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Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.
Wang, Y, Hernandez, G, Mack, WJ, Schneider, LS, Yin, F, Brinton, RD
Menopause (New York, N.Y.). 2020;(1):57-65
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Abstract
OBJECTIVE PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.
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Familial Hypertrophic Cardiomyopathy - Identification of cause and risk stratification through exome sequencing.
Biswas, A, Das, S, Kapoor, M, Shamsudheen, KV, Jayarajan, R, Verma, A, Seth, S, Bhargava, B, Scaria, V, Sivasubbu, S, et al
Gene. 2018;:151-156
Abstract
BACKGROUND Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results. METHODS In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants. RESULTS A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members. CONCLUSION This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
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No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population.
Kan, M, Weng, X, Wang, T, Liu, F, Ye, J, Zhang, H, Xu, M, Zhou, D, He, L, Liu, Y
Experimental biology and medicine (Maywood, N.J.). 2015;(2):230-4
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Abstract
Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease. Genes related to lipid metabolism are important in AMD pathogenesis. Recently, a variant rs2075650 located in lipid metabolism-related locus APOE/TOMM40 was identified to be associated with advanced AMD and early AMD, respectively, in two genome-wide association studies with European ancestry, while no association study between rs2075650 and overall advanced AMD in Chinese population has been conducted before. We evaluated the potential effect of this variant on advanced AMD in a Han Chinese cohort with 204 advanced AMD patients and 1536 healthy controls. The results suggested that rs2075650 was neither associated with advanced AMD in allele level (P = 0.348) nor in genotype level (P = 0.890 under additive model with age and sex adjusted). In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population.
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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?
Conway, V, Allard, MJ, Minihane, AM, Jackson, KG, Lovegrove, JA, Plourde, M
Lipids in health and disease. 2014;:148
Abstract
BACKGROUND We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n - 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n - 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4-). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 - 400 (VLDL1), and Sf 20 - 60 (VLDL2) according to APOE genotype. METHODS Postprandial TRL fractions were obtained in 11 E4+ (ϵ3/ϵ4) and 12 E4- (ϵ3/ϵ3) male from the SATgenϵ study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography. RESULTS At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P = 0.063) in the Sf >400 fraction of E4+. Total n - 3 PUFA in the Sf 60 - 400 and Sf 20 - 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P = 0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2 = 0.816). CONCLUSION Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n - 3 PUFA metabolism after receiving a high-dose of DHA. TRIAL REGISTRATION Registered at clinicaltrials.gov/show/NCT01544855.
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Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease.
Talayero, B, Wang, L, Furtado, J, Carey, VJ, Bray, GA, Sacks, FM
Journal of lipid research. 2014;(10):2167-77
Abstract
Human HDLs have highly heterogeneous composition. Plasma concentrations of HDL with apoC-III and of apoE in HDL predict higher incidence of coronary heart disease (CHD). The concentrations of HDL-apoA-I containing apoE, apoC-III, or both and their distribution across HDL sizes are unknown. We studied 20 normal weight and 20 obese subjects matched by age, gender, and race. Plasma HDL was separated by sequential immunoaffinity chromatography (anti-apoA-I, anti-apoC-III, anti-apoE), followed by nondenaturing-gel electrophoresis. Mean HDL-cholesterol concentrations in normal weight and obese subjects were 65 and 50 mg/dl (P = 0.009), and total apoA-I concentrations were 119 and 118 mg/dl, respectively. HDL without apoE or apoC-III was the most prevalent HDL type representing 89% of apoA-I concentration in normal weight and 77% in obese (P = 0.01) individuals; HDL with apoE-only was 5% versus 8% (P = 0.1); HDL with apoC-III-only was 4% versus 10% (P = 0.009); and HDL with apoE and apoC-III was 1.5% versus 4.6% (P = 0.004). Concentrations of apoE and apoC-III in HDL were 1.5-2× higher in obese subjects (P ≤ 0.004). HDL with apoE or apoC-III occurred in all sizes among groups. Obese subjects had higher prevalence of HDL containing apoE or apoC-III, subfractions associated with CHD, whereas normal weight subjects had higher prevalence of HDL without apoE or apoC-III, subfractions with protective association against CHD.