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Abstract Context Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia. Objective The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids. Data Sources We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018. Study Selection Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism. Data Extraction Pairs of independent reviewers extracted data and appraised studies. Data Synthesis Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration. Conclusions Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4 – 23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice. A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China1,2. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS1,2. Stroke incidence and ICH proportion are higher in China than in Western populations3–5, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD)6,7, but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD8–10. Mendelian randomization studies of LDL-C and IS have reported conflicting results11–13, and concerns about the excess risks of ICH associated with lowering LDL-C14,15 may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.In a nested case-control study from the China Kadoorie Biobank, lowering blood low-density lipoprotein cholesterol levels confers lower risk for ischemic stroke but elevated risk for intracerebral hemorrhage, which was confirmed by genetic Mendelian randomization analyses.

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n  > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease). Analysis of genetic data and blood lipid measurements from over 300,000 participants in the Million Veteran Program identifies new associations for blood lipid traits.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk. We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci ( JAK2 and A1CF ), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins ( TM6SF2 and PNPLA3 ) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis ( LPL and ANGPTL4 ) had no effect on liver fat but decreased risks for both T2D and CAD.

Background Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals. Results This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and ABCG1 (for HDL cholesterol), which are all key regulators of lipid metabolism. Conclusions Our analysis suggests a role for epigenetic priming in end-product feedback control of lipid metabolism and highlights Mendelian randomization as an effective tool to infer causal relationships in integrative genomics data.

Kari Stefansson and colleagues report discovery of 13 variants with large effects on non-HDL cholesterol, LDL cholesterol, HDL cholesterol or triglyceride lipid fractions. They further show that, among these lipid fractions, the non-HDL cholesterol genetic risk score associates most strongly with coronary disease and confers risk beyond that of LDL cholesterol and that, after accounting for non-HDL cholesterol, neither HDL cholesterol nor triglyceride genetic risk scores associate with coronary disease. Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3 , APOB , ABCA1 , NR1H3 , APOA1 , LIPC , CETP , LDLR , and APOC1 ) and replicated 14 variants. Five variants within PCSK9 , APOA1 , ANGPTL4 , and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD ( P = 2.7 × 10 −28 ), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol ( P = 5.5 × 10 −8 ), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.

A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33–42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease. Genome-wide association analysis using electronic health record data from >94,000 individuals identifies loci associated with plasma lipid concentrations. Longitudinal measurements allow for the calculation of genetic risk scores and increase the variance explained.

Background Exposures to perfluoroalkyl substances (PFAS) have shown positive associations with serum lipids in previous studies. While many studies on lipids investigated associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), there are only a few studies regarding other PFAS, such as perfluorohexane sulfonic acid (PFHxS). The purpose of the current study is to investigate if associations with serum lipids were present, not only for serum PFOS and PFOA, but also for PFHxS, and if the associations with PFAS remained also in a comparison based only on residency in areas with contrasting exposure to PFAS. Methods 1945 adults aged 20–60 were included from Ronneby, Sweden, a municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area. The exposure was categorized based on either been living in areas with contrasting PFAS exposure or based on the actual serum PFAS measurements. Regression analyses of serum lipids were fitted against serum PFAS levels, percentile groups, smooth splines and between exposed and reference areas, adjusting for age, sex and BMI. Results Drinking water contamination caused high serum levels of PFOS (median 157 ng/ml) and PFHxS (median 136 ng/ml) and PFOA (median 8.6 ng/ml). These serum PFAS levels in the exposed groups were 5 to 100-fold higher than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, PFAS exposure were positively associated with serum lipids. This was observed both when quantifying exposure as contrast between exposed and controls, and in terms of serum PFAS. Due to high correlations between each PFAS, we cannot separate them. Conclusions In conclusion, the present study provides further evidence of a causal association between PFAS and serum lipids, especially for PFHxS.

Abstract Background Excess adipose tissue is associated with an abnormal lipid profile that may improve with weight reduction. In this meta-analysis, we aimed to estimate the magnitude of change in lipid parameters associated with weight loss in adults who are overweight or obese. Methods We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus from 2013 to September, 2018. We included randomized controlled trials (RCTs) that evaluated interventions to treat adult obesity (lifestyle, pharmacologic and surgical) with follow-up of 6 months or more. Results We included 73 RCTs with moderate-to-low risk of bias, enrolling 32 496 patients (mean age, 48.1 years; weight, 101.6 kg; and body mass index [BMI], 36.3 kg/m2). Lifestyle interventions (diet, exercise, or both), pharmacotherapy, and bariatric surgery were associated with reduced triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentrations and increased high-density lipoprotein cholesterol (HDL-C) at 6 and 12 months. The following data are for changes in lipid parameters after 12 months of the intervention with 95% CI. Following lifestyle interventions, per 1 kg of weight lost, TGs were reduced by –4.0 mg/dL (95% CI, –5.24 to –2.77 mg/dL), LDL-C was reduced by –1.28 mg/dL (95% CI, –2.19 to –0.37 mg/dL), and HDL-C increased by 0.46 mg/dL (95% CI, 0.20 to 0.71 mg/dL). Following pharmacologic interventions, per 1 kg of weight lost, TGs were reduced by –1.25 mg/dL (95% CI, –2.94 to 0.43 mg/dL), LDL-C was reduced by –1.67 mg/dL (95% CI, –2.28 to –1.06 mg/dL), and HDL-C increased by 0.37 mg/dL (95% CI, 0.23 to 0.52 mg/dL). Following bariatric surgery, per 1 kg of weight lost, TGs were reduced by –2.47 mg/dL (95% CI, –3.14 to –1.80 mg/dL), LDL-C was reduced by –0.33 mg/dL (95% CI, –0.77 to 0.10 mg/dL), and HDL-C increased by 0.42 mg/dL (95% CI, 0.37 to 0.47 mg/dL). Low-carbohydrate diets resulted in reductions in TGs and increases in HDL-C, whereas low-fat diets resulted in reductions in TGs and LDL-C and increases in HDL-C. Results were consistent across malabsorptive and restrictive surgery. Conclusions Weight loss in adults is associated with statistically significant changes in serum lipids. The reported magnitude of improvement can help in setting expectations, inform shared decision making, and facilitate counseling.