Hepatic Lipase C-480T Genotype-Dependent Benefit from Long-Term Hormone Replacement Therapy for Atherosclerosis Progression in Postmenopausal Women

Hepatic lipase (HL) is a lipolytic enzyme that hydrolyzes triglycerides and phospholipids in almost all major classes of lipoproteins. The HL gene has a functional promoter polymorphism at position -480, which affects transcription and leads to CC, CT, and TT genotypes. We investigated the effect of long-term hormone replacement therapy (HRT) on the progression of atherosclerosis in a 5-yr follow-up observational study of 88 postmenopausal women with different HL genotypes (CC, n = 49; CT, n = 34; TT, n = 5). These women, aged 45-71 yr, were divided into three groups based on the use of HRT. The HRT-EVP group (n = 26) used sequential estradiol valerate (EV) plus progestin (levonorgestrel), the HRT-EV group used EV alone (n = 32), and the control group (n = 30) used no HRT. The HRT-EV and HRT-EVP groups started estrogen at menopause for estrogen-deficiency symptoms, whereas the control group took no estrogen due to either the absence of such symptoms or a dislike of estrogen therapy. In addition to serum lipid concentration and HL genotype, the atherosclerosis severity score (ASC) for the abdominal aorta and carotid arteries was determined by ultrasonography. There was a significant interaction between HRT therapy and HL genotypes on the increase in ASC (P = 0.046) after adjustment for age, body mass index, changes in high-density lipoprotein cholesterol and baseline ASC. In subjects with the T allele, the progression of ASC was significantly faster in the control group than the HRT group (P = 0.0006), whereas in the CC genotype, there were no significant differences in ASC progression between the control and HRT groups. Our results suggest that the beneficial effect of HRT on atherosclerosis progression was restricted to women with the T allele, in whom the progression of ASC was slower by half. These results may help us understand in greater detail the benefits and possible risks associated with HRT in atherosclerotic diseases.