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• W2109991844 abstract "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 simvastatin treatment in coronary patients:realtion to basal serum cholestanol.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1340-1346Crossref PubMed Scopus (198) Google Scholar, 20Duane W.C. Effects of lovastatin and dietary cholesterol on sterol homeostasis in healthy human subjects.J. Clin. Invest. 1993; 92: 911-918Crossref PubMed Scopus (38) Google Scholar). Moreover, it has been reported that a subset of patients placed on simvastatin in the Scandinavian Simvastatin Survival Study showed no benefit from therapy compared with placebo if they had elevated baseline levels of markers of cholesterol absorption, including cholestanol (21Miettinen T.A. Gylling H. Stransberg T. Sarna S. Baseline serum cholestanol as predictopr of recurrent coronary events in subgroup of Scandinavian simvastatin survival study.BMJ. 1998; 316: 1127-1130Crossref PubMed Scopus (219) Google Scholar). Given the significant role of the NPC1L1 gene in cholesterol absorption and its reported involvement in the pharmacogenetics of ezetimibe and the ezetimibe/statin combination, our goal was to examine potential associations of the SNPs selected on the basis of previously published associations (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), functional relevance, and minor allele frequencies of >10%, namely, -133A>G, -18A>C, L272L, V1296V, and U_28650A>G, with baseline lipid levels, history, and incidence of CHD and lipid-lowering response to pravastatin in Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). The protocol of the PROSPER study has previously been published (22Shepherd J. Blauw G.J. Murphy M.B. Cobbe S.M. Bollen E.L. Buckley B.M. Ford I. Jukema J.W. Hyland M. Gaw A. et al.The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am. J. Cardiol. 1999; 84: 1192-1197Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar), as have the PROSPER results (22Shepherd J. Blauw G.J. Murphy M.B. Cobbe S.M. Bollen E.L. Buckley B.M. Ford I. Jukema J.W. Hyland M. Gaw A. et al.The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am. J. Cardiol. 1999; 84: 1192-1197Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). Briefly, 2,804 men and 3,000 women, age range 70–82 years, with preexisting vascular disease (n = 2404) or at least one of three major vascular risk factors (diabetes n = 575, smoking n = 1433, or hypertension n = 3360) were randomized to pravastatin 40 mg/day (n = 2891) or placebo (n = 2913) and followed up on average for 3.2 years. Over this period, the mean LDL-C reduction in the active treatment group was 32%, and the risk of developing CHD was decreased by 19% (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). No significant lipid changes were noted in the placebo group. Lipid levels were similar at onset of the study in subjects randomized to pravastatin or placebo. Analysis of response to pravastatin was based on subjects reporting good compliance (65% of the subjects in the pravastatin group were in this category, with good compliance being defined as taking 90% or more of the medication). Total cholesterol (TC), HDL-cholesterol, and triglycerides were assessed after an overnight fast, at baseline, and at 6 months, and LDL-C was calculated by the Friedewald formula, as previously described (22Shepherd J. Blauw G.J. Murphy M.B. Cobbe S.M. Bollen E.L. Buckley B.M. Ford I. Jukema J.W. Hyland M. Gaw A. et al.The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am. J. Cardiol. 1999; 84: 1192-1197Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 23Shepherd J. Blauw G.J. Murphy M.B. Bollen E.L. Buckley B.M. Cobbe S.M. Ford I. Gaw A. Hyland M. Jukema J.W. et al.PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet. 2002; 360: 1623-1630Abstract Full Text Full Text PDF PubMed Scopus (3005) Google Scholar). Apolipoprotein B (apoB) was measured only at baseline as described (23Shepherd J. Blauw G.J. Murphy M.B. Bollen E.L. Buckley B.M. Cobbe S.M. Ford I. Gaw A. Hyland M. Jukema J.W. et al.PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet. 2002; 360: 1623-1630Abstract Full Text Full Text PDF PubMed Scopus (3005) Google Scholar). DNA was available from 5,783 subjects and isolated from peripheral blood. DNA and subject characteristics were available on 2,621 males and 2,796 females. ApoE phenotype was determined on plasma samples by Western blotting, using the method of Havekes et al. (24Havekes L.M. de Knijff P. Beisiegel U. Havinga J. Smit M. Klasen E. A rapid micromethod for apolipoprotein E phenotyping directly in serum.J. Lipid Res. 1987; 28: 455-463Abstract Full Text PDF PubMed Google Scholar) in the central laboratory of the Royal Infirmary in Glasgow, Scotland. Subjects were classified according to the presence of apoE2, apoE3, or apoE4 bands on gel blotting. Five SNPs in the NPC1L1 locus were genotyped in this study: two in the promoter region [-18A>C (dbSNP reference number is not available) and -133A>G (rs17655652)], two in the protein coding region [1679C>T, or L272L (rs2072183), and 27621T>C, or V1296V (rs217434)], and one in the 3′ untranslated region [U3_28650A>G (rs3187907)]. The SNPs were selected based on previously published associations (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), functional relevance, and minor allele frequencies of >10%. We used Taq Man® SNP genotyping assays (Applied Biosystems, Foster City, CA). The Genbank/EMBL accession number for NPC1L1 is NC_000007.12, mim 608010. The end point read was performed using an Applied Biosystems 7900 HT sequence detection system, subsequent to PCR amplification. Genotypes with quality scores below 95% were repeated, and 5% blinded replicates for genotype determinations were performed. In addition, subjects with the apoE4/2 phenotype (n = 119; 2.2%) were excluded from further analyses, as were subjects whose apoE phenotypes had not been ascertained (n = 246). These exclusions were implemented because apoE phenotype or genotype has been demonstrated to affect statin-induced LDL lowering response, as well as CHD risk (25Lahoz C. Osgood D. Wilson P.W. Schaefer E.J. Ordovas J.M. Frequency of phenotype-genotype discrepancies at the apolipoprotein E locus in a large population study.Clin. Chem. 1996; 42: 1817-1823Crossref PubMed Scopus (38) Google Scholar, 26Ordovas J.M. Lopez-Miranda J. Perez-Jimenez F. Rodriguez C. Park J.S. Cole T. Schaefer E.J. Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy.Atherosclerosis. 1995; 113: 157-166Abstract Full Text PDF PubMed Scopus (151) Google Scholar, 27Pedro-Botet J. Schaefer E.J. Bakker-Arkema R.G. Black D.M. Stein E.M. Corella D. Ordovas J.M. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner.Atherosclerosis. 2001; 158: 183-194Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 28Wilson P.W.F. Schaefer E.J. Larson M.G. Ordovas J.M. Apolipoprotein E alleles and risk of coronary disease: a meta-analysis.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 1250-1255Crossref PubMed Scopus (507) Google Scholar, 29Lahoz C. Schaefer E.J. Cupples L.A. Wilson P.W. Levy D. Osgood D. Parpos S. Pedro-Botet J. Daly J.A. Ordovas J.M. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study.Atherosclerosis. 2001; 154: 529-537Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar), with apoE2 and apoE4 phenotypes having opposite effects. Observed genotype frequencies were compared with those expected under Hardy-Weinberg equilibrium using a χ2 test. For data analysis, multivariable ANCOVA was performed to detect associations of the genotypes with lipoprotein levels at baseline and with the response to treatment at 6 months, adjusted for gender, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country of origin (Scotland, Ireland, or The Netherlands). Prevalence at baseline of myocardial infarction (MI) and all types of vascular disease (history of angina, claudication, MI, stroke, transient ischemic attack, peripheral arterial disease surgery, or amputation for vascular disease more than 6 months before study entry) as well as incidence of CHD death or nonfatal MI were compared between carriers of different NPC1L1 SNP genotypes using multivariable logistic regression analysis in the pooled sample and stratified by gender and treatment. Pooled analyses were adjusted for gender and randomized treatment, when appropriate, and age, country, history of vascular disease, body mass index, history of diabetes, and history of hypertension, alcohol use, current smoking, and apoE phenotype. To evaluate the modifying effects of genotypes and gender on the response to treatment, multiplicative gene-treatment and gene-gender interaction terms were added to the regression models. Lewontin's D value was calculated to assess the linkage disequilibrium (LD) between the SNPs of interest (30Lewontin R.C. The interaction of selection and linkage. II. Optimum models.Genetics. 1964; 50: 757-782Crossref PubMed Google Scholar). Haplotypes were inferred using the expectation-maximization algorithm as implemented in SAS/Genetics proc haplotype. To account for allelic interaction, haplotypes were used as predictors in the regression models instead of SNPs along with the nongenetic covariates. P values were adjusted for multiple comparisons across genotypes within each SNP using the permutation test using 10,000 permutations. All analyses were performed using SAS/STAT (SAS version 9.1; SAS Institute, Cary, NC). As summarized in Table 1, the participating subjects had a mean age of 75 ± 3 years at baseline. Mean LDL-C levels were in the moderate-risk category (130–160 mg/dl), as defined by the US National Cholesterol Education Program (31Expert Panel Executive summary of the third report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA. 2001; 285: 2486-2497Crossref PubMed Scopus (24465) Google Scholar). Also, 1,371 men and 1,033 women reported a history of all types of vascular disease, including 508 men and 222 women with a history of MI. Data on apoE phenotype distribution in this population are also shown in Table 1. Allele frequencies for the NPC1L1 SNPs are given in Fig. 1, along with the haplotype block structure. Genotype frequencies conformed to Hardy-Weinberg equilibrium (P > 0.05; data not shown).TABLE 1Subject characteristics (n = 5418)Study Characteristics Mean (SD)aMeans (SD) unless otherwise specified; differences between men and women were assessed using a t-test for continuous traits and χ2 test for binary traits.Men (n = 2,621)Women (n = 2,797)Age (years)75.0 (3.3)75.6 (3.4)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).BMI (kg/m2)26.6 (3.6)27.1 (4.6)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).History diabetes mellitus, n (%)324 (12.4)251 (9.0)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).History hypertension, n (%)1333 (50.9)2027 (72.5)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).History vascular disease, n (%)1371 (52.3)1033 (36.9)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).History of MI, n (%)508 (19.4)222 (7.9)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).Current smoking, n (%)847 (32.3)586 (21.0)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).Alcohol consumption, n (%)1851 (70.6)1165 (41.7)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).TC (mg/dl)207.0 (30.7)231.9 (34.5)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).LDL-C (mg/dl)138.5 (27.8)154.9 (35.3)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).HDL-cholesterol (mg/dl)45.6 (12.2)53.0 (13.4)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).Triglyceride (mg/dl)132.4 (64.3)140.6 (59.4)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).apoA-I (mg/dl)124.4 (22.2)139.9 (24.1)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).apoB (mg/dl)110.6 (21.3)119.1 (22.6)bP < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods).apoE 2/2 + 2/3 (%)13.0511.30apoE 3/3 (%)63.165.7apoE 3/4 + 4/4 (%)23.823.0BMI, body mass index.a Means (SD) unless otherwise specified; differences between men and women were assessed using a t-test for continuous traits and χ2 test for binary traits.b P < 0.001, apoE 2/4 carriers were excluded (see Materials and Methods). Open table in a new tab BMI, body mass index. Baseline lipid and apoB levels stratified by genotype and gender are shown in Table 2. In the sex-pooled adjusted model, the minor alleles of -18A>C, L272L, V1296V, and U3_28650A>G were associated with slightly higher TC, LDL-C, and apoB levels in both men and women (differences ranged between 2% and 8% when comparing homozygotes for the minor allele with homozygotes for the common allele; P < 0.05).TABLE 2Adjusted baseline lipid levels (mean ± SE, mg/dl) by gender and genotypenTCLDL-CapoBSNPGenotypeMenWomenMenWomenPaP values using the three genotypes, men and women combined; adjusted for sex, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country.MenWomenPaP values using the three genotypes, men and women combined; adjusted for sex, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country.MenWomenPaP values using the three genotypes, men and women combined; adjusted for sex, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country.−133 A>GAA11311280203.6 ± 1.3222.8 ± 1.50.04134.6 ± 1.1146.1 ± 1.30.03108.8 ± 0.9113.8 ± 1.00.08AG11851223202.1 ± 1.2220.7 ± 1.5132.7 ± 1.1143.9 ± 1.3107.1 ± 0.8113.3 ± 1.0GG292281203.3 ± 2.0217.0 ± 2.3135.9 ± 1.8139.7 ± 2.1108.9 ± 1.3110.4 ± 1.5−18 A>CAA18822007202.4 ± 1.1220.4 ± 1.40.03133.3 ± 1.4143.9 ± 1.20.02107.7 ± 0.8113.2 ± 0.90.08AC665718204.4 ± 1.5223.4 ± 1.7135.3 ± 1.3146.0 ± 1.5108.7 ± 1.0113.4 ± 1.1CC6462205.8 ± 3.9224.9 ± 4.4138.9 ± 3.4146.3 ± 3.9112.9 ± 2.6115.6 ± 2.8L272LCC16111685202.2 ± 1.2219.9 ± 1.40.007133.1 ± 1.0143.8 ± 1.30.02107.4 ± 0.8113.0 ± 0.90.04CG872968203.8 ± 1.4223.3 ± 1.6134.8 ± 1.2145.6 ± 1.4108.8 ± 0.9114.0 ± 1.0GG129130207.0 ± 2.8224.5 ± 3.2138.1 ± 2.5148.0 ± 2.8111.6 ± 1.9114.8 ± 2.0V1296VCC16861746202.8 ± 1.2220.8 ± 1.40.006133.6 ± 1.0143.9 ± 1.30.004108.0 ± 0.8113.1 ± 0.90.04CT822924202.5 ± 1.4221.5 ± 1.6133.6 ± 1.2145.1 ± 1.4107.6 ± 0.9113.4 ± 1.0TT103113211.9 ± 3.1227.5 ± 3.4143.6 ± 2.7148.7 ± 3.0114.7 ± 2.1115.2 ± 2.2U3_28650AA16771739202.8 ± 1.2220.7 ± 1.40.005133.6 ± 1.0143.8 ± 1.30.002108.0 ± 0.8113.1 ± 0.90.03A>GGA828934202.3 ± 1.4221.6 ± 1.6133.4 ± 1.2145.1 ± 1.4107.5 ± 0.9113.4 ± 1.0GG104113212.1 ± 3.1227.6 ± 3.4143.8 ± 2.8148.9 ± 3.0114.8 ± 2.1115.3 ± 2.2a P values using the three genotypes, men and women combined; adjusted for sex, body mass index, age, alcohol, smoking, diabetes, apoE phenotype, and country. Open table in a new tab Significant associations between the -133A>G variant and lipid levels were most pronounced in women, with -133GG female carriers having the lowest TC and LDL-C levels compared with -133AA and -133AG carriers (P for trend = 0.0032 for TC and 0.023 for LDL-C; Table 2). Similar trends were noted in men, but did not reach statistical significance (P for trend = 0.46 for TC and 0.09 for LDL; Table 2). Haplotype analysis detected two LD blocks with two SNPs each and one SNP between the blocks. In order to test allelic interactions and preserve power, we constructed haplotypes that included one SNP from each haplotype block and the SNP outside of either haplotype block (-18A>C, L272L, and U3_28650A>G) (Fig. 1; Table 3), resulting in four common haplotypes (frequencies >5%). The tests that compared a common haplotype (-18A>C[A]L272L[C]U3_28650A>G[A]) present in 68% of the participants to the others five haplotypes showed that carriers of the common haplotype had 1.8 mg/dl lower base­line LDL-C levels for each copy of this haplotype com­pared with the alternative haplotype (-18[C]L272L[G]U3_28650G), which was present in 10% of participants (Table 3). This is consistent with the data shown in Table 2, where individual variations in these SNPs were significantly associated with LDL-C levels with homozygous carriers for the minor alleles having the highest levels. These data indicate that most of the variation in TC and LDL-C levels could be explained by individual SNPs and that haplotype analysis did not add significantly to the model performance. The proportion of variation explained by multivariable models with individual SNPs was on average 15.5% for baseline LDL-C levels and 17.4% for baseline TC, while multivariate models with haplotypes explained 15.6% and 17.4%, respectively (P for model comparison >0.05).TABLE 3Incremental effect of rare NPC1L1 haplotypes on baseline lipid levelsHaplotypeTCLDL-CApoBNPC1L1 HaplotypeFrequency-18A>CL272LU3_28650A>GEstimate, mg/dlaIncremental effect of each copy of haplotype.PbCompared to the common haplotype.Estimate, mg/dlaIncremental effect of each copy of haplotype.PbCompared to the common haplotype.Estimate, mg/dlaIncremental effect of each copy of haplotype.PbCompared to the common haplotype.10.681ACA–cReferent haplotype.–––––20.102CGG0.180.00060.170.00040.040.00730.097ACG0.060.290.080.14−0.120.0540.068AGA0.130.050.100.100.030.0950.043CGA0.140.110.100.20−0.070.5660.004CCA−0.360.14−0.290.180.010.52a Incremental effect of each copy of haplotype.b Compared to the common haplotype.c Referent haplotype. Open table in a new tab To assess differential responsiveness to pravastatin in carriers of various NPC1L1 genotypes, we tested the association between the SNPs under study and the 6 month change in lipid levels in treated individuals with good compliance. The -133A>G variant was associated with LDL-C lowering in the sex-pooled analysis (P = 0.02). However, while -133GG male carriers showed th" @default.
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• W2109991844 date "2010-05-01" @default.
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• W2109991844 title "Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly" @default.
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• W2109991844 doi "https://doi.org/10.1194/jlr.p001172" @default.
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