Association of rs2072183 SNP and serum lipid levels in the Mulao and Han populations

Ma, Lin; Yin, Rong; Hu, Xi‐Jiang; Wu, Dong‐Feng; Cao, Xiaoli; Li, Qing; Yan, Tingting; Aung, Lynn Htet Htet; Wu, Jin‐Zhen; Lin, Wei

doi:10.1186/1476-511x-11-61

Cited by 11 publications

(17 citation statements)

References 59 publications

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“…In both the Mulao and Han Chinese subsets, as well as in our data, the rs2072183 minor G allele was associated with an increase in total cholesterol in males. Although Miao et al (27) did not correct for multiple comparisons, we did fi nd a similar effect in our data for NPC1L1 SNP rs17725246, with the SNP effect on total cholesterol (TC) marginally signifi cant in males ( P = 0.054) and not females ( P = 0.94), and the ␤ coeffi cient indicating an increase in cholesterol levels in males only . Thus, we have identifi ed a potential explanation for the reported lack of this SNP's association with total cholesterol in females: differential absorption or processing of dietary cholesterol based on NPC1L1 genotype in males, which is not detectable in females.…”

Section: Discussionsupporting

confidence: 52%

“…The overall the marginal effect of the SNP on total cholesterol by gender and found that NPC1L1 SNP rs17725246 marginally predicted total cholesterol in males only (SNP effect ␤ coeffi cient = 5.2, P = 0.054) and not in females ( ␤ = Ϫ 0.243, P = 0.941) in this cohort. We formally tested for a SNPby-sex interaction effect in the prediction of total cholesterol and found it not signifi cant ( ␤ = Ϫ 5.258, P = 0.24); however, we identifi ed a report of this gender interaction in the literature ( 27 ). Although underpowered, we modeled a SNP-by-dietary cholesterol-by-sex interaction in the pooled analyses and found that the rs17725246-sex-dietary cholesterol interaction term was suggestive given limited power (SNP-by-dietary cholesterol-by-sex interaction beta coeffi cient = Ϫ 25.318, P = 0.096).…”

Section: Resultsmentioning

confidence: 90%

“…In humans, in vitro experiments have demonstrated the potential molecular mechanisms through which nonsense variants affect cholesterol absorption: namely, through impairment of NPC1L1 recycling, localization, glycosylation, or stability ( 40 ). Recently, Miao et al ( 27 ) reported a sexdependent difference for NPC1L1 SNP rs2072183 minor allele association with total cholesterol levels in a Mulao Chinese cohort of 688 subjects and 288 males (SNP × sex interaction, P = 0.03); while this interaction test was not signifi cant in a Han Chinese cohort of 738 subjects (274 males), the rs2072183 SNP effect in the Han subset was signifi cant in males, but not in the females. In both the Mulao and Han Chinese subsets, as well as in our data, the rs2072183 minor G allele was associated with an increase in total cholesterol in males.…”

Section: Discussionmentioning

confidence: 99%

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Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words dietary cholesterol • total cholesterol • cardiovascular disease • Niemann-Pick C1-like 1 Cardiovascular disease (CVD), including coronary heart disease and carotid artery disease (CAAD), is the leading cause of death in developed countries, accounting for approximately one-third of all deaths in adults over age 35 ( 1 ). One of the key risk factors for CVD is hypercholesterolemia ( 2 ), with epidemiologic studies demonstrating a graded relationship between total plasma cholesterol and CVD risk ( 3 ). Levels of total cholesterol and other lipids and lipoproteins are both heritable and targets for pharmacologic and lifestyle interventions ( 4 ). One of the primary methods of lifestyle intervention to alter lipid levels is through dietary changes, such as decreasing total fat intake ( 5, 6 ).Genome-wide association studies (GWASs) have implicated numerous genetic loci for association with total cholesterol levels. A recent meta-analysis by Teslovich et al. ( 7 ) of over 100,000 individuals of European ancestry confi rmed numerous previous GWAS fi ndings and identifi ed novel variants and loci for prediction of total lipid phenotypes, including total cholesterol levels.While genetic evidence is accumulating for many of these loci, less is known about the specifi c mechanisms through which these genetic variants affect cholesterol levels. We hypothesized that one pathway through which these genetic variants could alter cholesterol homeostasis is through differential absorption or processing of dietary Abstract Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both infl uence plasma cholesterol; however, little is known about dietary interactions with genetic variants infl uencing the absorption and transport of dietary cholesterol . We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes ( APOB , CETP , and NPC1L1 ) were signifi cantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for geneby-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with signifi cant fi ndings tested for replication. Novel GxE interactions were identifi ed and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5 ′ of NPC1L1 . This study identifi es the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" no...

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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“…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]. Recently, the rs2072183 genotype distribution was found to be significantly different in dyslipidemic vs. healthy Japanese individuals [59].…”

Section: Discussionsupporting

confidence: 52%

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

et al. 2015

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“…The rs2072183 polymorphism is the top SNP within the NPC1L1 gene most significantly associated with an increased plasma LDL-C level according to a genomewide analysis of Caucasians. However, this polymorphism appears to be associated with reduced LDL-C levels in East Asians 17) , and other recent studies have demonstrated that the rs2072183 polymorphism is associated with increased cholesterol levels in men only and may interact with dietary cholesterol to determine the cholesterol levels 18,19) . It is also possible that mutations in NPC1L1 or polymorphisms in some other genes influencing cholesterol absorption or other pathways inherited from the mother, who also had a low LDL-C level (1.7 mmol/L), may have contributed to the reduced plasma sitosterol, campesterol and LDL-C levels in the affected sibling relative to the proband.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

Yuen

Kwok

et al. 2014

JAT

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increased absorption and decreased biliary excretion of cholesterol (similar to plant sterols), usually have normal to moderately elevated plasma cholesterol levels, despite the downregulation of endogenous cholesterol synthesis in hepatocytes 4) . Intestinal sterol/cholesterol absorption is governed by three key transporter molecules, including the two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8 (previously known as sterolin-1 and -2, respectively), which heterodimerise to form a sterol efflux transporter in the liver and intestine to transport sterols (cholesterol and plant sterols) and the Niemann-Pick C1-like 1 (NPC1L1) transporter, a polytopic transmembrane protein that mediates intestinal absorption of cholesterol and sterols 5) . Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8 6) . It has been estimated that sitosterolaemia occurs in 1 in 5 million people, although the true Introduction Sitosterolaemia (MIM #210250) is a very rare autosomal recessive disease characterized by excessive absorption and high plasma levels (＞30-fold) of plant sterols, particularly sitosterol and campesterol, the two major plant-derived sterols 1,2) . The clinical manifestations include tendon and tuberous xanthomas and premature atherosclerotic disease as a result of sterol deposition in the skin, tendons and coronary arteries [1][2][3] . Patients with sitosterolaemia, in whom there is Sitosterolaemia is caused by mutations in either ABCG5 or ABCG8. Chinese and Japanese individuals usually have mutations in ABCG5. We herein report a known and a novel mutation in ABCG8 and their potential interaction with NPC1L1 polymorphisms in a Chinese family with sitosterolaemia. We sequenced ABCG5 and ABCG8 and measured the levels of plasma plant sterols in a 15-yearold Chinese girl with clinical sitosterolaemia (xanthomas with elevated low-density lipoprotein cholesterol (LDL-C) and plant sterols) and her apparently healthy family members. NPC1L1 was sequenced in the genetically affected sibling and other family members. A known mutation, c.490C＞T (p. Arg164 ＊ ), in exon 4 and a novel mutation, c.1949T＞G (p.Leu650Arg), in exon 13 of ABCG8 were detected in the proband and her sister, who had elevated sterols but low LDL-C levels and no xanthomas. The genetically affected sister, but not the proband, carried two additional heterozygous changes in NPC1L1 (rs2072183 C＞G, rs2301935 A＞C), which were inherited from the mother, who also had a low LDL-C level. In this study, we detected a known and a novel mutation in ABCG8 in a Chinese patient with sitosterolaemia. The same mutations were found in her clinically normal sister, suggesting that the contrasting features with the proband may be related to different variants in NPC1L1 and/or some other undetermined lipid-related genetic factors. J Atheroscler Thromb, 2014; 21:989-995.

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Association of rs2072183 SNP and serum lipid levels in the Mulao and Han populations

Cited by 11 publications

References 59 publications

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

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

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

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