LPL methylation of peripheral blood leukocytes - Prophet of atherothrombotic stroke

Abstract Background: Lipoprotein lipase (LPL) is a glycoprotein enzyme playing a pivotal role in energy and lipoprotein metabolism. It hydrolyzes triglyceride-rich lipoprotein and produces fatty acids as well as monoacylglycerol. Multiple risk factors including age, sex, hypertension, smoking and hyperlipidemia contribute to ischemic stroke (IS). Hyperlipidemia is an extremely pivotal risk factor for ischemic stroke especially atherothrombotic stroke (ATS) in that it can lead to intracranial or extracranial vessels’ atherosclerosis analogous to atherosclerosis of coronary artery. However, potential epigenetic mechanisms contributing to IS are not been explored thoroughly. The aim of this study was to illuminate relationship among individuals’ peripheral blood leukocytes methylation level of LPL-promoter-CpG dinucleotides, serum lipid and ATS of Chinese Han population in Hunan Province. Methods: Peripheral blood samples were collected from acute atherothrombotic stroke patients and healthy people, and methylation level of cytosine–phosphate–guanine (CpG) island in LPL promoter region was measured by qPCR and pyrosequencing. Biochemical and anthropometric variables have also been taken into consideration.Results: Integral LPL-promoter-CpG dinucleotides methylation level of case group is evidently higher than control group (38.8±8.4% percentile vs 25.7±6.6% percentile, P value=0.000). DNA methylation at the CpG9~16 locus and CpG20~21 locus was related to ATS after adjusting for gender, previous history of diabetes and hypertension, smoking, drinking, body mass index, and blood lipid levels(CpG9 49.3±24.9, 31.3±13.6, P value =0.02; CpG10 61.3±24.5, 34.0±18.4, P value =0.002; CpG11 71.3±17.3, 32.0±21.1, P value =0.000; CpG12 75.3±17.7, 44.7±19.6, P value =0.000; CpG13 72.0±20.4, 50.0±25.4, P value =0.014; CpG14 63.3±18.0, 45.3±22.0, P value =0.021; CpG15 56.7±13.5, 34.7±14.6, P value =0.000; CpG16 50.0±12.5, 31.3±20.0, P value =0.005; CpG20 52.0±13.2, 27.3±20.9, P value =0.001; CpG21 55.3±11.9, 34.0±22.3, P value =0.004). There is no statistically significant connection between either carotid atherosclerosis or gender and methylation level. Besides, we found a negative association between LPL methylation status and HDL-C levels, whereas LPL gene methylation was linked with LDL-C levels and age positively.Conclusion: We illustrate that epigenetic modification of LPL methylation may have an influence on lipids metabolism and occurrence of ATS, which may be a promising indicator for occurrence risk of ischemic stroke. Whether these findings are valid need further warrant and future prospective.