Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to prava­statin 40 mg/day or placebo and were followed on average for 3.2 years. In the adjusted gender-pooled analyses, homozygous carriers of the minor alleles at four NPC1L1 sites (-18A>C, L272L, V1296V, and U3_28650A>G, minor allele frequencies 0.15–0.33) had 2–8% higher LDL-cholesterol (LDL-C) levels at baseline than homozygous carriers of the common alleles (P < 0.05). Homozygotes for the rare alleles also had a significant increase in the risk of CHD events on trial (range of hazard ratios 1.50–1.67; P < 0.02), regardless of the treatment regimen. The -133 A>G polymorphism and not other variants was associated with 6 month LDL-C lowering (P = 0.02). Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL-C levels and CHD risk. Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to prava­statin 40 mg/day or placebo and were followed on average for 3.2 years. In the adjusted gender-pooled analyses, homozygous carriers of the minor alleles at four NPC1L1 sites (-18A>C, L272L, V1296V, and U3_28650A>G, minor allele frequencies 0.15–0.33) had 2–8% higher LDL-cholesterol (LDL-C) levels at baseline than homozygous carriers of the common alleles (P < 0.05). Homozygotes for the rare alleles also had a significant increase in the risk of CHD events on trial (range of hazard ratios 1.50–1.67; P < 0.02), regardless of the treatment regimen. The -133 A>G polymorphism and not other variants was associated with 6 month LDL-C lowering (P = 0.02). Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL-C levels and CHD risk. Elevated plasma LDL-cholesterol (LDL-C) and reduced HDL-cholesterol levels independently predict risk of developing coronary heart disease (CHD) (1Ingelsson E. Schaefer E.J. Contois J.H. McNamara J.R. Sullivan L. Keyes M.J. Pencina M.J. Schoonmaker C. Wilson P.W. D'Agostino R.B. et al.Clinical utility of different lipid measures for prediction of coronary heart disease in men and women.JAMA. 2007; 298: 776-785Crossref PubMed Scopus (462) Google Scholar, 2Wilson P.W. D'Agostino R.B. Levy D. Belanger A.M. Silbershatz H. Kannel W.B. Prediction of coronary heart disease using risk factor categories.Circulation. 1998; 97: 1837-1847Crossref PubMed Scopus (7496) Google Scholar). Dietary cholesterol consumption and intestinal absorption contribute to plasma cholesterol levels. Markers of intestinal cholesterol absorption, such as β-sitosterol and campesterol, have been related to variation in levels of plasma LDL-C in human population studies (3Miettinen T.A. Kesaniemi Y.A. Cholesterol absorption: regulation of cholesterol synthesis and elimination and within population variations of serum cholesterol levels.Am. J. Clin. Nutr. 1989; 49: 629-635Crossref PubMed Scopus (175) Google Scholar, 4Tikkanen M.J. Plant sterols and stanols.Handbook of Experimental Pharmocology. Springer-Verlag, Berlin2005: 215-230Crossref Scopus (39) Google Scholar, 5Gylling H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 6Gylling H. Laaksonen D.E. Atalay M. Hallikainen M. Niskanen L. Miettinin T.A. Markers of absorption and synthesis of cholesterol in men with type 1 diabetes.Diabetes Metab. Res. Rev. 2007; 23: 372-377Crossref PubMed Scopus (24) Google Scholar). Niemann-Pick C1-like 1 (NPC1L1) is an essential protein for intestinal cholesterol absorption (7Davies J.P. Levy B. Ioannou Y.A. Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1.Genomics. 2000; 65: 137-145Crossref PubMed Scopus (189) Google Scholar). NPC1L1 was identified based on its homology to human Niemann-Pick C1 protein, which is defective in an autosomal recessive lipid storage disorder (8Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. et al.Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science. 1997; 277: 228-231Crossref PubMed Scopus (1230) Google Scholar, 9Davis Jr., H.R. Altmann S.W Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter.Biochim. Biophys. Acta. 2009; 1791: 679-683Crossref PubMed Scopus (110) Google Scholar). NPC1L1-deficient mice exhibit a substantial reduction in cholesterol absorption, which is unaffected by dietary supplementation of bile acids (10Altmann S.W. Jr. Davis H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1442) Google Scholar). Recent data indicate that hepatic NPC1L1 also facilitates the retention of biliary cholesterol by hepatocytes, thus protecting the body from excessive biliary loss of cholesterol (11Temel R.E. Tang W. Ma Y. Rudel L.L. Willingham M.C. Ioannou Y.A. Davies J.P. Nilsson L.M. Yu L. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe.J. Clin. Invest. 2007; 117: 1968-1978Crossref PubMed Scopus (306) Google Scholar). Cohen et al. (12Cohen J.C. Pertsemlidis A. Fahmi S. Esmail S. Vega G.L. Grundy S.M. Hobbs H.H. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.Proc. Natl. Acad. Sci. USA. 2006; 103: 1810-1815Crossref PubMed Scopus (328) Google Scholar) sequenced NPC1L1 and showed that individuals who carry rare NPC1L1 variants associated with decreased cholesterol absorption have mean LDL-C levels that are significantly lower than values in noncarriers. Moreover, NPC1L1 is the target for the drug ezetimibe, which inhibits cholesterol absorption (13Garcia-Calvo M. Lisnock J. Bull H.G. Hawes B.E. Burnett D.A. Braun M.P. Crona J.H. Davis Jr., H.R. Dean D.C. Detmers P.A. et al.The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).Proc. Natl. Acad. Sci. USA. 2005; 102: 8132-8137Crossref PubMed Scopus (657) Google Scholar). Genetic variation at NPC1L1 in humans has been shown to affect LDL-C lowering response to ezetimibe (14Wang J. Williams C.M. Hegele R.A. Compound het­erozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177Crossref PubMed Scopus (67) Google Scholar, 15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar). Simon et al. (15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar) assessed a number of single nucleotide polymorphisms (SNPs) at NPC1L1 and reported that carriers of the rare alleles (most significantly the promoter variant at -18A>C) had a 15% greater LDL-C lowering response to ezetimibe compared with noncarriers. Furthermore, Hegele et al. (16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar) have shown that individuals with dyslipidemia who carry a rare NPC1L1 haplotype, including the minor alleles at L272L, V1296V, and 25342A>C, were more responsive to ezetimibe (36% LDL-C reduction) than subjects not carrying the haplotype (18% LDL-C reduction). We and others have documented that alterations in specific plasma markers of cholesterol absorption, namely, campesterol and β-sitosterol, can affect LDL-C lowering response to statins (17van Himbergen T.M. Matthan N.R. Resteghini N.A. Otokozawa S. Ai M. Stein E.A. Jones P.H. Schaefer E.J. Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers.J. Lipid Res. 2009; 50: 730-739Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 18Miettinen T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment.Eur. J. Clin. Invest. 2003; 33: 976-982Crossref PubMed Scopus (120) Google Scholar, 19Miettinen T.A. Stranberg T.E. Gylling H. Non­cholesterol sterols and cholesterol lowering by long term treatment in coronary to serum 2000; PubMed Scopus Google Scholar, of and dietary cholesterol on sterol in human Clin. Invest. PubMed Scopus Google Scholar). Moreover, has been reported that a of on in the showed from therapy compared with placebo had baseline levels of markers of cholesterol absorption, including T.A. Gylling H. S. serum as of coronary events in of 1998; PubMed Scopus Google Scholar). the significant role of the NPC1L1 gene in cholesterol absorption and its reported in the of ezetimibe and the was to examine of the on the of (14Wang J. Williams C.M. Hegele R.A. Compound het­erozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177Crossref PubMed Scopus (67) Google Scholar, 15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google and minor allele frequencies of namely, -18A>C, L272L, V1296V, and with baseline lipid levels, and incidence of CHD and lipid-lowering response to in of in the at The of the PROSPER has been J. S.M. M. A. et al.The of a of in the at PROSPER of in the at J. Full Text Full Text PDF PubMed Scopus Google as have the PROSPER J. S.M. M. A. et al.The of a of in the at PROSPER of in the at J. Full Text Full Text PDF PubMed Scopus Google Scholar). men and with disease = or at of risk = = or = were randomized to 40 mg/day = or placebo = and followed on average for 3.2 years. the mean LDL-C reduction in the treatment was and the risk of developing CHD was decreased by T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment.Eur. J. Clin. Invest. 2003; 33: 976-982Crossref PubMed Scopus (120) Google Scholar). significant lipid were in the placebo Lipid levels were at of the in subjects randomized to or of response to was based on subjects of the subjects in the were in with as or more of the cholesterol and were assessed an at and at 6 and LDL-C was by the as J. S.M. M. A. et al.The of a of in the at PROSPER of in the at J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. S.M. A. M. et of in the at in elderly individuals at risk of disease a 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). was at baseline as J. S.M. A. M. et of in the at in elderly individuals at risk of disease a 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). was from subjects and from and were on and was on plasma by using the of et al. L.M. P. J. M. E. for in Lipid Res. Full Text PDF PubMed Google Scholar) in the of the in were to the of or on in the NPC1L1 were in two in the promoter number is not and two in the protein or and or and in the The were based on (15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google and minor allele frequencies of We The number for NPC1L1 is The was using an to with were and for were In subjects with the = were from analyses, as were subjects had not been = were or has been to affect lowering as as CHD risk C. D. Wilson P.W. Schaefer E.J. of at the in a large population PubMed Scopus Google Scholar, J. C. J.S. Schaefer E.J. of and on the low lipoprotein response to Full Text PDF PubMed Scopus Google Scholar, J. Schaefer E.J. Stein D. plasma lipid response to atorvastatin in a specific Full Text Full Text PDF PubMed Scopus Google Scholar, Schaefer E.J. M.G. alleles and risk of coronary a PubMed Scopus Google Scholar, C. Schaefer E.J. Wilson P.W. Levy D. D. S. J. J.A. and disease in the Full Text Full Text PDF PubMed Scopus Google with and frequencies were compared with using a data was to of the with lipoprotein levels at baseline and with the response to treatment at 6 adjusted for body and of or The at baseline of and of disease of disease or for disease more than 6 as as incidence of CHD or were compared carriers of different NPC1L1 using in the and by and were adjusted for and randomized and of body of and of and the effects of and on the response to and were to the was to the the of The of and 50: PubMed Google Scholar). were using the as in for were as in the of with the P values were adjusted for within using the using were using in the subjects had a mean of at LDL-C levels were in the as by the Cholesterol of the of the Cholesterol on and of Cholesterol in PubMed Scopus Google Scholar). men and reported a of of including men and with a of on in population are also shown in frequencies for the NPC1L1 are in with the haplotype frequencies to (P data not = men and were assessed using a for and for = = < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and of < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and < carriers were and body men and were assessed using a for and for P < carriers were and in a body lipid and levels by and are shown in In the adjusted the minor alleles of -18A>C, L272L, V1296V, and were associated with higher and levels in men and and for the minor allele with for the common P < baseline lipid levels by and values using the men and adjusted for body and values using the men and adjusted for body and values using the men and adjusted for body and P values using the men and adjusted for body and in a the variant and lipid levels were in with carriers the and LDL-C levels compared with and carriers (P for = for and for were in not (P for = for and for two with two and the In to and that from haplotype and the of haplotype (-18A>C, L272L, and U3_28650A>G) in four common The that compared a common haplotype in of the participants to the others five showed that carriers of the common haplotype had lower LDL-C levels for of haplotype with the haplotype which was in of participants is with the data shown in variations in were significantly associated with LDL-C levels with homozygous carriers for the minor alleles the levels. data indicate that of the variation in and LDL-C levels by and that haplotype not significantly to the The of variation by with was on average for baseline LDL-C levels and for baseline with and (P for of rare NPC1L1 on baseline lipid of of to the common of of to the common of of to the common of of to the common in a to in carriers of NPC1L1 the association the and the 6 month in lipid levels in individuals with The variant was associated with LDL-C lowering in the (P = 0.02). carriers showed the reduction in LDL-C treatment compared with carriers of or two carriers had the reduction compared with carriers of or two alleles (P for is were not related to LDL-C lowering response to carriers had significantly lower of number of = adjusted P = other were associated with a of disease at baseline ratios for CHD or number of = by and are shown in the that were significantly associated with higher and were also to associated with a greater risk of CHD or in homozygous carriers of the minor alleles compared with and homozygous carriers of the common alleles (P < regardless of the treatment the of the trial was and placebo were and adjusted for to reduced in the of incidence of CHD or on trial by subjects values for men and adjusted for body randomized and significant were men and were values for men and adjusted for body and significant were men and were values for men and adjusted for body and significant were men and were of of subjects of subjects P values for men and adjusted for body randomized and significant were men and were P values for men and adjusted for body and significant were men and were in a The of was to of at the NPC1L1 with baseline lipid levels, of and LDL-C lowering response to in a large population of elderly subjects at risk of developing The NPC1L1 has been shown to critical for cholesterol absorption and is the of the of ezetimibe, a cholesterol lowering that inhibits cholesterol absorption (8Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. et al.Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.Science. 1997; 277: 228-231Crossref PubMed Scopus (1230) Google Scholar, 9Davis Jr., H.R. Altmann S.W Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter.Biochim. Biophys. Acta. 2009; 1791: 679-683Crossref PubMed Scopus (110) Google Scholar, M. Lisnock J. Bull H.G. Hawes B.E. Burnett D.A. Braun M.P. Crona J.H. Davis Jr., H.R. Dean D.C. Detmers P.A. et al.The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).Proc. Natl. Acad. Sci. USA. 2005; 102: 8132-8137Crossref PubMed Scopus (657) Google Scholar). In study, documented that homozygous carriers of the minor alleles at -18A>C, L272L, V1296V, and at the NPC1L1 had 2–8% higher and levels at baseline compared with common allele homozygous was for NPC1L1 in for the of the NPC1L1 and lipid levels was in a of association studies subjects that and of S. A. L.L. et identified that lipid and risk of coronary Genet. PubMed Scopus Google Scholar). In that study, carriers of the NPC1L1 common allele had higher LDL-C levels average P = not significant at the S. A. L.L. et identified that lipid and risk of coronary Genet. PubMed Scopus Google Scholar). or were to associated with lipid levels assessed in S. A. L.L. et identified that lipid and risk of coronary Genet. PubMed Scopus Google Scholar). is that population such as the risk and of as as in for by at in of and response to were by that NPC1L1 variants were related to LDL-C lowering response to ezetimibe (14Wang J. Williams C.M. Hegele R.A. Compound het­erozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177Crossref PubMed Scopus (67) Google Scholar, 15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar). We that the NPC1L1 not other NPC1L1 was associated with response to pravastatin. Simon et al. (15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google using two large from the on to for trial and reported that carrying at of the minor allele of had to 15% greater response 6 of treatment with ezetimibe to statin therapy compared with homozygous carriers of the common allele LDL-C from Our that NPC1L1 was not associated with response to Simon et al. (15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar) reported that NPC1L1 carriers had a LDL-C lowering response to compared with NPC1L1 to with therapy In study, were in Moreover, for had significantly greater than the was for carrying that the had lower LDL-C levels at the of is have for of Moreover, a that can also by in of and such as men and We have documented that variation at the gene is associated with in LDL-C lowering response to atorvastatin M.E. S. Schaefer E.J. specific effects of gene haplotype on lipid response to with promoter gene 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). data effects of the NPC1L1 on lipid-lowering of the NPC1L1 studies have reported for studies the are and can by different population baseline type of of and as as in the In study, carriers from and adjusted for a significant of plasma lipid not by other studies (14Wang J. Williams C.M. Hegele R.A. Compound het­erozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe.Clin. Genet. 2005; 67: 175-177Crossref PubMed Scopus (67) Google Scholar, 15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar). of is that whether was an association of NPC1L1 polymorphisms and than of the men and more than a of the in PROSPER had a of of the were associated with a of disease at is that the allele frequencies for the NPC1L1 that in PROSPER were to reported by other studies (15Simon J.S. Karnoub M.C. Devlin D.J. Arreaza M.G. Qiu P. Monks S.A. Severino M.E. Deutsch P. Palmisano J. Sachs A.B. et al.Sequence variation in NPC1L1 and association with improved LDL-cholesterol lowering in response to ezetimibe treatment.Genomics. 2005; 86: 648-656Crossref PubMed Scopus (108) Google Scholar, 16Hegele R.A. Guy J. Ban M.R. Wang J. NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe.Lipids Health Dis. 2005; 4: 16Crossref PubMed Scopus (103) Google Scholar) and to by with to variants was the rare alleles -18A>C, L272L, V1296V, and at NPC1L1 were associated with a risk of developing or CHD events on Moreover, the higher incidence of CHD or in carriers of minor alleles not to by statin that is not in CHD risk reduction in of subjects to identified by Miettinen et al. T.A. Gylling H. S. serum as of coronary events in of 1998; PubMed Scopus Google Scholar) that had higher baseline markers of cholesterol absorption and had significant CHD risk reduction treatment compared with placebo in the is to that the of not to the that to in lipid are for The promoter at and -133 affect and NPC1L1 with that from of the gene Jr., H.R. Altmann S.W Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter.Biochim. Biophys. Acta. 2009; 1791: 679-683Crossref PubMed Scopus (110) Google Scholar). studies are to can affect NPC1L1 gene such were associated with decreased gene in intestinal absorption of is data at to In NPC1L1 and polymorphisms in that not alterations in the and not to the of the is that rare which in and protein S.A. W. L. protein by 2006; PubMed Scopus Google Scholar, C. A.M. polymorphism in the gene 2007; PubMed Scopus Google Scholar). In the in the associated with alterations in the regulation that affect NPC1L1 gene The to the at and NPC1L1 and for and as variants that can the in The of the that is elderly and of of to of individuals and of other the and of to and and with specific markers of intestinal cholesterol absorption, such as β-sitosterol and campesterol (17van Himbergen T.M. Matthan N.R. Resteghini N.A. Otokozawa S. Ai M. Stein E.A. Jones P.H. Schaefer E.J. Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers.J. Lipid Res. 2009; 50: 730-739Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). In data are with the that variation at NPC1L1 is associated with plasma total cholesterol and LDL-C levels and CHD risk to alterations in cholesterol absorption in an elderly In the of NPC1L1 and of the effects of NPC1L1 variants on NPC1L1 gene and of variation at gene lipid CHD and response to lipid-lowering with coronary heart disease low Niemann-Pick C1-like 1 of in the at single nucleotide polymorphism total cholesterol

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