Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide ...association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genome-wide significance (P<5×10) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (q<0.05) and together explain 28% of the estimated heritability of CAD. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome.
Background and Aims
We hypothesized that a genetic risk score (GRS) for fatty liver disease influences the risk of cirrhosis and hepatocellular carcinoma (HCC). Three genetic variants (patatin‐like ...phospholipase domain–containing protein 3 PNPLA3 p.I148M; transmembrane 6, superfamily member 2 TM6SF2 p.E167K; and hydroxysteroid 17‐beta dehydrogenase 13 HSD17B13 rs72613567) were combined into a risk score, ranging from 0 to 6 for risk‐increasing alleles.
Approach and Results
We examined the association of the risk score with plasma markers of liver disease and with cirrhosis and HCC in 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. The frequencies of risk scores of 0, 1, 2, 3, 4, and 5 or 6 were 5%, 25%, 41%, 23%, 5.5%, and 0.5%, respectively. A higher GRS was associated with an increase in plasma alanine aminotransferase (ALT) level of 26% in those with score 5 or 6 versus 0. In meta‐analysis of the Copenhagen studies and the UK Biobank, individuals with scores 1, 2, 3, 4, and 5 or 6 had odds ratios (ORs) for cirrhosis of 1.6 (95% confidence interval CI, 1.3, 1.9), 2.0 (95% CI, 1.8, 2.2), 3.1 (95% CI, 2.7, 3.5), 5.2 (95% CI, 4.2, 6.4), and 12 (95% CI, 7.7, 19), respectively, as compared with those with a score of 0. The corresponding ORs for HCC were 1.2 (95% CI, 0.9, 1.7), 1.0 (95% CI, 0.7, 1.3), 2.4 (95% CI, 1.9, 3.0), 3.3 (95% CI, 2.2, 5.0), and 29 (95% CI, 17, 51).
Conclusion
A GRS for fatty liver disease confers up to a 12‐fold higher risk of cirrhosis and up to a 29‐fold higher risk of HCC in individuals from the general population.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objectives To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass ...index.Design Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).Setting Two large, prospective cohort studies in Denmark.Participants We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.Main outcome Blood pressure and prospectively assessed ischaemic heart disease.Results Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).Conclusion By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
Full text
Available for:
BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A common loss‐of‐function variant in HSD17B13 (rs72613567:TA) was recently found to protect from chronic liver disease. Whether the variant confers protection from specific risk factors for liver ...disease is unclear. We tested the association of rs72613567 with plasma levels of alanine transaminase (ALT) and clinical liver disease and mortality in 111,612 individuals from the Danish general population, including 497 with cirrhosis and 113 with hepatocellular carcinoma. HSD17B13 rs72613567:TA was associated with stepwise lower levels of plasma ALT of up to 1.3 U/L in TA/TA homozygotes versus T/T homozygotes. For each TA‐allele, the risk of cirrhosis and hepatocellular carcinoma was reduced by 15% and 28%, respectively. In prospective analyses, the TA‐allele was associated with up to 33% lower rates of liver‐related mortality in the general population, and with up to 49% reduced liver‐related mortality in patients with cirrhosis. The ALT‐lowering effect of rs72613567:TA was amplified by increasing adiposity, alcohol consumption, and genetic risk of fatty liver disease. The TA‐allele was associated with only marginally lower ALT in lean nondrinkers with low genetic risk of hepatic steatosis. In contrast, compared with T/T homozygotes, TA/TA homozygotes had 12% to 18% lower plasma ALT among the most obese, in heavy drinkers, and in individuals carrying three or four steatogenic alleles in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) and transmembrane 6 superfamily 2 (TM6SF2). Conclusion: High risk of fatty liver disease amplifies the ALT‐lowering effect of HSD17B13 rs72613567:TA in the Danish general population.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Sequencing of the gene encoding apolipoprotein C3 (
APOC3
) in participants in two general-population studies identified three rare loss-of-function mutations associated with low plasma triglyceride ...levels. The risk of ischemic vascular disease was reduced by 41% among carriers of these mutations.
Low-density lipoprotein (LDL) cholesterol is the principal target of lipid drugs that have been developed for the prevention of cardiovascular disease. However, even among patients with substantial reductions in LDL cholesterol levels, residual cardiovascular risk persists.
1
Spurred by the strong association between high levels of both fasting and nonfasting triglycerides and the risk of cardiovascular disease,
2
–
6
recent genetic studies involving mendelian randomization have suggested that high levels of nonfasting triglycerides are causally associated with an increased risk of ischemic cardiovascular disease, independent of high-density lipoprotein (HDL) cholesterol levels.
7
,
8
Plasma triglycerides are markers of so-called remnant particles, which include . . .
Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not ...universally available. The aim of the present study was to assess the frequency and predictors of FH causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study.
We genotyped for LDLRW23X;W66G;W556S and APOBR3500Q accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information. The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH vs. unlikely FH. Using the Simon Broome criteria, the odds ratio was 27 (20-36) for possible vs. unlikely FH, and using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, 40 (28-58) for probable vs. unlikely FH. Odds ratios for an FH mutation were 17 (9-31) for LDL-cholesterol of 4-4.9 mmol/L, 69 (37-126) for LDL-cholesterol of 5-5.9 mmol/L, 132 (66-263) for LDL-cholesterol of 6-6.9 mmol/L, 264 (109-637) for LDL-cholesterol of 7-7.9 mmol/L, and 320 (129-798) for LDL-cholesterol above 7.9 mmol/L vs. LDL-cholesterol below 4 mmol/L. The most optimal threshold for LDL-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L.
Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L.
Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and ...accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.
Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary.
This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
Abstract Introduction The adenosine triphosphate-binding cassette transporter A1 ( ABCA1 ) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates ...apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways. Methods We tested whether a loss-of-function mutation in ABCA1 , N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. Results N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE ( P = 1 × 10−11 ). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32–12.9) for AD, 2.46 (1.10–5.50) for cerebrovascular disease, and 8.28 (2.03–33.7) for the hemorrhagic stroke subtype. Discussion A loss-of-function mutation in ABCA1 , present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
