Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.Peer reviewe

Effects of PNPLA3 I148M on hepatic lipid and very-low-density lipoprotein metabolism in humans

Background The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL1), and smaller VLDL2 in homozygotes for the PNPLA3-148M variant. Methods and results The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2-apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2, were not significantly different. Conclusions Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.Peer reviewe

Genomic prediction of alcohol-related morbidity and mortality

While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85-12.58 g, p = 2.3 x 10(-58)). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66-2.01, p = 1.6 x 10(-36)). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26-1.99, p = 8.2 x 10(-5)). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20-1.47, p = 4.5 x 10(-8)) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.Peer reviewe

Multiparametric platform for profiling lipid trafficking in human leukocytes

Summary Systematic insight into cellular dysfunction can improve understanding of disease etiology, risk assessment, and patient stratification. We present a multiparametric high-content imaging platform enabling quantification of low-density lipoprotein (LDL) uptake and lipid storage in cytoplasmic droplets of primary leukocyte subpopulations. We validate this platform with samples from 65 individuals with variable blood LDL-cholesterol (LDL-c) levels, including familial hypercholesterolemia (FH) and non-FH subjects. We integrate lipid storage data into another readout parameter, lipid mobilization, measuring the efficiency with which cells deplete lipid reservoirs. Lipid mobilization correlates positively with LDL uptake and negatively with hypercholesterolemia and age, improving differentiation of individuals with normal and elevated LDL-c. Moreover, combination of cell-based readouts with a polygenic risk score for LDL-c explains hypercholesterolemia better than the genetic risk score alone. This platform provides functional insights into cellular lipid trafficking and has broad possible applications in dissecting the cellular basis of metabolic disorders.Peer reviewe

Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

The Contribution of GWAS Loci in Familial Dyslipidemias

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.Peer reviewe

Coronary Artery Disease Risk and Lipidomic Profiles Are Similar in Hyperlipidemias With Family History and Population-Ascertained Hyperlipidemias

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.Peer reviewe

The Contribution of GWAS Loci in Familial Dyslipidemias

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 FCH affecteds. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 FCH affecteds 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. There was large between-family variation in how much the polygenic scores contributed to the FCH phenotype. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. This reinforces the clinical tenet that FCH is a cluster of overlapping genetic defects instead of an etiologically homogenous disease entity

Polygenic contributions to dyslipidemias and related cardiometabolic diseases

.Sydän- ja verisuonisairaudet sekä syövät ovat yleisimmät kuolinsyyt maailmanlaajuisesti. Ennaltaehkäisy on paras tapa vähentää näiden pääosin parantumattomien sairauksien aiheuttamaa haittaa. Koska nykyään tunnetaan kymmeniä tuhansia yhteyksiä geenien ja sairauksien välillä, geeniperimästä saatava tieto on lupaava lisätyökalu nykyisten kliinisten sairastumisriskinarviotyökalujen rinnalle. Veren poikkeavat rasva-arvot, eli suuri kolesteroli- tai triglyseridipitoisuus, ovat tärkein hoidettavissa oleva ja perinnöllinen sydän- ja verisuonisairauksien riskitekijä. Familiaalinen kombinoitunut hyperlipidemia (FKH) on yleisin perinnöllinen rasva-aineenvaihdunnan häiriö, johon liittyy suvuittain esiintyvät poikkeavat rasva-arvot ja väestöön verrattuna noin viisinkertainen sydäntautiriski. FKH:n on aiemmin epäilty olevan yhden geenin aiheuttama sairaus. Väitöstutkimuksen ensimmäisessä osatyössä tutkimme perimänlaajuiseen testaukseen perustuvilla menetelmillä FKH:n perinnöllistä taustaa suomalaisissa FKH-perheissä. Havaitsimme, että vain pieni osa (3% sairastuneista) FKH:sta selittyi yksittäisillä, harvinaisilla suurivaikutteisilla alttiusgeeneillä, kun taas yli kolmasosa (35%) johtui usean pienivaikutteisen alttiusgeenin yhteisvaikutuksesta. Koska noin puolet alttiusgeeneistä periytyy jälkeläisille, niiden kasautuminen perheissä selittää suuren osan FKH:n taudinkuvasta. Toisessa osatyössä tutkimme pienivaikutteisten veren poikkeavien rasva-arvojen alttiusgeenien kasautumisen vaikutusta sydäntautiriskiin suomalaisessa väestöaineistoissa. Henkilöillä, joille oli kasautunut useita poikkeavien rasva-arvojen alttiusgeenejä, oli 10-30% muita suuremmat rasva-arvot ja 30-40% suurempi sydäntautiriski. Kolmannessa osatyössä laajensimme alttiusgeenien kasautumistutkimuksemme sydäntaudista tyypin 2 diabetekseen, eteisvärinään sekä rinta- ja eturauhassyöpään. Henkilöillä, joille oli kasautunut useita alttiusgeenejä näille sairauksille, oli 20-40% muita suurempi sairastumisriski ja he sairastuivat 3-9 vuotta muita nuorempina. Suomalaisessa väestöaineistossamme alttiusgeenit ja kliiniset riskitekijät yhdessä ennustivat sairastumista paremmin kuin pelkät kliiniset riskitekijät erikseen. Kaiken kaikkiaan pienivaikutteisten alttiusgeenien kasautumisella oli suuri merkitys yleisissä sairauksissa kuten rasva-aineenvaihdunnan häiriöissä, sydäntaudissa, tyypin 2 diabeteksessa, eteisvärinässä ja syövissä. Koska alttiusgeenit voidaan mitata missä vaiheessa elämää vain, perimän avulla voidaan tulevaisuudessa kohdistaa entistä paremmin sairauksien riskinarviota, seulontaa ja elämäntapa- ja lääkehoitoja