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One of the great challenges in therapeutic oncology is determining who might achieve survival benefits from a particular therapy. Studies on longitudinal circulating tumor DNA (ctDNA) dynamics for the prediction of survival have generally been small or nonrandomized. We assessed ctDNA across 5 time points in 466 non-small-cell lung cancer (NSCLC) patients from the randomized phase 3 IMpower150 study comparing chemotherapy-immune checkpoint inhibitor (chemo-ICI) combinations and used machine learning to jointly model multiple ctDNA metrics to predict overall survival (OS). ctDNA assessments through cycle 3 day 1 of treatment enabled risk stratification of patients with stable disease (hazard ratio (HR) = 3.2 (2.0–5.3), P P P = 0.00012). Simulations of clinical trial scenarios employing our ctDNA model suggested that early ctDNA testing outperforms early radiographic imaging for predicting trial outcomes. Overall, measuring ctDNA dynamics during treatment can improve patient risk stratification and may allow early differentiation between competing therapies during clinical trials.

Introduction: IMbassador250 was a prospective phase III international multicenter trial enrolling 759 men with mCRPC who had prior progression on abiraterone, with or without prior taxane, randomizing to enzalutamide +/- atezolizumab. For this retrospective biomarker study, we hypothesized that decreases in ctDNA after 6 weeks of therapy, as measured from a novel low-pass, whole genome methylation sequencing assay from Foundation Medicine, will have greater discriminatory power to distinguish overall survival (OS) than PSA alone in a post-abiraterone mCRPC setting. Methods: Pre-treatment and C3D1 plasma samples from IMbassador250 were sequenced using a novel research assay that examines global copy number changes and methylation patterns through low pass, whole genome sequencing from Foundation Medicine. Kinetic changes in ctDNA were estimated between pre-treatment and C3D1 timepoints and patients were dichotomized into significant decreases vs. not using a predefined cutoff. PSA was examined as both 50% reduction from baseline to disease progression as well as a cutoff that matched the prevalence captured by the ctDNA reduction group at C3D1. Cox proportional hazards were calculated from Kaplan-Meier survival plots of overall survival between the reduction vs. no reduction groups. Results: Stratifying OS according to PSA 50% reduction from baseline to disease progression yielded an HR = 2.71 (95%CI:2.04-3.62). 370 patients (48%) had available ctDNA at both C1D1 and C3D1, and the median OS (mOS) in the reduction vs. non-reduction groups were 17.4 vs. 9.1 months, respectively (HR of 3.01; 95%CI:1.96-4.64). Evaluation of PSA reduction at C3D1 in the patients with available ctDNA yielded mOS of 16.3 and 9.5 months in the reduction vs. non-reduction groups, respectively (HR=2.70; 95%CI:1.77-4.12). Spearman’s correlation of ctDNA fold change between the research assay and an orthogonal FDA approved liquid biopsy assay was 0.95. Discussion: In this study, early ctDNA kinetic changes provided numerically superior estimation of overall survival compared to PSA in mCRPC patients receiving enzalutamide +/- atezolizumab in the post-abiraterone setting. Furthermore, ctDNA kinetic changes through C3D1 were apparent mostly prior to both PSA 50 and radiographic progression (6 weeks vs mean 3.3 months), providing a non-invasive strategy that is independent of PSA for monitoring therapy response when the disease is less AR dependent. Citation Format: Christopher Sweeney, Chang Xu, Jie He, Amanda Young, Alexander Robertson, Russell Petry, Daniel Zollinger, Alexander Fine, Neil Peterman, Eliana Polisecki, Tyler Warner, Kobe Yuen, Yanmei Huang, Zoe Assaf, Ryon Graf, Sanjeev Mariathasan, Priti Hegde, David Fabrizio, Thomas Powles. Evaluation of circulating tumor DNA kinetics as a prognostic biomarker for overall survival in metastatic castrate resistant prostate cancer using a novel methylation sequencing research assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3362.

We assessed secondary and genetic causes of severe HDL deficiency in 258,252 subjects, of whom 370 men (0.33%) and 144 women (0.099%) had HDL cholesterol levels G; 2) LCAT (12.4%): 1 homozygote, 3 compound heterozygotes, 13 heterozygotes, and 8 heterozygotes with variant rs4986970/p.S232T; 3) APOA1 (5.0%): 1 homozygote and 9 heterozygotes; and 4) LPL (4.5%): 1 heterozygote and 8 heterozygotes with variant rs268/p.N318S. In addition, 4.5% had other mutations, and 46.8% had no mutations. Atherosclerotic cardiovascular disease (ASCVD) prevalence rates in the ABCA1,LCAT,APOA1, LPL, and mutation-negative groups were 37.0%, 4.0%, 40.0%, 11.1%, and 6.4%, respectively. Severe HDL deficiency is uncommon, with 40.1% having secondary causes and 48.8% of the subjects sequenced having ABCA1,LCAT,APOA1, or LPL mutations or variants, with the highest ASCVD prevalence rates being observed in the ABCA1 and APOA1 groups.

International audience; Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.

Background and aims: Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. Methods: In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300 mg/dL and/or LDL-C≥190 mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. Results: In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (n = 20, 2 novel), ABCG5/8 (n = 7, 2 novel), APOB (n = 3, 1 novel), CYP27A1 (n = 3, 1 novel), LIPA (n = 2, 1 novel), APOE (n = 2), LIPC (n = 1, novel), LIPG (n = 1, novel), and SCARB1 (n = 1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. Conclusions: Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy. Fil: Corral, Pablo. Universidad Fasta; Argentina Fil: Geller, Andrew S.. Boston Heart Diagnostics; Estados Unidos Fil: Polisecki, Eliana Y.. Boston Heart Diagnostics; Estados Unidos Fil: Lopez, Graciela Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Bañares, Virginia Gabriela. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina Fil: Cacciagiu, Leonardo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina Fil: Berg, Gabriela Alicia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Hegele, Robert A.. University Western Ontario; Canadá Fil: Schaefer, Ernst J.. Boston Heart Diagnostics; Estados Unidos Fil: Schreier, Laura Ester. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina

Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk.We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case.Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay.Of 207,926 subjects tested, 4.3% had LDL-C ≥190 mg/dL. Plasma β-sitosterol concentrations ≥8.0 mg/L (99th percentile) were found in 4.3% of these subjects vs 0.72% with LDL-C130 mg/dL. Among all subjects, 0.050% had β-sitosterol levels ≥15.0 mg/L, consistent with sitosterolemia, while among those with LDL-C ≥190 mg/dL, 0.334% had this rare disorder. A 13-year-old boy with the highest LDL-C (679 mg/dL) of all subjects had planar xanthomas and a β-sitosterol level of 53.5 mg/L (normal3.3 mg/L). He was a compound heterozygote for 2 ABCG8 mutations (p.N409D and an intron 11+2TA splice site mutation). On a low-cholesterol and plant-sterol diet, his LDL-C decreased to 485 mg/dL (-29%) and β-sitosterol to 44.6 mg/L (-27%). On atorvastatin 20 mg/d, his LDL-C decreased to 299 mg/dL (-38%). With added ezetimibe 10 mg/d, his LDL-C normalized to 60 mg/dL (-80% further decrease); and his β-sitosterol decreased to 14.1 mg/L (-68% further decrease).Our data indicate that about 4% of subjects with LDL-C concentrations ≥190 mg/dL have plasma β-sitosterol concentrations above the 99th percentile and about 0.3% have concentrations consistent with sitosterolemia. Therefore, this diagnosis should be considered in such patients.

Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5,783 elderly participants in PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p

Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLR C44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCR i18T>G, MAF 0.019) gene loci with baseline lipid values, statin induced LDL- cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease on trial (CVD). Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels

PURPOSE OF REVIEW Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary heart disease. Response to treatment varies considerably from person to person; however, inherited traits (genetic variability) may play a central role in this inter-individual variation. The purpose of this review is to summarize recent progress in the research for exploring genetic determinants of clinical efficacy and safety of statin therapy. RECENT FINDINGS In addition to 41 previous studies of 19 genes, the results of 17 pharmacogenomic studies investigating the relationship between common genetic variants and response to statin therapy in terms of lipid responses, clinical outcomes, and adverse events have been reported since January 2004 - 15 candidate genes related to pharmacodynamics and three to pharmacokinetics of statins. These reported data suggest that genetic variations influencing intestinal cholesterol absorption, cholesterol production, and lipoprotein catabolism may all play a role in modulating responsiveness, as well as genes involved in drug metabolism of statins. They also suggest that combined analysis of multiple variants in several genes, all of which have possible functional relations, is more likely to give significant results, especially when being performed with a larger number of participants. SUMMARY Pharmacogenomic studies of statin therapy will provide a better picture as to who is most likely and least likely to benefit from treatment, which results in more individualized management of coronary artery disease.

Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to interindividual variations in clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, >30 candidate genes related to pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of low-density lipoprotein cholesterol lowering. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E; adenosine triphosphate–binding cassette transporter G5 and G8; cholesterol production, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase; and lipoprotein catabolism, such as apoB and the low-density lipoprotein receptor, all may play a role in modulating responsivesness as well genes involved in metabolism of statins such as cytochrome P450. However, there is considerable variation in results reported, and the data suggest that combined analysis of multiple genetic variants in several genes, all of which have possible functional significance, is more likely to give significant results than single gene studies in small sample populations. In the future, pharmacogenomic studies with a greater number of participants (>2,000 participants) should provide a better picture as to who is most likely and who is least likely to benefit from statin therapy.

One of the most frequent causes of death in developed countries is sudden natural death (SND), which is the most common indication for medico-legal autopsies. Cardiac diseases are frequently detected among SND. Mitochondrial DNA (mtDNA) is easily damaged by reactive oxygen species, and it may cause dysfunction in tissues, leading to early events in cardiovascular disease. A specific mtDNA deletion of 4977 bp is associated to aging, myocardial dysfunction, and bioenergetic deficit. The potential link between mtDNA damage and SND has not been investigated before. Our aim was to evaluate the accumulation of the common mtDNA4977-deletion in cardiac muscle samples from autopsies of SND in adults (n = 14) in comparison to control samples from unnatural deaths (n = 12). Serial dilution-polymerase chain reaction method was performed to estimate the proportion of the total mtDNA harboring the mtDNA4977-deletion. Coefficient variation intra-assay was 8%, and inter-assay was 12%. MtDNA4977-deletion percentage was higher in samples obtained from victims of SND than in those from subjects who died of unnatural causes (p < 0.05). No differences in mtDNA4977-deletion were found between SND victims 39-51 years old, and no correlation was found between these samples and age, r = 0.30, p = 0.29 while it was significant among control samples, r = 0.68, p < 0.05. The association between mtDNA4977 deletion with SND victims might offer a tool to provide additional information to clarify complex SND investigations.

Aims Our goals were to examine the relationships of a specific ATP-binding cassette transporter A1 ( ABCA1 ) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial. Methods and results The ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Of these subjects 47.6% carried the variant, with 40.0% carrying one allele, and 7.6% carrying both alleles. No effects on baseline LDL-C levels were noted, but mean HDL-C increased modestly according to the number of variant alleles being present (1.27 vs 1.28 vs 1.30 mmol/L, p = 0.024). No relationships between the presence or absence of this variant and statin induced LDL-C lowering response or CHD at baseline were noted. However within trial those with the variant as compared to those without the variant, the overall adjusted hazard ratio for new cardiovascular disease (fatal CHD, non-fatal myocardial infarction, or fatal or non-fatal stroke) was 1.22 (95% CI 1.06–1.40, p = 0.006), while for those in the pravastatin group it was 1.41 (1.15–1.73, p = 0.001), and for those in the placebo group it was 1.08 (0.89–1.30, p = 0.447) ( p for interaction 0.058). Conclusion Our data indicate that subjects with the ABCA1 R219K variant may get significantly less heart disease risk reduction from pravastatin treatment than those without the variant.

We report a novel heterozygous apolipoprotein A-I (apoA-I) missense mutation (c.517C>A, p.Arg149Ser, designated as apoA-IBoston) in a 67-year-old woman and her 2 sons, who had mean serum high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-I in very large α-1 HDL that were 10%, 35%, and 16% of normal, respectively (all P

Objective We report a novel apolipoprotein (apo) A-I truncation (apoA-I Mytilene ) due to a heterozygous nonsense mutation (c.718C > T, p.Gln216*) in a 68-year-old male proband with premature coronary heart disease (CHD), corneal arcus, and very low plasma concentrations of HDL cholesterol (HDL-C) and apoA-I. Two family members also had the same mutation. Our objectives were to characterize the kindred and to examine the kinetics of apoA-I, as well as cellular cholesterol efflux capacity in the proband. Methods We carried out the kinetic studies using a primed constant infusion of [5,5,5-D 3 ]L-leucine and isotopic enrichment was determined by gas chromatography mass spectrometry in the proband and seven controls with low HDL-C. To assess cellular cholesterol efflux capacity, we used a validated ex vivo system that involved incubation of J774 macrophages with apoB-depleted serum from the proband, five controls with normal HDL-C, and two controls with low HDL-C. Results Stable isotope kinetic studies indicated that the proband had an apoA-I production rate (PR) that was 41% lower than the mean PR observed in low HDL-C controls ( n = 7). The cellular cholesterol efflux capacity assessment showed normalized cholesterol efflux capacity in the proband was decreased by 36% compared to the mean normalized cholesterol efflux capacity of normal controls ( n = 5). Conclusions Our data indicate that this novel heterozygous apoA-I truncation is associated with markedly decreased levels of HDL-C, plasma apoA-I, and apoA-I in large α-1 HDL particles, as well as decreased total cellular cholesterol efflux and decreased apoA-I production.

Sudden death constitutes one of the most frequent causes of death in adults. In order to look for genetic markers that could play a role in the sudden death in adults (SDA), the common deletions of 4977 bp in the mitochondrial DNA and variations in the apoB gene were studied. The correlation of mtDNA common deletion with SDA victims might offer a rapid and simple tool to provide additional information in complex SDA investigations

s 677 4. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987;84(19):6919–6923. 5. Soria L, Ludwig E, Clarke H, Vega G, Grundy S, McCarthy B. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(2):587–591. 6. Hansen PS. Familial defective apolipoprotein B-100. Dan Med Bull. 1998;45(4):370–382. 7. Horvath A, Ganev V. The mutation APOB-100 R3500Q in Eastern Europe. European Heart Journal. 2001;156(1):241–242. 8. Horvath A, Savov A, Kirov S, et al. High frequency of the ApoB-100 R3500Q mutation in Bulgarian hypercholesterolaemic subjects. J Med Genet. 2001;38(8):536–540. 9. Klancar G, Groselj U, Kovac J, et al. Universal Screening for Familial Hypercholesterolemia in Children. J Am Coll Cardiol. 2015;66(11): 1250–1257. 10. Tichy L, Freiberger T, Zapletalova P, Soska V, Ravcukova B, Fajkusova L. The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLRmutations and genotype-phenotype correlations. European Heart Journal. 2012;223(2):401–408. 11. Vohnout B, Raslova K, Gasparovic J, et al. Lipid levels and their genetic regulation in patients with familial hypercholesterolemia and familial defective apolipoprotein B-100: the MEDPED Slovakia Project. Atheroscler Suppl. 2003;4(3):3–5. 12. Marz W, Ruzicka C, Pohl T, Usadel KH, Gross W. Familial defective apolipoprotein B-100: mild hypercholesterolaemia without atherosclerosis in a homozygous patient. Lancet. 1992;340(8831):1362. 13. Schaefer JR, Scharnagl H, Baumstark MW, et al. Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arterioscler Thromb Vasc Biol. 1997;17(2):348–353. 14. Ejarque I, Civer M, Francisco Ascaso J, et al. [Identification and characterization of the first Spanish familial ligand-defective apolipoprotein B homozygote]. Med Clin (Barc). 2001;116(4):138–141. 15. Ceska R, Vrablik M, Horinek A. Familial defective apolipoprotein B100: a lesson from homozygous and heterozygous patients. Physiol Res. 2000;49(Suppl 1):S125–130. 16. Shen H, Damcott CM, Rampersaud E, et al. Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish. Arch Intern Med. 2010;170(20):1850–1855. 17. Horinek A, Ceska R, Sobra J, Vrablik M. Familial defective apolipoprotein B-100 homozygote with premature coronary atherosclerosis. A case report. J Intern Med. 1999;246(2):235–236. 18. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol. 2015;9(2):129–169.

Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis.

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups (p = 0.025, −34.2 vs. −36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes (p = 0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype (p = 0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice.

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, −37.0%; heterozygotes, 25.8% of the population, −36.0%; and homozygotes, 2.7% of the population, −31.8%, p = 0.003 at 6 months, and p = 0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Low serum high density lipoprotein cholesterol level (HDL-C)