An evaluation of lipid abnormalities found in renal and cardiac transplant patients: The role of apolipoprotein E phenotype

38TH ANNUALCONFERENCE OF THE CANADIANSOCIETY OF CLINICALCHEMISTS GENETIC SCREENING FOR F A M I L I A L H Y P E R C H O L E S T E R O L E M I A IN FRENCH CANADIANS Chamberland, A., Lavigne, J., Davignon, J., and Minnich, A., Clinical Research Institute of Montreal, Hyperlipidemia and Atherosclerosis Research Group, 110 Pine Ave West, Montreal, Quebec, H2W 1R7 The frequency of familial hypercholesterolemia (FH) in Quebec is twice that observed in most population samples. FH heterozygotes have severely elevated plasma LDLcholesterol associated with tendon xanthomas and accelerated atherosclerosis. In general, FH is caused by any of over 200 known mutations in the gene encoding the LDL receptor, which is normally responsible for the catabolism of plasma LDL. Due to a genetic founder effect, 5 mutations in the LDL-receptor gene account for approximately 87% of FH diagnosed in French Canadians. The most frequent mutation, present in 62% of heterozygotes, is a >10kb deletion of the 5' region of the gene which removes the promotor and the first exon, resulting in a null allele. In addition, a gene deletion of approximately 5kb removes exons 2 and 3 (2% of cases) and three missense mutations are: Yrp66 ---->Gly (exon 3) (13%), Glu207 ~ Lys (exon 4) (3%) and Cys646 Tyr (exon 14) (7%). The >10 and 5 kb deletions are detected by Southern blotting of genomic DNA. Missense mutations are rapidly detected by enzymatic digestion of PCR-amplifled DNA for exons 3 and 4, and by competitive oligonucleotide priming of the PCR and fluorescence analysis for exon 14. Thus, the French Canadian population presents a rare opportunity for early screening of FH, potentially allowing for early intervention and prevention of hypercholesterolemia and premature atherosclerosis. In addition, large numbers of subjects with identical LDL receptor mutations allows the study of factors which determine the large amount of phenotypic variability observed in FH.

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AN EVALUATION OF LIPID ABNORMALITIES FOUND IN RENAL AND CARDIAC TRANSPLANT PATIENTS: THE ROLE OF APOLIPOPROTEIN E PHENOTYPE Crawhall, J.C., Gilfix, B.M., and Pomerleau, V., D6partement de biochimie, H6pital Notre-Dame, 1560 est, Sherbrooke, Montr6al, QC, H2L 4M1

In order to better understand the various factors controlling serum cholesterol and triglyceride levels in (post)transplant patients, we have compared the serum total cholesterol and triglyceride levels in 450 non-transplant patients (representing consecutive requests for these determinations), 30 cardiac transplant patients, and 110 renal transplant patients. Analysis of the results showed cholesterol levels decreasing in the following order: cardiac transplant patients

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> renal transplant patients > non-transplant patients. Triglyceride values were more variable but showed a similar order. Apolipoprotein E (apoE) phenotypes were determined on 110 of the non-transplanted patients and on all the transplant patients by isoelectric focusing. The distribution of the E2, E3 and E4 isoforms of apoE was not significantly different among these groups. The total cholesterol values were frequently in the accepted reference range at the time of transplantation but increased significantly in the months post-transplantation. The relative increase in these values have been evaluated graphically and correlated with the apoE phenotype. Only cardiac transplant patients with the E3/E3 phenotype and renal transplant patients those with the E3/E3 and E3/4 phenotypes had a statistically significant increase in cholesterol post-transplant as compared to pre-transplant. The existence of increased cholesterol in transplant patients indicates a significant risk for accelerated ischemic heart disease which is particularly important for those transplanted at a younger age.

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DRAMATIC REDUCTION IN SERUM LIPOPROTEIN (A) BY NIACIN: CASE REPORT Dembinski, T.C.*, Nixon, R*, Mymin, D. +, Angel, A. +, Ren, S. +, and Shen, G.X. +, Department of Clinical Chemistry*, Health Sciences Centre and Department of Internal Medicine +, University of Manitoba, 820 Sherbrook St., Winnipeg, Manitoba, R3A 1R9, Canada Diet, lifestyle or pharmacological treatment of high serum lipoprotein (a) [Lp(a)] concentrations have on the whole been unsatisfactory. Nicotinic acid (niacin) is one of the few hypolipidemic agents shown to consistently lower Lp(a). Responses to niacin on Lp(a) have in general not exceeded 50% reductions. We are therefore reporting the following case which demonstrated a dramatic reduction of circulating Lp(a) levels in response to niacin. Patient EF, a 64 year old male, was enroled September 1991 at the Health Sciences Centre Lipid Clinic. Significant clinical history was a myocardial infarction 3 months prior and long standing hypertension. Niacin in increasing doses was started on month 7 post entry to Clinic for his high apolipoprotein (a) [apo(a)] (as determined by Pharmacia RIA) and low (0.7 mmol/L) HDL cholesterol (HDL -C) levels. Peak dosage of niacin (4 g/day) reduced serum apo(a) by 95% of the entry level (1554 U/L). Dose was reduced to titrate the effect; 2 g/d niacin was less suppressive (51% of initial level). The strongest inverse correlation observed was between doses of niacin received by the patient and his serum apo(a) level (r= -0.90, p<0.01). A less significant level of inverse correlation was found between niacin doses and total (r= -0.83, p<0.05) or LDL -C (r= -0.82, p<0.05). Correlations between HDL -C or triglycerides versus niacin were not significant. These results suggest that niacin may

CLINICALBIOCHEMISTRY,VOLUME 27, JUNE 1994