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

Kim, Daniel S.; Burt, Amber; Ranchalis, Jane; Jarvik, Ella R.; Rosenthal, Elisabeth; Hatsukami, Thomas S.; Furlong, Clement E.; Jarvik, Gail P.

doi:10.1194/jlr.p035238

Cited by 31 publications

(31 citation statements)

References 49 publications

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“…Further work is needed to elaborate the role that PCIF1 plays in PLTPa. on lipid levels ( 47,59 ), leading to a more conservative estimate of the effect of PLTPa on CAAD status.…”

Section: Discussionmentioning

confidence: 99%

“…The study population is a subset (n = 1,115) of the previously described CLEAR study ( 8,(10)(11)(12)(40)(41)(42)(43)(44)(45)(46)(47) PLTP region SNP associations with PLTPa. SNPs with у 1% frequency identifi ed in the PLTP region between 50 kb upstream of the fi rst codon or downstream of the last (n = 124 SNPs) were included in our analyses of the genetic predictors of PLTPa.…”

Section: Samplementioning

confidence: 99%

“…Therefore, in the model predicting CAAD status, we adjusted PLTPa for the effects of statin use by subtracting the covariate-adjusted difference in PLTPa from statin use in controls ( Ϫ 1.02, n = 601) using a previously described method ( 47,59,60 ).…”

Section: Samplementioning

confidence: 99%

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PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Kim

Burt

Ranchalis

et al. 2015

Journal of Lipid Research

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Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline ( 1, 2 ). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women ( 2 ). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline ( 3 ).In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9 ), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels ( P = 0.0042), diabetes ( P = 7.28 × 10 ؊ 5 ), paraoxonase 1 (PON1) activity ( P = 0.019), statin use ( P = 0.026), PLTP SNP rs4810479 ( P = 6.38 × 10 ؊ 7 ), and PCIF1 SNP rs181914932 ( P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of

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“…Further work is needed to elaborate the role that PCIF1 plays in PLTPa. on lipid levels ( 47,59 ), leading to a more conservative estimate of the effect of PLTPa on CAAD status.…”

Section: Discussionmentioning

confidence: 99%

Section: Samplementioning

confidence: 99%

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PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Kim

Burt

Ranchalis

et al. 2015

Journal of Lipid Research

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“…One of these hypotheses is that geneby-environment interactions among common SNVs comprise a large portion of heritability ( 18,19 ). Given the wide variety of pharmacologic and dietary determinants on PON1 expression and enzyme activity ( 20 ), the potential interaction of these environmental factors with PON1 variants could represent another important source of trait heritability.…”

Section: Discussionmentioning

confidence: 99%

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

Kim

Crosslin

Auer

et al. 2014

Journal of Lipid Research

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PON1Val109Ile (overall P = 7.88 × 10 ؊ 3 ; AA P = 6.52 × 10 ؊ 4 ), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identifi ed in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted . ). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of This work was supported in part by WA State

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

Cited by 31 publications

References 49 publications

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

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

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