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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2935-2939.)
© 1997 American Heart Association, Inc.

Articles

Two Alleles of the Human Paraoxonase Gene Produce Different Amounts of mRNA

An Explanation for Differences in Serum Concentrations of Paraoxonase Associated With the (Leu-Met54) Polymorphism

Ilia Leviev; Franco Negro; ; Richard W. James

From the Clinical Diabetes Unit, Division of Endocrinology and Diabetes (I.L., R.W.J.) and the Division of Gastroenterology (F.N.), University Hospital, Geneva, Switzerland.

Correspondence to Dr Richard W. James, Clinical Diabetes Unit, Division of Endocrinology and Diabetes, University Hospital, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail Richard-James{at}hcuge.ch

Abstract In a recent study we demonstrated that a polymorphism of the human paraoxonase gene affecting position 54 was linked to variations in serum concentrations of the enzyme. L allele carriers (leucine at position 54) have significantly higher concentrations of paraoxonase than M allele carriers (methionine at position 54). In the present study we examined the hypothesis that differences in mRNA production could contribute to variations in serum concentrations. Relative concentrations of L and M type mRNA were analyzed in total RNA extracted from heterozygous liver samples. This was achieved by cDNA synthesis, polymerase chain reaction amplification of the cDNA fragment containing the 54 polymorphism and restriction analysis to identify radiolabeled end fragments of L and M alleles. An allele mixing experiment using total RNA from liver samples of LL and MM homozygotes demonstrated the sensitivity of the approach to changes in the relative concentrations of each type of RNA. In 8 of 10 heterozygous samples, an excess of L allele type mRNA was observed. Overall there was a significantly higher level of L type mRNA (L:M ratio of 2.51±1.41, n=10, P<.01). These results support our hypothesis that increased concentrations of serum paraoxonase arise from greater production of L allele mRNA. In two samples, the L:M ratio was close to or below 1.0. This is consistent with the known spectrum of paraoxonase serum concentrations associated with the L and M alleles and suggests that factor(s) that preferentially modulate allele expression are usually, but not uniformly, associated with the L allele.

Key Words: atherosclerosis • HDL • LDL • oxidative stress

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