Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q.

Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results. We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06). Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.

A diastereoselective intramolecular hydroamination approach to the syntheses of (+)-, (+/-)-, and (-)-pinidinol.

A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts were examined using a model substrate to allow optimization of the diastereoselectivity. It was determined that the relationship between metal size and ligand bulk plays an integral role in the transformation. The complex Cp2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines to 2,6-disubsituted piperidines with greater than 100:1 selectivity for the formation of the cis isomer. A short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then carried out to exploit this stereoselective reaction.

Effect of orthotopic liver transplantation on employment and health status.

Employment, functional status, health status, and prevalence of anxiety and depression were assessed in patients who had undergone orthotopic liver transplantation at Duke University from 1984 to 1993 to identify social and economic factors that might influence return to work after liver transplantation. Patients were asked to complete mailed questionnaires. A transplant nurse coordinator assigned patients a Karnofsky score, unaware of the questionnaire responses. The response rate was 71% (52 of 72 patients). The median age of the post-liver transplantation patients was 49 years. Median years of education were 13. Sixty-five percent of patients were male. Sixty percent of patients were employed posttransplantation. Employed and unemployed posttransplantation patients showed no significant difference in age, education, gender, marital status, race, family coping skills, or cause of liver disease. Return to work after transplantation did not correlate with socioeconomic status or spouse's employment. Posttransplantation return to work was highly correlated with pretransplant employment (P < .0005). The prevalence of anxiety and depression, assessed by the Hospital Anxiety and Depression Scale (HAD), was 9% and was no different in the employed or unemployed patients. Health status, as measured by Karnofsky score, was excellent; all patients received Karnofsky scores > or = 80%. Health perceptions were compared in employed versus unemployed posttransplantation patients with the SF-36, a 36-item short form survey developed by the investigators of the Medical Outcome Study. This revealed significantly different values in the subscale, physical functioning, with a mean score of 70.6 in the employed and a mean score of 48.4 in the unemployed posttransplantation patients (P = .004) and role-physical with a mean score of 61.8 in the employed and a mean score of 27.6 in the unemployed posttransplantation patients (P = .005). Eighty percent of patients not returning to work cited "problems with their health" as their major obstacle to employment. Although objective health status was good to excellent in all patients after transplantation, patients perceived that their health status was poor, with the lowest scores observed in unemployed posttransplantation patients.