Abstract Background: Recent advances in the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have contributed to increased overall survival (OS). Despite advances, MBC remains incurable and there is a subset of patients with clinical features that are associated with poorer prognosis. This study described the patient characteristics, treatment patterns, and outcomes of a cohort of US patients with HR+, HER2- MBC as a function of various factors associated with poor prognosis, including presence (vs. absence) of liver metastases (LM). Methods: This retrospective study used US community oncology electronic health record data from the Vector Oncology Data Warehouse. Eligible women who received systemic treatment for MBC, had a diagnosis of MBC in 2008 or later, and had completed at least three Patient Care Monitor (PCM) surveys, (a patient-reported outcomes survey collected as a part of clinical care), were included. OS was measured from the start of the first three regimen-based lines (1L, 2L and 3L) of treatment; patients without evidence of death were censored at the last observed visit. The statistical significance of differences in categorical and continuous variables between LM positive (LM+) and LM negative (LM-) were evaluated with chi-square (X2) tests, and t-tests, respectively. Kaplan-Meier and Cox analyses were applied to evaluate differences in OS by LM status and by line of therapy at the start of MBC treatment (unadjusted for treatment). Results: A total of 378 women, 98.4% residing in the South and 40.5% African-American, were included; 295 (78.0%) were LM- at the time of diagnosis. Following 1L, approximately 82.8% and 60.8% of patients received 2L and 3L, respectively. Patients with a LM+ status had a lower mean age (mean: 57.2, SD: 13.8 vs. 61.2, 13.1; p=0.016) and a higher percentage had a grade 3 tumor (36.1 vs. 24.7%; p=0.039) compared to patients with LM-status. Table 1 shows the OS results for 1L-3L. For all 3 lines, median OS for LM+ was shorter than the LM- median OS. LM+ patients had a poorer prognosis as they were more likely to have an OS event across 1L-3L compared to LM- patients. Conclusions: Among this community oncology cohort, median OS in 1L was 14 months shorter in LM+ patients compared to LM- patients. It is important to note that the sample size and selection criteria may limit generalizability of these results. Despite progress in treating women with MBC, treatment options are lacking for patients with less favorable prognosis, including those with LM. Other potential indicators of poor prognosis, such as high tumor grade, are being explored. Table 1.OS (months) by regimen-based line of therapy Measure Liver Mets (LM+) No Liver Mets (LM-) HR p-value 1L, # of Events/ # of Patients55/83168/295 Median (95% CI)23.9 (15.5-28.6)35.2 (30.1-42.3) <0.0001* Cox Hazard Ratio 1.93<0.0001 2L, # of Events/ # of Patients48/72149/241 Median (95% CI)16.6 (12.0-22.6)24.2 (21.3-29.0) 0.002* Cox Hazard Ratio 1.490.040 3L, # of Events/ # of Patients35/52118/178 Median (95% CI)11.5 (7.0-21.0)17.4 (14.7-20.0) 0.038* Cox Hazard Ratio 1.540.060CI=Confidence Interval; *p-value was derived using log rank test. Citation Format: Saverno K, Cuyun Carter G, Dufour R, Price G, Li L, DeLuca A, Nash Smyth E, Battiato L, Gable J, Walker MS, Huang Y-J, Hannas S, Schwartzberg LS. Outcomes among metastatic breast cancer patients with characteristics that confer a less favorable prognosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-66.

BACKGROUND AND AIMS:Familial hypercholesterolemia (FH) is under-diagnosed and under-treated in most of the world, including Canada. National registries play a key role in identifying patients with FH, understanding gaps in care, and advancing the science of FH to better treat these patients.METHODS:FH Canada has established a national registry across 19 academic sites acting as "hubs" in Canada to increase awareness and access to standard-of-care therapies.RESULTS:To-date, more than 3000 patients with FH have been entered into a secure, web-based database. Early outcomes of this initiative include a greater understanding of treatment gaps for patients with FH in Canada, the development of a new, simplified Canadian definition of FH, and tools to aid in the diagnosis of FH, including imputation of baseline levels of LDL cholesterol.CONCLUSIONS:As the national registry expands in size and scope, further learning will emerge with ultimate benefit for the diagnosis and treatment of FH in Canada.

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. OBJECTIVE: The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. METHODS: After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. RESULTS: During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). CONCLUSIONS: In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels. (C) 2018 National Lipid Association. Published by Elsevier Inc.

Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.

Background and aims: ODYSSEY OLE (open-label extension; NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolemia (HeFH), receiving maximally tolerated statins, who had completed one of four Phase 3 double-blind parent studies (all 18 months' duration), with the aim to assess longer-term safety and efficacy of alirocumab. Methods: Patients received starting dose alirocumab 75 mg every 2 weeks (Q2W; patients from FH I, FH II, and LONG TERM) or alirocumab 150 mg Q2W (patients from HIGH FH). Low-density lipoprotein cholesterol (LDL-C) levels were blinded to the patient and physician until Week 8; from Week 8, LDL-C levels were communicated to physicians. From Week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible per physician's clinical judgment according to patients LDL-C levels. Results: Patients who had received alirocumab (n = 655) compared with placebo (n = 330) in the parent studies exhibited similar rates of treatment-emergent adverse events (TEAEs; 87.3% vs. 83.9%) during OLE (2.5 years median alirocumab exposure). Overall, 33 patients (3.4%) experienced TEAEs leading to permanent treatment discontinuation. At Week 8, alirocumab reduced mean LDL-C by 44.2% (reduction from 151.9 mg/dL at parent study baseline to 84.9 mg/dL); reduction in LDL-C was consistent to Week 96 of OLE. Reductions in lipid parameters were similar regardless of treatment allocation in the parent study. Conclusions: In patients with HeFH, no unexpected long-term safety concerns were observed with alirocumab compared with previously published data; durability of LDL-C-lowering over 3 years (including 1.5 years of parent trials) was demonstrated.

Background: The prevalence of cardio-metabolic diseases (CMD) is drastically increasing worldwide. Anthropometric measures of fat accumulation are correlated with CMD and Metabolic Syndrome (MS), but few studies have addressed this association in sub-Saharan African populations. Aim: To investigate the association between anthropometric features, MS and other CMD risk factors in a population from Kenya. Subjects and methods: In this cross-sectional study including 1405 Kenyans, anthropometric measurements including visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) were carried out. Fasting blood glucose and standard oral glucose tolerance test, fasting serum insulin and plasma lipids were analysed. Homeostatic model assessment of insulin resistance was calculated. Systolic and diastolic blood pressures were measured. Results: CMD risk factors and MS were associated with all anthropometric features, except for high-density lipoprotein cholesterol levels (p < 0.05). The strongest association between MS and anthropometrics was seen with SAT (beta = 1.45 +/- 0.32 in men and 0.88 +/- 0.14 in women, both p < 0.05). Conclusions: Anthropometric measures, especially features of central obesity such as VAT and SAT, are relevant indicators of cardio-metabolic health in Kenyan populations. SAT is the strongest predictor of MS. These results highlight the need for further research on the pathological implication of VAT and SAT, in order to understand patterns of fat distribution and cardio-metabolic health among different ethnic groups.

BACKGROUND:Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD.METHODS:A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study.RESULTS:Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender.CONCLUSION:Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.

Quantitative sensory testing (QST) has been previously used to study pain in chronic pancreatitis (CP) but included methods that are not suitable for clinical purposes. The aims of this study were to determine if pancreatic QST (P-QST) can differentiate patients into distinct pain phenotypes and to determine the association of these with their clinical pain and psychiatric comorbidities.A multicenter cross-sectional study was conducted where patients completed validated questionnaires assessing quality of life (QoL), depression and anxiety scores as well as clinical pain symptoms followed by P-QST which included a cold pressor test, repetitive pinprick stimuli and pressure stimulation of the upper abdominal (T10) and control dermatomes. P-QST categorized patients into pain phenotypes based on a previously established nomogram. QoL, clinical pain and psychiatric assessment scores were compared across these groups.A total of 179 patients were enrolled with a mean age of 54.1±13.6 years among whom 59% were males and 42% had an alcoholic etiology. P-QST showed no hyperalgesia in 91 (51%), segmental hyperalgesia in 50 (28%) and widespread hyperalgesia in 38 (21%) patients. Patients with widespread hyperalgesia had significantly higher pain intensity scores (P = .03) and rates of constant pain (P = .002) as well as decreased QoL (P < .001) and physical functioning (P =.03) in comparison with the other two pain phenotypes. In contrast, psychiatric comorbidities were similar across all groups.P-QST may serve as a novel unbiased pain assessment tool in CP as it categorizes patients into distinct pain phenotypes independent of their psychiatric comorbidities.

BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent autosomal codominant disease worldwide and is characterized by elevated low-density lipoprotein cholesterol and premature coronary artery disease (CAD). Polymorphisms in phosphatase and actin regulator 1 (PHACTR1) have been shown to be associated with cardiovascular risk in large genome-wide association studies studies. OBJECTIVE: The aim of the present study is to evaluate the association between the rsl2526453 polymorphism in the PHACTR1 gene and the prevalence of CAD in FH patients. METHODS: A cohort of 668 adult genetically confirmed heterozygous FH subjects were included in the present study. Logistic regression models were used to evaluate the strength of the association between rs12526453 genotype and CAD prevalence. RESULTS: Noncarriers (CC) of the rs12526453 represented 41% of the cohort, whereas heterozygous (CG) and homozygous (GG) carriers represented 44% and 15%, respectively. The prevalence of CAD was significantly higher in non-carriers of the rsl2526453 polymorphism compared to heterozygous and homozygous carriers (38.0%, 25.8%, 24.5%, respectively, P=.001). When a dominant logistic regression model was studied, the association between this single-nucleotide polymorphism and CAD prevalence was significant even after correction for all classical cardiovascular risk factors (odds ratio 0.48, 95% confidence intervals 0.31-0.74, P=.001). CONCLUSION: In the present study, we have shown that the rs12526453 single-nucleotide polymorphism of the PHACTR1 gene is significantly associated with a 50% reduction in the odds of CAD events in FH subjects. Because the protective G allele is frequent in the Caucasian population (allelic frequency of 0.26), screening for this polymorphism in Caucasian FH subjects could further help to stratify risk of CAD in this population. (C) 2018 National Lipid Association. All rights reserved.

Data presented in this article are supplementary material to our article entitled "Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an "FCS Score" (Moulin et al., 2018, in press). The data describe the genotypes of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS), from the validation and replication cohorts.

BACKGROUND: ODYSSEY OLE (NCT01954394) was an open-label extension (OLE) study for patients with heterozygous familial hypercholesterolemia (HeFH) who had completed previous phase 3 clinical trials with alirocumab. Alirocumab dose could be increased or decreased as per physician judgment. OBJECTIVE: To assess how the alirocumab dosing strategy was used by physicians during OLE. METHODS: Patients who entered OLE on a starting dose of alirocumab 75 mg every 2 weeks (Q2W) were included in the analysis (those from FH I, FH II, and LONG TERM trials). Those who completed LONG TERM entered an 8-week washout period before receiving alirocumab 75 mg Q2W at the start of OLE. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible, based on the physician's clinical judgment. RESULTS: In total, 909 patients with HeFH completed the 3 parent studies and were treated during OLE for a duration of up to 40 months. Most patients (56.7%) were maintained on 75 mg Q2W throughout OLE, whereas 43.3% of patients had their dose increased to 150 mg Q2W. The dose was subsequently decreased in 7.4% of the patients in whom alirocumab was initially uptitrated. Overall, treatment-emergent adverse events were similar between those who had received placebo or alirocumab in the parent studies. CONCLUSIONS: In the opinion of physicians, alirocumab 75 mg Q2W enabled over half of patients with HeFH to achieve sufficient low-density lipoprotein cholesterol lowering. (C) 2018 National Lipid Association. Published by Elsevier Inc.

BackgroundEvolocumab significantly lowers low‐density lipoprotein cholesterol (LDL‐C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously.HypothesisLDL‐C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials.MethodsA total of 3146 patients received ≥1 dose of evolocumab or control in four 12‐week phase 3 studies. Percent change from baseline in LDL‐C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested.ResultsIn the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non‐Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low‐magnitude variations in LDL‐C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control.ConclusionsConsistent reductions in LDL‐C were observed in the evolocumab group regardless of demographic and disease characteristics.

BACKGROUND A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol‐anchored high‐density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody–based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase–mediated processing of triglyceride‐rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.)

Alirocumab (ALI) is available in two doses, 75 and 150 mg (to be administered once every 2 weeks [Q2W]). ODYSSEY LONG TERM was a 78-week double-blind trial of ALI 150 mg Q2W versus placebo, as add-on to maximally tolerated statin ± other lipid-lowering therapy (LLT). Patients with heterozygous familial hypercholesterolemia (HeFH) who completed LONG TERM could enter the open-label ODYSSEY OLE (NCT01954394) following an 8-week off-drug wash out period. From the start of OLE up to Week 8, all patients received ALI 75 mg Q2W (with their existing statin/other LLT). For the first time, this gives the opportunity to assess on-treatment LDL-C levels when the dose of ALI is decreased from 150 to 75 mg Q2W in a cohort of HeFH patients. On-treatment LDL-C levels and % change from baseline were compared in the same cohort of patients at Week 8 of LONG TERM (when all patients received ALI 150 mg Q2W) versus Week 8 in OLE (when all received ALI 75 mg Q2W). Baseline and efficacy data were assessed in an on-treatment (mITT) analysis. Safety in OLE was assessed up to the cut-off date for this analysis. A total of 214 patients with HeFH who completed LONG TERM entered OLE (mITT population n=211). Mean (SD) LDL-C of this cohort of patients in LONG TERM was 162.3 (58.6) mg/dL at baseline and 61.6 (42.9) mg/dL at Week 8 with ALI 150 mg (63.1% reduction). For the same cohort of patients in OLE (following 78 weeks of LONG TERM study plus 8 weeks wash-out), mean (SD) LDL-C was 166.6 (59.5) mg/dL at baseline and 89.6 (54.9) mg/dL at Week 8 with ALI 75 mg (47.3% reduction). Safety data for this cohort from OLE were available for ∼12 months: 76.6% reported a treatment-emergent adverse event (TEAE) and 1.4% discontinued due to a TEAE. Local injection site reactions were reported by 4.7%, neurological TEAEs by 3.3%, neurocognitive TEAEs by 0.9%, and hepatic disorders by 1.9% of patients, consistent with what was observed in the 18-month double-blind parent trial. In the same cohort of patients with HeFH receiving statin ± other LLT, absolute LDL-C reductions were 77.0 mg/dL with ALI 75mg Q2W, and 100.7 mg/dL with ALI 150 mg Q2W.

Received research grants from Bayer HealthCare; honoraria and support for educational activities from Aegereon, DACH Society from the prevention of cardiovascular diseases, Genzyme, Quintiles, Chiesi, MSD, Novartis, Novo Nordisk, Pfizer, Ipsen, Bristol-Myers Squibb, Lilly Astra Zeneca, Amgen, Sanofi, and Otsuka. She has performed clinical trials with Amgen and Sanofi related to PCSK9 inhibitors, clinical trials with IONIS related to APOC3 and Lp(a) inhibitors and clinical trials with Genzyme (a Sanofi company) related to mipomersen.

Automated office blood pressure (AOBP) devices are increasingly recommended as preferred BP diagnostic tool. It is unclear how different AOBP devices compare and how the clinical environment impacts on their performance. This study is a prospective randomized factorial parallel four (4) group study comparing the BpTRU and the Omron HEM 907 devices in a closed or open area. Hypertensive patients were recruited during office visits. After standard open room AOBP measurement with a BpTRU device, patients were required to take a second BP measurement with either the BpTRU or Omron device and to either an open or closed area. Absolute BP levels and the difference between the first and second measurements were compared. Diagnostic performance was also assessed. In this study were included 258 patients. Mean age was 66.2±12.0 years and 62% were male. The mean first AOBP was 127.4/73.3 mmHg. The analyses of subsequent measurements showed that there was no influence of open or closed areas on BP means or diagnostic performance. On the other hand, HEM 907 exceeded systolic BpTRU measurements by 4.6 mmHg ( < 0.01) in a closed area and by 3.9 mmHg ( < 0.01) in an open area. There was no significant statistical difference in diastolic BP measures. Diagnostic agreement between the HEM 907 and BpTRU device was 73.4% in open area measurements. While different areas did not influence BP estimates, Omron HEM 907 measurements significantly exceeded BpTRU measurements on systolic average. These differences should be considered when interchanging devices.

BACKGROUND: Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk.OBJECTIVE: The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs).METHODS: Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. We evaluated the association of GRSs for several traits including coronary artery disease (CAD; GRS(CAD)) as well as plasma concentrations of low-density lipoprotein cholesterol (LDL-C; GRS(LDL-C)), high-density lipoprotein cholesterol (GRS(HDL-C)) and triglycerides (GRS(TG)).RESULTS: A total of 32% (n = 231) of FH subjects presented a CVD event before their first visit. Patients in the highest GRS(LDL-C) tertile presented an LDL-C 0.4 mmol/L (15.5 mg/dL) higher than the subjects in the lowest tertile (P =.01). The GRS(CAD) was strongly associated with CVD events (odds ratio 1.80; 95% confidence interval 1.14-2.85; P =.01) even after adjustment for cardiovascular risk factors. Compared with subjects in the first tertile, those in the third GRScAD tertile had a significantly higher prevalence of events (40.9% vs 24.7%, P <.0001) and a significantly higher number of events (average 0.97 vs 0.57 [P =.0001] events per individual).CONCLUSION: These results indicate that even in the context of a severe monogenic disease such as FH, common genetic variants can significantly modify the disease phenotype. The use of the 192-SNPs GRS(CAD) may refine CVD risk prediction in FH patients and this could lead to a more personalized approach to therapy. (C) 2017 National Lipid Association. All rights reserved.

BACKGROUND: Elevated plasma apoB is an independent predictor of T2D; however, underlying mechanisms remain unclear. Chronic reduction in white adipose tissue (WAT) function promotes T2D. We reported that differentiation of preadipocytes and acute incubation of human WAT with LDL induce their dysfunction (decreased hydrolysis and storage of triglyceride-rich lipoproteins [TRL]).OBJECTIVE: To examine the hypothesis that the association of plasma apoB with T2D risk factors, hypertriglyceridemia (hyperTG), insulin resistance (IR), and hyperinsulinemia, was dependent on WAT dysfunction.METHODS: Thirty normoglycemic subjects were enrolled (>= 27 kg/m(2), 45-74 years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a C-13-triolein-labeled-high-fat meal. WAT function was measured ex vivo as the hydrolysis and storage of H-3-triolein-labeled-TRL as H-3-lipids over 4 hours. Insulin sensitivity and secretion were measured by Botnia clamps.RESULTS: WAT function correlated with higher insulin sensitivity (M/I-clamp r = 0.60) and faster plasma clearance of chylomicrons in women (iAUC(6hrs) apoB48, r = -0.60). Plasma apoB correlated with WAT dysfunction (r = -0.52), postprandial hyperTG (iAUC(6hrs)-TG, r = 0.51, C-13-TG, r = 0.48), IR (M/I-clamp r = -0.38) and hyperinsulinemia (second phase-glucose-induced-insulin-secretion, r = 0.41). Co-incubation of subjects' WAT with their LDL increased medium accumulation of 3H-TRL and 3H-NEFA with no sex differences. Adjusting for WAT function eliminated the association of plasma apoB with IR independent of sex and body fat or adipocyte diameter. Its association with other risk factors was unaffected.CONCLUSIONS: Association of plasma apoB with IR. in obese subjects is dependent on gynoid WAT dysfunction. We propose that targeting hyperapoB, without increasing their uptake into nonhepatic peripheral tissues, ameliorates WAT function and risk for T2D. (C) 2016 National Lipid Association. All rights reserved.

BACKGROUND:Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy.METHODS:To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions.RESULTS:After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe.CONCLUSIONS:We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.