The g.−762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels

Abstract

Niemann-Pick type C1-like 1 (NPC1L1) protein is responsible for intestinal cholesterol absorption. The aim of the study was to identify genetic polymorphisms of the NPC1L1 gene as well as their functional significance. The method involved screening of promoter and coding regions of the NPC1L1 gene for genetic polymorphisms by direct DNA sequencing of genomic DNA from 50 individuals. Functional studies on promoter polymorphisms were performed using luciferase assay. Association between the polymorphisms and serum cholesterol levels were investigated in 224 individuals. The results showed that in total, 11 single nucleotide polymorphisms were identified. Among them, a promoter polymorphism, g.À762T4C, and a synonymous polymorphism, g.1679C4G, were common (34 and 36%, respectively). These two polymorphisms were highly linked (D¢ value¼0.7459, P-value o0.00001). For the g.À762T4C promoter polymorphism, luciferase assay in HepG2 cell line demonstrated that the À762C allele had a significantly higher promoter activity than the À762T allele (1.30 ± 0.22 vs 0.37 ± 0.06, 3.5-fold, Po0.05). We also showed that the NPC1L1 promoter activity was downregulated by cholesterol content in both genotypes. When association studies were performed, we found that À762C allele was associated with significantly higher serum total cholesterol and LDL-cholesterol content levels in a recessive model (LDL-cholesterol value¼131.2 ± 8.1 vs 116.4 ± 2.2 mg dl -1 ; total cholesterol value¼214.7 ± 9.0 mg dl -1 vs 196.9 ± 2.6, P-value o0.05, n¼224). In conclusion, the C allele at À762 position of the NPC1L1 gene was common in people of Chinese ethnicity. The À762C allele had a higher promoter activity and was associated with a higher serum total cholesterol and LDL-cholesterol level.

Efficacy of Ezetimibe Is Not Related to NPC1L1 Gene Polymorphisms in a Pilot Study of Chilean Hypercholesterolemic Subjects

“…There was no relation reported between this allele and basal cholesterol levels in control subjects from different ethnic backgrounds [46]. Similarly, it was not associated with cholesterol levels in subjects from Taiwan [55], similar to results obtained elsewhere [56]. Nevertheless, this variant was associated with higher total cholesterol levels in 127 Japanese subjects with Crohn's disease [57] and was documented to cause different plasma lipid profiles between the Mulao and Han populations in China [58].…”

A SNP of NPC1L1 Affects Cholesterol Absorption in Japanese

“…Recently, several studies have focused on NPC1L1 genotypes in different ethnic groups [16][17][18] . For instance, Chen CW et al reported that the 762 T C (relative to the translation start site) polymorphism was associated with higher TC and LDL-C levels in a Chinese population, possibly because of the higher NPC1L1 expression in those with the 762 C than 762 T allele 19) . We analyzed this polymorphism as well.…”

Polymorphisms of the Niemann-Pick C1-like 1 gene in a Japanese population

“…Furthermore, Siomon et al (12) reported that the minor allelic frequency was 21.9, 28.3 and 17.9% in healthy Caucasians, African Americans and Hispanics, respectively. In Asian populations, Chen et al (22) analyzed the genetic polymorphisms of the NPC1L1 gene in a Chinese population and found that the frequency of the minor allele was 35.7% and the frequencies of the CC and GG genotypes were 39.3 and 10.7%, respectively. These were lower compared to the results of the present study.…”