We read with great interest Kielson and colleagues' report [1] of severe hypertriglyceridemia and pancreatitis associated with pregnancy and the administration of cholestyramine in two sisters heterozygous for the missense mutation GlyGlu at position 188 of the lipoprotein lipase (LPL) gene. The medical care and subsequent molecular characterization of these sisters were excellent. However, both homozygosity and heterozygosity for this same mutation have been reported to be associated with pregnancy-induced pancreatitis [2, 3]. The mechanism was presumed to be an estrogen-related exacerbation of a preexisting lipolytic defect of triglyceride clearance. However, this mutation alone clearly cannot account for the phenotype because all other female relatives who were carriers did not become chylomicronemic with pregnancy [2, 3].

Furthermore, the severe hypertriglyceridemia of pregnancy is not always caused by a structural abnormality of LPL. We recently described a woman with severe hypertriglyceridemia associated with pregnancy at the eighth week of gestation. After the administration of heparin, lipolytic activity in the nonpregnant state was normal in this patient; the coding sequence of her LPL gene was also normal [4]. However, our patient was a compound heterozygote for the apolipoprotein E4/2 genotype. Others have shown that the presence of variant isoforms of apolipoprotein E may contribute to hypertriglyceridemia [5], but as discussed by Kielson and colleagues, variant apolipoprotein E is not sufficient to cause the phenotype.

These exceptions show that heterozygosity for variant LPL, apolipoprotein E, or both is not necessary or sufficient for the explanation of severe pregnancy-induced hyperlipidemia. We suggest that the LPL mutation in the sisters described by Kielson and colleagues was ascertained because LPL was a good candidate gene and that the mutation was not the sole cause of the phenotype. A second variant genetic locus causing increased hormone-dependent synthesis of triglyceride-rich lipoproteins could possibly complete the explanation for hypertriglyceridemia in these patients.