Combined PCSK9 and APOE Polymorphisms are Genetic Risk Factors Associated with Elevated Plasma Lipid Levels in a Thai Population

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apolipoprotein E (ApoE) play a key role in the regulation of lipid metabolism. We aimed to investigate the effects of PCSK9 (R46L, I474V, and E670G) and APOE polymorphisms on lipid levels in a Southern Thai population. A total of 495 participants (307 urban, 188 rural) were recruited for the study. Anthropometric and biochemical variables were evaluated. PCSK9 and APOE polymorphisms were analyzed using PCR-RFLP. The 46L urban male carriers had significantly higher diastolic blood pressure (DBP) and fasting blood sugar compared with non-carriers. In contrast, the 46L urban female carriers had significantly lower total cholesterol (TC) and LDL-C levels compared with non-carriers. The 474V rural female carriers had significantly lower HDL-C levels than non-carriers. The 670G urban female carriers showed significantly higher TC and LDL-C levels compared with non-carriers. APOE4 carriers had increased TC and LDL-C levels relative to APOE3 carriers in the urban males. APOE2 carriers had decreased TC and/or LDL-C levels compared with APOE3 carriers in urban males and females. A significant trend of increased TC and LDL-C levels was observed in non-APOE4-PCSK9 670EE carriers to APOE4-PCSK9 670EG carriers in urban subjects. In summary, R46L, I474V, and E670G may be genetic risk factors for cardiovascular disease (CVD) in urban males, rural females, and urban females, respectively. In contrast, R46L had a favorable lipid profiles that may protect against CVD in urban females. The combination of PCSK9 E670G and APOE polymorphisms may represent an independent factor for the determination of lipid levels.

The effect of APOE, CETP, and PCSK9 polymorphisms on simvastatin response in Thai hypercholesterolemic patients

“…In addition, the frequency of PCSK9 474V allele was 1.78% in this study. Our finding was similar to a previous report in the Thai population (1.86%) . However, the higher frequency of 474V allele has been observed in Japanese (2.48%), Brazilian (19.10%‐21.6%), African Canadian (19.40%), and African American (22%) populations.…”

“…Previous studies have also reported that E4 allele is generally associated with increased plasma cholesterol and LDL‐C, and E2 allele is associated with decreased plasma cholesterol and LDL‐C compared with the E3 allele . The allele frequencies of the APOE polymorphisms (E2 7.11%, E3 79.56%, E4 13.33%) in this study were similar to previous reports among the Thai population (E2 7.18%‐10.42%, E3 77.04%‐77.51%, E4 12.54%‐15.43%) . APOE4 allele in our study was higher than Japanese (10.5%), Han Chinese (7.5%), Taiwanese (7.5%), and Korean (9%) populations but lower than the Malaysian population (20.20%) .…”

“…In this study, PCSK9 46L allele was 0.44%. This result was similar to Thai (0%‐2.28%), black (0.28%), and Hispanic (0.75%) populations, whereas the higher frequency of 46L allele was observed in Caucasian individuals (2.40%) and the French Canadian population (4.80%) . In addition, the frequency of PCSK9 474V allele was 1.78% in this study.…”

“…Gain‐of‐function and loss‐of‐function PCSK9 mutations are associated with hypercholesterolemia and hypocholesterolemia, respectively . Moreover, PCSK9 polymorphisms have been reported to be associated with LDL‐C levels, LDL‐C lowering response to statins, and risk of premature CVD and ischemic stroke …”

“…The quality and quantity of DNA were estimated using a NanoDrop 2000 UV‐Vis spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA, USA). Genotyping of APOE (rs429358, rs7412); CETP TaqIB (rs708272); and PCSK9 R46L (rs11591147), I474V (rs562556), and E670G (rs505151) polymorphisms were performed using polymerase chain reaction‐restriction fragment length polymorphism (PCR–RFLP) as previously described …”