represent the functional relationship between the continuous environment and the genetic variance.