The island of Gran Canaria: A genetic isolate for familial hypercholesterolemia.

BACKGROUND: Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain). OBJECTIVES: This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria. METHODS: Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR. RESULTS: On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype. CONCLUSIONS: These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis.

BACKGROUND: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. OBJECTIVE: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. METHODS: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory -biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. RESULTS: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. CONCLUSIONS: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.

Familial hypercholesterolemia in pediatric patients. The success begins here

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Sleep duration and subclinical atherosclerosis: The Aragon Workers' Health Study.

BACKGROUND AND AIMS: Few studies have evaluated the association of sleep duration with subclinical atherosclerosis, and with heterogeneous findings. We evaluated the association of sleep duration with the presence of coronary, carotid, and femoral subclinical atherosclerosis in healthy middle-age men with low prevalence of clinical comorbidities. METHODS: We performed a cross-sectional analysis of 1968 men, 40-60 years of age, participating in the Aragon Workers' Health Study (AWHS). Duration of sleep during a typical work week was assessed by questionnaire. Coronary artery calcium scores (CACS) was assessed by computed tomography and the presence of carotid plaque and femoral plaque by ultrasound. RESULTS: In fully adjusted models, the odds ratios (95% CI) for CACS >0 comparing sleep durations of ≤5, 6, and ≥8 h with 7 h were 1.34 (0.98-1.85), 1.35 (1.08-1.69) and 1.21 (0.90-1.62), respectively (p = 0.04). A similar U-shaped association was observed for CACS ≥100 and for CACS. The corresponding odds ratios for the presence of at least one carotid plaque were ≤5, 6, and ≥8 h with 7 h were 1.23 (0.88-1.72), 1.09 (0.86-1.38), and 0.86 (0.63-1.17), respectively (p = 0.31), and for the presence of at least one femoral plaque were 1.25 (0.87-1.80), 1.19 (0.93-1.51) and 1.17 (0.86-1.61), respectively (p = 0.39). CONCLUSIONS: Middle-aged men reporting 7 h of sleep duration had the lowest prevalence of subclinical coronary atherosclerosis as assessed by CACs. Our results support that men with very short or very long sleep durations are at increased risk of atherosclerosis.

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

Twelve years of experience with miglustat in the treatment of type 1 Gaucher disease: The Spanish ZAGAL project.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

Autosomal recessive hypercholesterolemia in Spain.

BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in LDL protein receptor adaptor 1 (LDLRAP1). It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. We aimed to characterize ARH in Spain. METHODS: Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia of Spain were reviewed. RESULTS: Seven patients with ARH were identified, 6 true homozygous and one compound heterozygous with a novel mutation: c.[863C>T];p.[Ser288Leu]. High genetic heterogeneity was found in this cohort. True homozygous subjects for LDLRAP1 have more severe phenotypes than the compound heterozygous patient, but similar to patients with homozygous familial hypercholesterolemia (HoFH). Cardiovascular disease was present in 14% of the ARH patients. LDL-C under treatment was above 185 mg/dl and the response to PCSK9 inhibitors was heterogeneous. Finally, the estimated prevalence in Spain is very low, with just 1 case per 6.5 million people. CONCLUSIONS: ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of ASCVD than HoFH.

ABCG5/G8 gene is associated with hypercholesterolemias without mutation in candidate genes and noncholesterol sterols.

CONTEXT: Approximately 20% to 40% of clinically defined familial hypercholesterolemia (FH) cases do not show a causative mutation in candidate genes (mutation-negative FH), and some of them may have a polygenic origin. OBJECTIVE: The aim of this work was to study the prevalence of ABCG5/G8 genetic variants in mutation-negative FH, as defects in these genes relate to intestinal hyperabsorption of cholesterol and thus ABCG5/G8 variants could explain in part the mechanism of hypercholesterolemia. DESIGN, SETTING, AND PATIENTS: We sequenced the ABCG5/G8 genes in 214 mutation-negative FH and 97 controls. Surrogate markers of cholesterol absorption (5α-cholestanol, ß-sitosterol, campesterol, stigmasterol, and sitostanol) were quantified by high-performance liquid chromatography-tandem mass spectrometry in both studied groups. RESULTS: We found 8 mutation-negative FH patients (3.73%) with a pathogenic mutation in ABCG5/G8 genes. We observed significantly higher concentration of surrogate markers of cholesterol absorption in mutation-negative FH than in controls. In addition, we found significantly higher concentrations of cholesterol absorption markers in mutation-negative FH with ABCG5/G8 defects than in mutation-negative, ABCG5/G8-negative FH. A gene score reflecting the number of common single nucleotide variants associated with hypercholesterolemia was significantly higher in cases than in controls (P = .032). Subjects with a gene score above the mean had significantly higher 5α-cholestanol and stigmasterol than those with a lower gene score. CONCLUSIONS: Mutation-negative FH subjects accumulate an excess of rare and common gene variations in ABCG5/G8 genes. This variation is associated with increased intestinal absorption of cholesterol, as determined by surrogate makers, suggesting that these loci contribute to hypercholesterolemia by enhancing intestinal cholesterol absorption.

Functional analysis of new 3' untranslated regions genetic variants in genes associated with genetic hypercholesterolemias.

BACKGROUND: Familial hypercholesterolemia (FH) is the best-described autosomal dominant genetic hypercholesterolemia (GH). Mutations in candidate genes can explain a high proportion of FH cases, but for many, no causative mutations are detected (designed non-FG-GH), suggesting the existence of additional genetic variants associated with the disease. OBJECTIVE: We aimed to identify new single-nucleotide variants (SNVs) located at the 3' untranslated regions (3'UTRs) of the low-density lipoprotein receptor, low-density lipoprotein receptor-related protein-associated protein 1, ATP-binding cassette sub-family G member 5, and sterol regulatory element-binding protein 2 genes in non-FH-GH individuals and investigated whether the association of these SNVs with non-FH-GH could be explained by changes in the affinity of regulatory microRNAs (miRNA) targeting the sequences modified by the SNVs. METHODS: The study includes probands with non-FH-GH attending 2 lipid clinics in Spain. We performed functional analyses of selected variants using a luciferase reporter system. Through in silico target-prediction tools, we identified miRNAs, which binding to the 3'UTR could be affected by the presence of specific SNVs. We used analogs and inhibitors of these miRNAs to test this possibility. RESULTS: We identified 11 new SNVs showing significant association with non-FH-GH. We show that the presence of 4 of these SNVs leads to significant changes in the transcriptional levels of the reporter gene. Through mechanistic analysis, we identified 2 miRNAs (miR-27a and miR-133-3p) targeting the 3'UTR of sterol regulatory element-binding protein 2 and an additional miRNA (miR-92a) targeting the 3'UTR of low-density lipoprotein receptor-related protein-associated protein 1. CONCLUSION: Our findings reveal novel regulatory links between certain miRNAs and key genes regulating cholesterol homeostasis. They also highlight the potential of miRNAs as therapeutic targets for the treatment of FH.

Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease.

BACKGROUND: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. AIM: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. METHODS: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (≤1994, cohort A; ≥1995, cohort B). RESULTS: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed ≤ 1994 and 53 ≥ 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed ≤1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001). CONCLUSIONS: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.

The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. METHODS: Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. FINDINGS: Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. CONCLUSIONS: Several clinical niches have been identified that harbor patients at increased risk of NP-C.

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. METHODS: In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. RESULTS: In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. CONCLUSION: This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis.

Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update.

PURPOSE OF REVIEW: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. RECENT FINDINGS: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified. SUMMARY: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. METHODS AND RESULTS: Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH-of whom, 47 were true homozygous (1 for APOB, 5 for LDLRAP1, and 41 for LDLR), 45 compound heterozygous for LDLR, 3 double heterozygous for LDLR and PSCK9, and 2 double heterozygous for LDLR and APOB. No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. CONCLUSIONS: HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.

Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.

La PCSK9 sigue dando sorpresas / PCSK9 continues surprising us

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Genetic Variants of LDLR and PCSK9 Associated with Variations in Response to Antihypercholesterolemic Effects of Armolipid Plus with Berberine.

BACKGROUND: Armolipid Plus (AP) is a nutraceutical that contains policosanol, fermented rice with red yeast, berberine, coenzyme Q10, folic acid, and astaxanthin. It has been shown to be effective in reducing plasma LDL cholesterol (LDLc) levels. In the multicenter randomized trial NCT01562080, there was large interindividual variability in the plasma LDLc response to AP supplementation. We hypothesized that the variability in LDLc response to AP supplementation may be linked to LDLR and PCSK9 polymorphisms. MATERIAL AND METHODS: We sequenced the LDLR 3' and 5' untranslated regions (UTR) and the PCSK9 5' UTR of 102 participants with moderate hypercholesterolemia in trial NCT01562080. In this trial, 50 individuals were treated with AP supplementation and the rest with placebo. RESULTS: Multiple linear regression analysis, using the response of LDLc levels to AP as the dependent variable, revealed that polymorphisms rs2149041 (c.-3383C>G) in the PCSK9 5' UTR and rs14158 (c.*52G>A) in the LDLR 3' UTR explained 14.1% and 6.4%, respectively, of the variability after adjusting for gender, age, and BMI of individuals. Combining polymorphisms rs2149041 and rs14158 explained 20.5% of this variability (p < 0.004). CONCLUSIONS: Three polymorphisms in the 3' UTR region of LDLR, c.*52G>A, c.*504G>A, and c.*773A>G, and two at the 5' UTR region of PCSK9, c.-3383C>G and c.-2063A>G, were associated with response to AP. These results could explain the variability observed in the response to berberine among people with moderate hypercholesterolemia, and they may be useful in identifying patients who could potentially benefit from supplementation with AP.

Femoral and Carotid Subclinical Atherosclerosis Association With Risk Factors and Coronary Calcium: The AWHS Study.

BACKGROUND: Early subclinical atherosclerosis has been mainly researched in carotid arteries. The potential value of femoral arteries for improving the predictive capacity of traditional risk factors is an understudied area. OBJECTIVES: This study sought to evaluate the association of subclinical carotid and femoral plaques with risk factors and coronary artery calcium score (CACS) in middle-aged men. METHODS: Participants (n = 1,423) of the AWHS (Aragon Workers' Health Study), a study designed to assess cardiovascular risk and subclinical atherosclerosis in a cohort of middle-aged men (40 to 59 years of age), underwent carotid and femoral ultrasound plus noncontrast coronary computed tomography. Subclinical atherosclerosis was defined as the presence of any plaque in carotid or femoral arteries and/or CACS ≥1. Logistic regression models were used to estimate the prevalence of atherosclerosis adjusted for risk factors and age, to evaluate the association of atherosclerosis with risk factors, and to calculate areas under the receiver-operating characteristic curves for the presence of positive CACS. RESULTS: Subclinical atherosclerosis was found in 72% of participants. Plaques were most common in femoral arteries (54%), followed by coronary calcification (38%) and carotid plaques (34%). Association of atherosclerosis with risk factors was stronger in femoral arteries than carotid or coronary arteries. The area under the receiver-operating characteristic curve for prediction of positive CACS increased from 0.665 when considering only risk factors (dyslipidemia, current smoking, hypertension, diabetes, and age) to 0.719 when adding femoral and carotid plaques (p < 0.001). In this model, the femoral odds ratio (2.58) exceeded the carotid odds ratio (1.80) for prediction of positive CACS. CONCLUSIONS: Subclinical atherosclerosis was highly prevalent in this middle-aged male cohort. Association with risk factors and positive CACS was stronger in femoral than carotid arteries. Screening for femoral plaques may be an appealing strategy for improving cardiovascular risk scales and predicting coronary disease.