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  • Ramo, Joel T.; Ripatti, Pietari; Tabassum, Rubina; Soderlund, Sanni; Matikainen, Niina; Gerl, Mathias J.; Klose, Christian; Surma, Michal A.; Stitziel, Nathan O.; Havulinna, Aki S.; Pirinen, Matti; Salomaa, Veikko; Freimer, Nelson B.; Jauhiainen, Matti; Palotie, Aarno; Taskinen, Marja-Riitta; Simons, Kai; Ripatti, Samuli (2019)
    Background-We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol (LDL-C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results-We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (>2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias (LDL-C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL-C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL-C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3x 10(-56)). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population (LDL-C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions-Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL-C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.
  • Taskinen, Marja-Riitta; Björnson, Elias; Andersson, Linda; Kahri, Juhani; Porthan, Kimmo; Matikainen, Niina; Söderlund, Sanni; Pietiläinen, Kirsi; Hakkarainen, Antti; Lundbom, Nina; Nilsson, Ralf; Stahlman, Marcus; Adiels, Martin; Parini, Paolo; Packard, Chris; Boren, Jan (2020)
    BACKGROUND: Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. OBJECTIVE: This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. METHODS: The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. RESULTS: Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P <.0001) and VLDL i triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P <.0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in "remnant-like particles" cholesterol (by 29%; P <.0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P <.0001) and VLDL2 triglyceride by 29% (P <.0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P <.001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting beta-hydroxybutyrate but did increase total body cholesterol synthesis (P <.01). CONCLUSION: Evolocumab treatment improved postprandial responses of triglyceride-rich lipo-proteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals. (C) 2020 Published by Elsevier Inc. on behalf of National Lipid Association.
  • Ripatti, Pietari; Ramo, Joel T.; Soderlund, Sanni; Surakka, Ida; Matikainen, Niina; Pirinen, Matti; Pajukanta, Paivi; Sarin, Antti-Pekka; Service, Susan K.; Laurila, Pirkka-Pekka; Ehnholm, Christian; Salomaa, Veikko; Wilson, Richard K.; Palotie, Aarno; Freimer, Nelson B.; Taskinen, Marja-Riitta; Ripatti, Samuli (2016)
    Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.