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1.
Circ Cardiovasc Genet ; 8(6): 823-31, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26374825

ABSTRACT

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Cholesterol, LDL/blood , Coronary Artery Disease , Hyperlipoproteinemia Type II , Mutation , Proprotein Convertases , Serine Endopeptidases , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Coronary Artery Disease/genetics , Double-Blind Method , Female , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Male , Middle Aged , Proprotein Convertase 9 , Proprotein Convertases/antagonists & inhibitors , Proprotein Convertases/genetics , Proprotein Convertases/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism
2.
Curr Atheroscler Rep ; 15(3): 310, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23371064

ABSTRACT

The link between proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesterol metabolism was established only in 2003 when genetic mapping and positional cloning in patients with autosomal dominant hypercholesterolemia in which linkage to the loci coding for the LDL receptor and apolipoprotein B had been excluded identified the genetic defect missense as mutations in PCSK9, a protein/enzyme previously unknown to be related to lipid metabolism. Laboratory-based investigations confirmed that these were gain-of-function mutations. Further studies in cohorts with low LDL cholesterol (LDLc) levels from large epidemiological cardiovascular studies reported that loss-of-function mutations in PCSK9 were associated with protection from cardiovascular disease. An additional critical observation provided evidence that the interaction of PCSK9 and the LDL receptor was through circulating, not intracellular, PCSK9, which bound to the receptor, and then mediated the recycling of the LDL receptor. These findings established PSCK9 as a potential therapeutic target and resulted in biopharmaceutical companies developing interventions designed to lower LDLc levels. Clinical development programs for monoclonal antibodies against PCSK9 have advanced rapidly with completion of comprehensive phase 1 and 2 trials with both REGN727/SAR236553 (REGN727) and AMG 145, clearly demonstrating substantial reductions in LDLc levels in patients receiving diet alone, low, moderate, and high doses of statins, or statin combined with ezetimibe, and both heterozygous familial hypercholesterolemia and nonfamilial hypercholesterolemia subjects. Concomitant and parallel reductions in the levels of apolipoprotein B and its related lipoproteins, and small but significant increases in HDL cholesterol levels were seen as anticipated. An unanticipated and robust decrease in lipoprotein(a) levels was also noted. Although these trials have been relatively short term, no significant safety issues or target organs of interest have emerged. Larger and much longer phase 3 trials are now in progress to assess the long-term tolerability, safety, and impact on cardiovascular disease events of these very effective LDLc lowering compounds.


Subject(s)
Anticholesteremic Agents/therapeutic use , Cholesterol, LDL/blood , Hypercholesterolemia/drug therapy , Proprotein Convertases/metabolism , Serine Endopeptidases/metabolism , Cholesterol, LDL/drug effects , Humans , Hypercholesterolemia/blood , Proprotein Convertase 9
3.
N Engl J Med ; 366(12): 1108-18, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-22435370

ABSTRACT

BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS: In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS: Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS: In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).


Subject(s)
Antibodies, Monoclonal/administration & dosage , Anticholesteremic Agents/administration & dosage , Cholesterol, LDL/blood , Hypercholesterolemia/drug therapy , Proprotein Convertases/antagonists & inhibitors , Receptors, LDL/drug effects , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/therapeutic use , Atorvastatin , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Heptanoic Acids/therapeutic use , Humans , Hypercholesterolemia/metabolism , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/metabolism , Injections, Intravenous , Injections, Subcutaneous , Least-Squares Analysis , Lipoproteins/blood , Male , Middle Aged , Proprotein Convertase 9 , Proprotein Convertases/immunology , Proprotein Convertases/metabolism , Pyrroles/therapeutic use , Receptors, LDL/metabolism , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism
4.
Cardiovasc Ther ; 30(6): 342-50, 2012 Dec.
Article in English | MEDLINE | ID: mdl-21884017

ABSTRACT

INTRODUCTION: The increased thrombotic cardiovascular (CV) risk in trials of cyclo-oxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nonsteroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP). AIMS: We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospective randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists' Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated. RESULTS: We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk. CONCLUSIONS: Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BP-elevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Blood Pressure/drug effects , Diclofenac/administration & dosage , Pyridines/adverse effects , Sulfones/adverse effects , Thrombosis/chemically induced , Aged , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis/drug therapy , Body Weight , Comorbidity , Cyclooxygenase 2 Inhibitors/adverse effects , Diclofenac/therapeutic use , Double-Blind Method , Etoricoxib , Female , Heart Failure/chemically induced , Heart Failure/epidemiology , Humans , Male , Middle Aged , Prospective Studies , Pyridines/therapeutic use , Racial Groups , Risk Assessment , Sulfones/therapeutic use , Thrombosis/epidemiology
5.
J Hypertens ; 27(4): 886-93, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19516186

ABSTRACT

OBJECTIVE: To evaluate the hypertensive effects of etoricoxib and diclofenac relative to baseline hypertension risk factors in arthritis patients. METHODS: Multivariate analysis of data from the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study (n = 23 504). We evaluated risk factors for change in systolic blood pressure (BP) (SBP) and diastolic BP (DBP) at 4 months versus baseline; exceeding predefined limits of change (PLoC) in BP anytime during the study; and the effect of concomitant antihypertensive class on SBP and exceeding SBP PLoC. RESULTS: Increased SBP was most highly associated with history of hypertension (+3.04 mmHg; P < 0.0001), as were increased DBP (+1.28 mmHg; P < 0.0001), and exceeding DBP PLoC [odds ratio (OR) = 1.83; P < 0.0001]. Exceeding SBP PLoC (OR = 1.50; P < 0.0001) was most highly associated with age at least 65 years. Etoricoxib (vs. diclofenac) was also significantly associated with increased SBP (P < 0.0001), DPB (P < 0.0001 to P = 0.0015), and exceeding SBP PLoC (P < 0.0001 to P = 0.002). Compared with no antihypertensive medication, background calcium channel blockers (CCB) were associated with a small, nonsignificant decrease in SBP (-0.60 mmHg) and no increased odds of exceeding SBP PLoC [OR = 1.00 (95% CI 0.71, 1.42)]. All other antihypertensive classes were associated with either no change or numerically or statistically significantly increased SBP and increased odds of exceeding PLoC. CONCLUSION: History of hypertension and age at least 65 years were most strongly associated with increased BP. Treatment with etoricoxib vs. diclofenac was also a significant factor for increased BP. CCBs appear to maintain antihypertensive effects with concurrent NSAID therapy better than other examined antihypertensive drug classes.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Arthritis, Rheumatoid/drug therapy , Blood Pressure/drug effects , Cyclooxygenase 2 Inhibitors/adverse effects , Diclofenac/adverse effects , Osteoarthritis/drug therapy , Pyridines/adverse effects , Sulfones/adverse effects , Aged , Arthritis, Rheumatoid/physiopathology , Etoricoxib , Female , Humans , Hypertension/chemically induced , Male , Middle Aged , Multivariate Analysis , Osteoarthritis/physiopathology
6.
Clin Auton Res ; 19(3): 175-81, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19370373

ABSTRACT

OBJECTIVES: In order to determine the reliability of a self-administered instrument to diagnose excessive sweating conditions, including palmar hyperhidrosis (PH), we designed two successive questionnaires and compared responses with physical examination and sweat measurement in normal volunteers and a cohort of patients with documented PH. The reliable diagnosis of PH via questionnaire would enable molecular epidemiological studies without the need for physical examination or direct sweat measurement. METHODS: Subjects self identified as either normal or affected by PH. Each completed one or both questionnaires and underwent physical examination. Sweat production from the thenar eminence and forehead was measured at rest and following mental/emotional stress. Correlation among sweat measurement, physical examination, and questionnaire score was assessed. RESULTS: Forty-seven subjects enrolled in the study, 29 of whom underwent sweat measurements. The participants' perception of whether they were affected agreed with the examiner's visual and tactile observation of PH in all cases (P < 0.0005). The mean peak sweat rate for those participants with PH was 1.59 mg/cm(2)/min, while that of the normal cohort was 0.37 mg/cm(2)/min (P = 0.001). The mean questionnaire #1 and #2 scores for those participants with PH and the normal cohort was 7.10 versus 0.36 (P = 0.0005) and 5.145 versus 0.045 (P = 0.0005), respectively. Peak sweat rate correlated with questionnaire score (Pearson correlation coefficient = 0.723). INTERPRETATION: Palmar hyperhidrosis can be accurately diagnosed via questionnaire. Molecular epidemiological studies of PH may be reliably conducted without the need for direct physical examination.


Subject(s)
Hand/pathology , Hyperhidrosis/diagnosis , Surveys and Questionnaires , Humans
7.
Rheumatology (Oxford) ; 48(4): 425-32, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19223284

ABSTRACT

OBJECTIVE: To compare cardiovascular (CV) and other safety and efficacy parameters of etoricoxib 60 and 90 mg, and diclofenac 150 mg. METHODS: This double-blind study randomized OA patients to etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on etoricoxib dose and disease. RESULTS: A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with etoricoxib was 3.4-3.6 mmHg (diastolic BP: 1.0-1.5 mmHg), while diclofenac produced a maximum average change of 0.9-1.9 mmHg (diastolic BP: 0.0-0.5 mmHg). Both agents resulted in similar efficacy regardless of etoricoxib dose. CONCLUSION: Long-term etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.


Subject(s)
Cyclooxygenase Inhibitors/adverse effects , Diclofenac/adverse effects , Osteoarthritis/drug therapy , Pyridines/adverse effects , Sulfones/adverse effects , Thrombosis/chemically induced , Aged , Cardiovascular Diseases/chemically induced , Cyclooxygenase Inhibitors/therapeutic use , Diclofenac/therapeutic use , Double-Blind Method , Emergencies , Etoricoxib , Female , Gastrointestinal Diseases/chemically induced , Humans , Male , Middle Aged , Odds Ratio , Osteoarthritis/complications , Pyridines/therapeutic use , Safety , Sample Size , Sulfones/therapeutic use
8.
Hum Genet ; 113(1): 60-70, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12644935

ABSTRACT

The conservation of genomic organization of mammalian species has been of interest for its usefulness in characterizing the genetics of traits and diseases and as one tool for examining evolution. The recent rough draft sequencing of the mouse and human genomes provides the opportunity for more detailed analyses. The current study examines the extent of homology between human chromosome 20 and the mouse genome by comparing putative coding and non-coding sequence to provide insight into organizational and sequence similarities between the species. The relative position of each of 460 putative coding orthologues was the same in both species, except for a single genomic segment rearrangement. The similarity extended to exon/intron structure, the size of introns, as well as strong evidence for the conservation of position of ancient LINE-1, LINE-2 and LTR repetitive sequence and the subtelomeric region of the long arm of human chromosome 20 and that of mouse chromosome 2. There was also evidence for conservation of a limited amount of non-coding single-copy sequence. Together these data provide additional insight into the extent of conservation of mammalian genomic organization and sequence.


Subject(s)
Chromosomes, Human, Pair 20/genetics , Conserved Sequence/genetics , Genome , Mice/genetics , Animals , Base Sequence , Biological Evolution , Exons/genetics , Humans , Introns/genetics , Models, Genetic , Molecular Sequence Data , Repetitive Sequences, Nucleic Acid/genetics , Sequence Homology, Nucleic Acid , Untranslated Regions/genetics
9.
Am J Hum Genet ; 72(3): 739-48, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12574987

ABSTRACT

The genomic evolution and causes of phenotypic variation among humans and great apes remain largely unknown, although the phylogenetic relationships among them have been extensively explored. Previous studies that focus on differences at the amino acid and nucleotide sequence levels have revealed a high degree of similarity between humans and chimpanzees, suggesting that other types of genomic change may have contributed to the relatively large phenotypic differences between them. For example, the activity of long interspersed element 1 (LINE-1) retrotransposons may impose significant changes on genomic structure and function and, consequently, on phenotype. Here we investigate the relative rates of LINE-1 amplification in the lineages leading to humans, bonobos (Pan paniscus), and chimpanzees (P. troglodytes). Our data indicate that LINE-1 insertions have accumulated at significantly greater rates in bonobos and chimpanzees than in humans, provide insights into the timing of major LINE-1 amplification events during great ape evolution, and identify a Pan-specific LINE-1 subfamily.


Subject(s)
Long Interspersed Nucleotide Elements/genetics , Pan troglodytes/genetics , Animals , Base Sequence , Chromosome Mapping , Gene Amplification , Humans , Molecular Sequence Data , Phylogeny , Species Specificity
10.
Proc Natl Acad Sci U S A ; 99(16): 10522-7, 2002 Aug 06.
Article in English | MEDLINE | ID: mdl-12138175

ABSTRACT

The amplification of DNA by LINE-1 (L1) retrotransposons has created a large fraction of the human genome. To better understand their role in human evolution we endeavored to delineate the L1 elements that have amplified since the emergence of the hominid lineage. We used an approach based on shared sequence variants to trace backwards from the currently amplifying Ta subfamily. The newly identified groups of insertions account for much of the molecular evolution of human L1s. We report the identification of a L1 subfamily that amplified both before and after the divergence of humans from our closest extant relatives. Progressively more modern groups of L1s include greater numbers of insertions. Our data are consistent with the hypothesis that the rate of L1 amplification has been increasing during recent human evolution.


Subject(s)
Evolution, Molecular , Long Interspersed Nucleotide Elements/genetics , Animals , Base Sequence , DNA, Complementary , Genotype , Hominidae , Humans , Molecular Sequence Data , Mutagenesis, Insertional , Phylogeny , Poly A
11.
Am J Hum Genet ; 71(2): 312-26, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12070800

ABSTRACT

The Ta (transcribed, subset a) subfamily of L1 LINEs (long interspersed elements) is characterized by a 3-bp ACA sequence in the 3' untranslated region and contains approximately 520 members in the human genome. Here, we have extracted 468 Ta L1Hs (L1 human specific) elements from the draft human genomic sequence and screened individual elements using polymerase-chain-reaction (PCR) assays to determine their phylogenetic origin and levels of human genomic diversity. One hundred twenty-four of the elements amenable to complete sequence analysis were full length ( approximately 6 kb) and have apparently escaped any 5' truncation. Forty-four of these full-length elements have two intact open reading frames and may be capable of retrotransposition. Sequence analysis of the Ta L1 elements showed a low level of nucleotide divergence with an estimated age of 1.99 million years, suggesting that expansion of the L1 Ta subfamily occurred after the divergence of humans and African apes. A total of 262 Ta L1 elements were screened with PCR-based assays to determine their phylogenetic origin and the level of human genomic variation associated with each element. All of the Ta L1 elements analyzed by PCR were absent from the orthologous positions in nonhuman primate genomes, except for a single element (L1HS72) that was also present in the common (Pan troglodytes) and pygmy (P. paniscus) chimpanzee genomes. Sequence analysis revealed that this single exception is the product of a gene conversion event involving an older preexisting L1 element. One hundred fifteen (45%) of the Ta L1 elements were polymorphic with respect to insertion presence or absence and will serve as identical-by-descent markers for the study of human evolution.


Subject(s)
Evolution, Molecular , Genetic Variation , Long Interspersed Nucleotide Elements , Animals , Base Sequence , Cell Line , Gene Conversion , Gene Dosage , Genome, Human , HeLa Cells , Humans , Phylogeny , Polymorphism, Genetic , Primates , Sequence Alignment , Transduction, Genetic
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