Lipoprotein(a) and risk of cardiovascular disease

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Central nervous system tumours in Icelandic children; diagnoses, treatment results and late effects

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenObjective: Tumours in the central nervous system are the second most common malignant diseases in children. With improved treatment, the number of survivors is increasing. Therefore, better knowledge of the long-term effects of the disease and the therapy is needed. The aim of the current study was to find the incidence of central nervous system tumours in Iceland, evaluate the treatment results and study the long-term effects on the individuals. Material and methods: Data on diagnosis and treatment as well as demographic data were gathered from hospital records from the Reykjavik City Hospital and The University Hospital and operating lists at the Department of Neurosurgery were reviewed. On survivors, physical examination was carried out, blood tests and urine-analysis were done and hearing was tested. Social adaptation, school performance, memory, concentration and general well being were studied by a questionnaire. Results: In the years 1970-1995, 57 children, aged 16 and younger, were diagnosed in Iceland with central nervous system tumours, 30 girls and 27 boys. Two children with brain metastases were excluded. Of the 55 individuals, 38 are alive today, 19 girls and 19 boys. Seventeen children had astrocytoma, grade 1 or 2 and seven had astrocytoma of grade 3 or 4. Seven children had medulloblastoma, other tumours were less common. Four patients with benign tumours in the spine were excluded from the study; three are living abroad and three refused participation. Therefore, 28 patients were included in the further study, 15 males and 13 females. The mean age at diagnoses was 7 years and 8 months (7:8) (median 6:7 years, span 0:0-15:11), the mean age at study was 21:4 years (median 20:2 years, span 7:6-39:9) and the mean time from diagnosis until study was 12:8 years (median 11:5 years, span 2:5-26:3). The mean standard deviation score for height (SDS) was -0.63 at the time of study, five of the patients had SDS below two. Five individuals need hormone replacement therapy and one patient has scoliosis. Three patients have disabilities; two of those are incapable of activities of daily life. Three patients have hearing impairment; one of them is also blind. Of five patients who had seizures when diagnosed, two still have convulsions. Of 28 patients, twelve (43%) had learning difficulties in school and ten (36%) needed remedial teaching. Conclusions: The incidence of central nervous tumours in Icelandic children is comparable to what has been reported in other countries. The results of the treatment are similar to what has been found in the other Nordic countries which maybe better than in other countries. The most prominent long-term effects among the survivors are endocrine dysfunctions and specific learning disabilities. Other, severe long-term complications are rare but have considerable effect on the individuals. We emphazise that organised, long-term follow-up is essential for these individuals, paying special attention to learning difficulties and endocrine dysfunction.Inngangur: Æxli í miðtaugakerfi er annar algengasti illkynja sjúkdómurinn í börnum, næst á eftir hvítblæði. Árangur meðferðar hefur farið stöðugt batnandi og því eykst mikilvægi þess að greina möguleg langtímaáhrif og síðkomna fylgikvilla meðferðar. Tilgangur rannsóknarinnar var að finna heildarfjölda sjúklinga á Íslandi, greiningu þeirra og árangur meðferðar og kanna síðkomna fylgikvilla og langtímaáhrif meðferðar á eftirlifandi einstaklinga. Aðferðir: Sjúklingar voru fundnir með leit í sjúkraskrám á Sjúkrahúsi Reykjavíkur og Landspítalanum auk þess sem farið var yfir aðgerðarbækur á SHR. Upplýsingar um sjúkdóminn, greiningu og meðferð var safnað. Allir þátttakendur í rannsókninni komu í viðtal og skoðun, heyrnarmælingu, blóð- og þvagrannsóknir. Spurningalisti varðandi félagslega aðlögun, skólagöngu, minni, einbeitingu og líðan var einnig lagður fyrir þátttakendur. Niðurstöður: Á árunum 1970-1995 greindust 57 börn á Íslandi yngri en 16 ára með æxli í miðtaugakerfi, 30 stelpur og 27 strákar. Tveir sjúklingar með meinvörp í heila voru útilokaðir frá frekari uppvinnslu. Nú eru 38 þessara einstaklinga á lífi, 19 konur og 19 karlar. Sautján sjúklingar höfðu astrocytoma af gráðu 1 eða 2 en sjö sjúklingar astrocytoma af gráðu 3 eða 4. Sjö sjúklingar höfðu greinst með medulloblastoma, aðrar tegundir voru sjaldgæfari. Fjórir sjúklingar með góðkynja æxli í mænu voru útilokaðir frá rannsókn. Þrír búa erlendis og þrír neituðu þátttöku. Því tóku 28 einstaklingar þátt í rannsókninni, 15 karlmenn og 13 konur. Aldur við greiningu var að meðaltali sjö ár og átta mánuðir (7:8) (miðgildi 6:7 ár, bil 0:0-15:11), meðalaldur við rannsókn var 21:4 ár (miðgildi 20:2 ár, bil 7:6-39:9) og meðaltími frá greiningu að rannsókn var 12:8 ár (miðgildi 11:5 ár, bil 2:5-26:3). Hæð þátttakenda við rannsókn var að meðaltali -0,63 staðalfráviksskor (standard deviation score; SDS), fimm þátttakendur eru með -2 eða minna í staðalfráviksskori. Fimm einstaklingar fá hormónameðferð vegna vanstarfsemi innkirtla í kjölfar meðferðar. Einn einstaklingur hefur hryggskekkju sem rekja má til meðferðar. Þrír einstaklingar hafa verulega skerta hreyfifærni sem rekja má til sjúkdómsins og/eða meðferðar og þar af eru tveir ófærir um athafnir daglegs lífs. Þrír einstaklingar eru heyrnarskertir, þar af er einn einnig blindur. Af fimm sjúklingum sem höfðu krampa sem einkenni um sjúkdóminn fá tveir enn krampa. Af 28 sjúklingum áttu 12 (43%) við sérstaka námsörðugleika að stríða í grunnskóla og tíu (36%) fengu stuðningskennslu. Umræður: Tíðni heila- og mænuæxla virðist sú sama hér og þekkist annars staðar. Árangur meðferðar virðist svipaður og á hinum Norðurlöndunum sem er oft betri en í öðrum löndum. Þau langtímaáhrif sem eru mest áberandi hjá einstaklingum sem lifað hafa æxli í miðtaugakerfi í æsku eru vanstarfsemi innkirtla og sértækir námsörðugleikar. Aðrir alvarlegir fylgikvillar eru ekki algengir en skerða þó lífsgæði einstaklingsins. Nauðsynlegt er að bjóða upp á skipulagt og markvisst eftirlit með þessum sjúklingum að meðferð lokinni með áherslu á að greina námsörðugleika og starfstruflanir í innkirtlum

Association of Genetically Predicted Lipid Levels With the Extent of Coronary Atherosclerosis in Icelandic Adults.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadImportance: Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary atherosclerosis. Objective: To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis. Design, setting, and participants: This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait. Exposures: Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides. Main outcomes and measures: The extent of angiographic CAD and coronary artery calcium quantity. Results: A total of 12 460 adults (mean [SD] age, 65.1 [10.7] years; 8383 men [67.3%]) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) was associated with greater odds of obstructive CAD (odds ratio [OR], 1.83 [95% CI, 1.63-2.07]; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 [95% CI, 1.11-1.44]; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 [95% CI, 1.26-1.72]; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 [95% CI, 1.70-2.44]; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 [95% CI, 0.53-0.87]; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol. Conclusions and relevance: In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.deCODE genetics/Amgen Inc

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadObjective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.Landspitali University Hospital Research Fun

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study

AimsAlthough highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.Methods and resultsA genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.ConclusionDyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis : a genome-wide study

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageMutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.Dutch Heart Foundation (2006B190) and Unilever, UK. Additional funding was provided by Pfizer and MSD The Netherlands. SEH acknowledges BHF support (RG 2008/008) and also funding from the Department of Health’s NIHR Biomedical Research Centre funding scheme. ER is supported by grant FIS PS09/01292 from ISCIII, Spain