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IntroductionAmong African Americans, tobacco smokers have 2.5 times higher risk for stroke compared to non-smokers; the tobacco-related stroke risk being higher than in other races/ethnicities. About one half of African Americans carry at least one of two genetic variants (G1 and G2; rare in other races) of apolipoprotein L1 (apoL1), a component of high-density lipoproteins. Several studies showedAPOL1G1/G2 risk variants associate with stroke. However, the role ofAPOL1variants in tobacco-related stroke is unknown.MethodsIn a cross-sectional study, we examined whetherAPOL1risk variants modify the relationship between smoking and stroke in 513 African American adults (median age 58 years, 52% female) recruited through the University of California, San Francisco Lipid Clinic. Using DNA, plasma, and questionnaires we determinedAPOL1variants, smoking status, and history of stroke. Using unstratified and stratified multivariable logistic regression models we examined the association between smoking history (eversmokers vs.neversmokers) and odds of stroke overall, and among carriers of risk variants and non-carriers, separately.ResultsAmong participants, 41% wereever(currentandpast) smokers, 54% were carriers of theAPOL1risk variant, and 41 have had stroke. In all stroke cases, where full medical records were available, stroke types were determined to be an ischemic, and not hemorrhagic, stroke. The association of smoking history and stroke differed byAPOL1genotype status in the unstratified model (Pinteraction term=0.016). Among carriers of risk variants,eversmokers had odds ratio (OR) =2.88 for stroke compared toneversmokers (P=0. 0.038). The OR for stroke comparingevervs.neversmokers showed a dose-response trend among carriers of one risk allele of 2.35 and two risk alleles of 4.96. Among non-carriers, smoking history was not associated with a stroke.ConclusionIn conclusion, current and past smokers who carryAPOL1G1 and/or G2 risk variants may be more susceptible to stroke, in particular ischemic stroke, among African Americans.

Susceptibility to severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) levels ≥10 mmol/L (880 mg/dL), is conferred by both heterozygous rare variants in five genes involved in TG metabolism and numerous common single-nucleotide polymorphisms (SNPs) associated with TG levels.To date, these genetic susceptibility factors have been comprehensively assessed primarily in severe HTG patients of European ancestry. Here, we expand our analysis to HTG patients of East Asian and Hispanic ancestry.The genomic DNA of 336, 63 and 199 severe HTG patients of European, East Asian and Hispanic ancestry, respectively, was evaluated using a targeted next-generation sequencing panel to screen for: 1) rare variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1; 2) common, small-to-moderate effect SNPs, quantified using a polygenic score; and 3) common, large-effect polymorphisms, APOA5 p.G185C and p.S19W.While the proportion of individuals with high polygenic scores was similar, frequency of rare variant carriers varied across ancestries. Compared with ancestry-matched controls, Hispanic patients were the most likely to have a rare variant (OR = 5.02; 95% CI 3.07-8.21; p 0.001), while European patients were the least likely (OR = 2.56; 95% CI 1.58-4.13; p 0.001). The APOA5 p.G185C polymorphism, exclusive to East Asians, was significantly enriched in patients compared with controls (OR = 10.1; 95% CI 5.6-18.3; p 0.001), showing the highest enrichment among the measured genetic factors.While TG-associated rare variants and common SNPs are both found in statistical excess in severe HTG patients of different ancestral backgrounds, the overall genetic profiles of each ancestry group were distinct.

Objective: Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11–366.1; P =0.03) more likely than controls to carry a rare loss-of-function variant in CREB3L3 , which encodes a transcription factor that regulates several target genes with roles in triglyceride metabolism. Conclusions: Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely CREB3L3 , contribute significantly to severe hypertriglyceridemia. Secondary genes and pathways should be considered when evaluating the genetic architecture of this complex trait.

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

Diabetes mellitus is a complex disease. We are increasingly gaining a better understanding of its mechanisms at the molecular level. From these new insights, better therapeutic approaches should emerge. Diabetes mellitus is a syndrome with many associated subphenotypes. These include mitochondrial disorders, lipodystrophies, and inflammatory disorders involving cytokines. Levels of sphingosine-1-phosphate, which has recently been shown to play a role in glucose homeostasis, are low in diabetics, whereas levels of ceramides are increased. Major phenotypes associated with diabetes mellitus are dyslipidemias, notably hypertriglyceridemia and low high-density lipoprotein cholesterol levels. Both diabetes and dyslipidemia are strongly associated with increased risk for atherosclerotic vascular disease.

Background We previously showed that levels of prebeta‐1 high‐density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from cells, including artery wall macrophages, are positively associated with coronary heart disease (CHD) and myocardial infarction (MI) risk. Methods and Results In a multiethnic follow‐up cohort of 1249 individuals from University of California–San Francisco clinics, we determined the degree to which prebeta‐1 HDL levels, both absolute and percentage of apolipoprotein AI, are associated with CHD and history of MI. Independent, strong, positive associations were found. Meta‐analysis revealed for the absolute prebeta‐1 HDL for the top tertile versus the lowest, unadjusted odds ratios of 1.90 (95% CI, 1.40–2.58) for CHD and 1.79 (95% CI, 1.35–2.36) for MI. For CHD, adjusting for established risk factors, the top versus bottom tertiles, quintiles, and deciles yielded sizable odds ratios of 2.37 (95% CI, 1.74–3.25, P P P Conclusions Analysis of 2507 subjects showed conclusively that levels of prebeta‐1 HDL are strongly associated with a history of CHD or MI, independently of traditional risk factors. Addition of prebeta‐1 HDL can significantly improve clinical assessment of risk of CHD and MI.

Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1;Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely

BackgroundAs per the 2017 WHO fact sheet, Coronary Artery Disease (CAD) is the primary cause of death in the world, and accounts for 31% of total fatalities. The unprecedented 17.6 million deaths caused by CAD in 2016 underscores the urgent need to facilitate proactive and accelerated pre-emptive diagnosis. The innovative and emerging Machine Learning (ML) techniques can be leveraged to facilitate early detection of CAD which is a crucial factor in saving lives. The standard techniques like angiography, that provide reliable evidence are invasive and typically expensive and risky. In contrast, ML model generated diagnosis is non-invasive, fast, accurate and affordable. Therefore, ML algorithms can be used as a supplement or precursor to the conventional methods. This research demonstrates the implementation and comparative analysis of K Nearest Neighbor (k-NN) and Random Forest ML algorithms to achieve a targeted “At Risk” CAD classification using an emerging set of 35 cytokine biomarkers that are strongly indicative predictive variables that can be potential targets for therapy. To ensure better generalizability, mechanisms such as data balancing, repeated k-fold cross validation for hyperparameter tuning, were integrated within the models. To determine the separability efficacy of “At Risk” CAD versus Control achieved by the models, Area under Receiver Operating Characteristic (AUROC) metric is used which discriminates the classes by exhibiting tradeoff between the false positive and true positive rates.ResultsA total of 2 classifiers were developed, both built using 35 cytokine predictive features. The best AUROC score of .99 with a 95% Confidence Interval (CI) (.982,.999) was achieved by the Random Forest classifier using 35 cytokine biomarkers. The second-best AUROC score of .954 with a 95% Confidence Interval (.929,.979) was achieved by the k-NN model using 35 cytokines. Ap-value of less than 7.481e-10 obtained by an independent t-test validated that Random Forest classifier was significantly better than the k-NN classifier with regards to the AUROC score.Presently, as large-scale efforts are gaining momentum to enable early, fast, reliable, affordable, and accessible detection of individuals at risk for CAD, the application of powerful ML algorithms can be leveraged as a supplement to conventional methods such as angiography. Early detection can be further improved by incorporating 65 novel and sensitive cytokine biomarkers. Investigation of the emerging role of cytokines in CAD can materially enhance the detection of risk and the discovery of mechanisms of disease that can lead to new therapeutic modalities.

Introduction While annual influenza vaccination of healthcare workers (HCWs) is recommended, uptake is often suboptimal. We sought to evaluate influenza vaccination uptake by HCWs in Victorian public healthcare facilities, where non-mandatory programs are used. Methods All participating facilities completed an annual survey (2014–2019) recording HCW influenza vaccination status. Uptake in high-risk departments (emergency and intensive care units) was evaluated for the 2019 season. Results The proportion of vaccinated HCWs increased annually, from 72.2% (2014) to 87.7% (2019), with pre-set targets generally achieved. In 2019, 110,324 HCWs in 107 facilities were vaccinated (87.7%). Of those without documented vaccination, 7591 (6.0%) declined and 7906 (6.3%) had unknown status. Uptake was higher in high-risk departments (91.4%). Conclusion Increasing annual influenza vaccination uptake by HCWs in Victorian public healthcare facilities has been achieved in the context of performance monitoring targets. Small proportions declined or had unknown status. Future policies should focus on these HCWs.

Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels.Our objective was to review the diagnosis and treatment results in 43 CTX cases.We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases.The mean age at diagnosis was 32 years; the average follow-up was 8 years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190 mg/dL; the mean plasma cholestanol level was 32 mg/L (normal5.0 mg/L), which decreased to 6.0 mg/L (-81%) with CDCA therapy generally given as 250 mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of5.0 mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data.Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease.

Background Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low‐density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis. Objective We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds. Methods We applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked‐Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR‐based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL. Results In the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs. Conclusions While the application of WES can provide a cost‐effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked‐Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES., The genetic defects underlying homozygous familial hypercholesterolemia (HoFH) are difficult to ascertain due to its genetic heterogeneity. Here, we applied whole exome and whole genome sequencing with Linked‐Reads on three HoFH patients and they revealed a deleterious missense mutation, a frameshift mutation, and a novel 3kb deletion, all of which are in the LDLR gene. Our study underlines the importance of accurate structural variation detection in clinical sequencing pipelines.

Elevated plasma levels of prebeta-1 high-density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from macrophages, are associated with increased risk of atherosclerotic coronary heart disease and myocardial infarction.The objective of the study was to assess the effects on prebeta-1 HDL levels of 6-week moderate-dose statin treatment.We studied 101 patients (mean age 52.7 years; 53.5% female; 63 with primary hypercholesterolemia; 38 with combined hyperlipidemia) before and after treatment with statins. Mean atorvastatin potency equivalence was 23.6 mg/d. Prebeta-1 HDL plasma levels were measured by immunofixation of agarose gels using anti-apolipoprotein A-1 antibody.We observed a 42.0% reduction of low-density lipoprotein cholesterol (181 ± 56 vs 105 mg/dL, P .001). Triglyceride (TG) levels decreased by 22.3% (157 vs 122 mg/dL, P .001), HDL cholesterol levels remained similar (56.0 vs 57.1, P = NS). Levels of prebeta-1 HDL were significantly reduced by 17.9% after statin treatment (mean 11.4 vs 9.4 mg apoA-1/dL, P .001). The magnitude of this decrease was similar with each of 3 statins (atorvastatin, simvastatin, and rosuvastatin). The decrease in prebeta-1 HDL was strongly associated with the decline in TG, but not with the decline in low-density lipoprotein cholesterol.The association of high prebeta-1 HDL with coronary heart disease identifies it as an inferential measure of the rate of cholesterol efflux from the artery wall. Our observations demonstrate a reduction of prebeta-1 HDL with statin therapy, partially reflecting the reduced TGs, and probably reflecting a direct beneficial impact on cholesterol efflux.

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

Schimke immunoosseous dysplasia (SIOD) is a multisystemic condition characterized by early arteriosclerosis and progressive renal insufficiency, among other features. Many SIOD patients have severe, migraine-like headaches, transient neurologic attacks, or cerebral ischemic events. Cerebral events could be exacerbated or precipitated by hypertension, and it is unclear how these are related to arteriosclerotic changes as dyslipidemia is also a feature of SIOD. The correlation between hypercholesterolemia and cardiovascular risk in SIOD is unclear. Also, the etiology and management of headaches is not well characterized. Here we report our clinical observations in the management of SIOD in a patient who was diagnosed in school age despite early signs and symptoms. We describe biallelic variants, including a previously unreported c.1931G>A (p.Arg644Gln) variant in SMARCAL1. We specifically investigated whether migraine-like headaches and progressive nephropathy may be related to blood pressure dysregulation. We found a correlation between tighter blood pressure regulation using ambulatory blood pressure monitoring and a subjective decrease in headache symptoms. We discuss blood pressure medication management in SIOD. We also characterize dyslipidemia relative to atherosclerosis risks and provide new management strategies to consider for optimizing care.

Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P .0001) more likely to carry one of these types of genetic susceptibility compared with controls.We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG.

Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4-expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-β (Aβ) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Aβ production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD.

Introduction: Inflammation plays an important role in the induction of CAD and the progression to deadly coronary syndromes. Cytokines are key mediators of inflammation, both in pro- and anti-inflammatory capacities. HDL has a vital role in the maintenance of cardiovascular health, and recent discoveries highlight the diversity of HDL functions to include the transport of lipid signaling molecules, microRNAs, and other effectors of metabolic regulation. Given the importance of HDL in transporting molecules involved in cardiovascular health, we questioned if HDL has a direct role in transporting cytokines and effecting inflammatory responses in CAD. Hypothesis: HDL plays an important role in the transport of cytokines involved in CAD. Methods: To explore the role of HDL in arterial inflammation, we profiled the abundance of 35 cytokines in plasma and HDL of men and women with and without CAD. We analyzed whole plasma and native HDL isolated using a selected-affinity immunosorption technique from patients who suffered myocardial infarction at an early age ( Results: Of 35 cytokines analyzed, 25 appear to be significantly transported in HDL. Three cytokines (IL-12, MCP-1, and IL-RA) are excluded from HDL and are only detectable in plasma. IL-3 and IL-7 are predominately associated with HDL and are elevated in both males and females with MI. There are differences in several HDL-associated cytokines that appear to be sex-dependent. Conclusions: We have discovered that a number of cytokines are transported in HDL complexes. Significant elevations or decreases in a number of these cytokines are observed in patients with CAD, and vary in abundance between males and females.

Background Prebeta-1 high-density lipoprotein (HDL) is a small subspecies of HDL that functions as the HDL quantum particle and is the principal acceptor of cholesterol effluxed from macrophages through the ATP-binding cassette transporter, ABCA1. High levels of prebeta-1 HDL are associated with increased risk of structural coronary artery disease and myocardial infarction. Objective We aimed to compare prebeta-1 HDL levels in normal subjects and in 3 phenotypes of dyslipidemia. Methods We studied 2435 individuals (1388 women; 1047 men). Of these, 2018 were not taking lipid-lowering medication when enrolled: 392 were normolipidemic controls; 713 had elevated levels of low-density lipoprotein cholesterol; 623 had combined hyperlipidemia; and 290 had hypertriglyceridemia. Results Relative to controls, prebeta-1 HDL levels were increased in all 3 dyslipidemic phenotypes, particularly the combined and hypertriglyceridemia groups. This increase possibly reflects increased acceptor capacity of apolipoprotein B-100 containing lipoproteins for entropically driven transfer of cholesteryl esters from HDL via cholesteryl ester transfer protein. Multiple regression analysis revealed that the main predictor variables significantly associated with prebeta-1 HDL levels were apolipoprotein A-I (apoA-1) (β = 0.500), triglyceride (β = 0.285), HDL-C (β = −0.237), and age (β = −0.169). There was an interaction between apoA-1 and sex (female vs male; β = −0.110). Among postmenopausal women, estrogenized subjects had a similar level of prebeta-1 HDL compared to those not receiving estrogens. Conclusions Prebeta-1 HDL levels are elevated in the 3 most common types of hyperlipidemia and are most strongly influenced by the levels of apoA-1, triglyceride, and HDL-C.

Role of a 4q25 Genetic Variant in Atrial Flutter Background The prediction of atrial fibrillation (AF) following catheter ablation of atrial flutter (Afl) would be helpful to facilitate targeted arrhythmia monitoring and anti-coagulation strategies. A single nucleotide polymorphism, rs2200733, is strongly associated with AF. We sought to characterize the association between rs2200733 and prevalent Afl and to determine if the variant could predict AF after cavotricuspid isthmus ablation. Methods and Results We performed a genetic association study of 295 patients with Afl and/or AF and 469 controls using multivariable logistic regression. The variant was then assessed as a predictor of incident AF after cavotricuspid isthmus ablation in 87 consecutive typical Afl patients with Cox proportional hazards models. The rs2200733 rare allele was associated with an adjusted 2.06-fold increased odds of isolated Afl (95% CI: 1.13–3.76, P = 0.019) and an adjusted 2.79-fold increased odds of a combined phenotype of AF and Afl (95% CI: 1.81–4.28, P

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.

Background: Gene variants associated with disease could reveal novel mechanisms. We searched for single nucleotide polymorphisms (SNPs) associated with noncardioembolic stroke (nonCES). Methods: We tested 24,926 SNPs in or near genes for association with nonCES in the Vienna Study (551 cases, 815 controls) and then evaluated the associated SNPs in the UCSF-CC Study (570 cases, 1,604 controls) first in pooled DNA samples and then in individual DNA samples. We then asked whether the risk alleles of the SNPs associated with increased risk in both studies were also associated with increased risk of nonCES in the German Study (728 cases, 1,041 controls). Results: Six of the 46 SNPs that were associated with nonCES in both the Vienna and the UCSF-CC Studies were also associated with nonCES in the German Study: rs362277 in HTT (OR 1.39, 90% CI 1.12–1.71), rs2924914 near CSMD1 (OR 1.22, 90% CI 1.04–1.43), rs1264352 near DDR1 (OR 1.20, 90% CI 1.02–1.41), rs544115 in NEU3 (OR 1.63, 90% CI 1.02–2.62), rs12481805 in UMODL1 (OR 1.31, 90% CI 1.01–1.81), and rs2857595 near NCR3 (OR 1.15, 90% CI 1.00–1.32). Accounting for multiple testing of 46 SNPs, these 6 SNPs had a false discovery rate of 0.69. Conclusions: Some of the 6 SNPs may be associated with nonCES but most may be false positives. These 6 SNPs merit investigation in additional nonCES study populations.

Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.

Hypertriglyceridemia is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. Membrane glycoprotein PC-1 (also termed ENPP1) is a direct insulin receptor inhibitor, and certain polymorphisms of the ENPP1/PC-1 gene have been associated with insulin resistance, type 2 diabetes, obesity, and diabetic complications.We examined the effect of 3 ENPP1/PC-1 variants (K121Q, rs1044498, and IVS20delT-11, rs1799774, and A--G+1044TGA, rs7754561) on plasma triglyceride levels in 1112 subjects of non-Hispanic American white European ancestry.Two of the ENPP1/PC-1 variants--A--G+1044TGA (odds ratio [OR] 1.48, 95% confidence interval [CI], 1.54-1.82, P = 0.002) and IVS20delT-11 (OR 1.41, 95% CI, 1.08-1.84, P = 0.012)--were significantly associated with hypertriglyceridemia. Haplotype analyses also revealed an association with hypertriglyceridemia. In the variant analyses and in the haplotype analysis, the associations with hypertriglyceridemia were observed in male but not female subjects. Interestingly, the more widely studied K121Q ENPP1/PC-1 variant was not associated with hypertriglyceridemia in any group or subgroup analysis.In the present study, we find that genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects, and may contribute to the development of the insulin resistance/metabolic syndrome in this population.

We previously demonstrated the role of a phospholipid transfer protein (PLTP) gene variation (rs2294213) in determining levels of high-density lipoprotein cholesterol (HDL-C) in hypoalphalipoproteinemia (HypoA). We have now explored the role of PLTP in hyperalphalipoproteinemia (HyperA). The human PLTP gene was screened for sequence anomalies by DNA melting in 107 subjects with HyperA. The association with plasma lipoprotein levels was evaluated. We detected 7 sequence variations: 1 previously reported variation (rs2294213) and 5 novel mutations including 1 missense mutation (L106F). The PLTP activity was unchanged in the p.L106F mutation. The frequency of the rs2294213 minor allele was markedly increased in the HyperA group (7.0%) in comparison with a control group (4.3%) and the hypoalphalipoproteinemia group (2.2%). Moreover, rs2294213 was strongly associated with HDL-C levels. Linear regression models predict that possession of the rs2294213 minor allele increases HDL-C independent of triglycerides. These findings extend the association of rs2294213 with HDL-C levels into the extremes of the HDL distribution.

Objectives— The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD). Methods and Results— We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA , CALM1 , HAP1 , AP3B1 , and ABCG2 ) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels ( P =0.003). Conclusions— The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.

Background Lysosomal acid lipase (LAL), encoded by the LIPA gene, catalyzes the intracellular hydrolysis of cholesteryl esters and triglycerides in hepatocytes and macrophages. LIPA defects cause accumulation of these lipids in lysosomes. LAL deficiency (LAL D) presents and progresses as a continuum with dyslipidemia, hepatomegaly, and liver fibrosis. Objective To improve the understanding of the genetic basis of LAL D, an underappreciated cause of dyslipidemia and cirrhosis, we studied DNA samples from patients with various phenotypes of dyslipidemia. Methods Participants (N = 1357) were identified by lipid profiles and screened for the common disease causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). Results Six patients were heterozygous for this variant. Complete LIPA sequencing revealed a patient, subsequently confirmed to have LAL D, with a heterozygous frameshift mutation involving deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and phenotype. Genetic, clinical, and lipoprotein profiles of these sisters plus 6 additional family members are reported. Profiles of 2 other LAL D patients monitored for 2 decades are presented. Cholesterol homeostasis was studied to investigate rates of cholesterol synthesis and absorption in 4 LAL D patients. High-density lipoprotein (HDL) subspecies were also analyzed. Conclusions We used this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to identify additional mutations) as a means to further elucidate the genetic basis of LAL D among individuals with a suggestive clinical phenotype.