Comparison between perfusion index, pleth variability index, and pulse pressure variability for prediction of hypotension during major abdominal surgery under general anaesthesia: A prospective observational study.

Background and Aims: Short-term hypotension after general anaesthesia can negatively impact surgical outcomes. This study compared the predictive potential of the pleth variability index (PVI), pulse pressure variability (PPV), and perfusion index (PI) for anaesthesia-induced hypotension. This study's primary objective was to evaluate the predictive potential of PI, PVI, and PPV for hypotension. Methods: This observational study included 140 adult patients undergoing major abdominal surgery under general anaesthesia. Mean arterial pressure, heart rate, PVI, PPV, and PI were collected at 1-min intervals up to 20 min post anaesthesia induction. Hypotension was assessed at 5-min and 15-min intervals. Receiver operating characteristic (ROC) curves were plotted to determine the diagnostic performance and best cut-off for continuous variables in predicting a dichotomous outcome. Statistical significance was kept at P < 0.05. Results: Hypotension prevalence within 5 and 15 min of anaesthesia induction was 36.4% and 45%, respectively. A PI cut-off of <3.5 had an area under the ROC curve (AUROC) of 0.647 (P = 0.004) for a 5-min hypotension prediction. The PVI's AUROC was 0.717 (P = 0.001) at cut-off >11.5, while PPV's AUROC was 0.742 (P = 0.001) at cut-off >12.5. At 15 min, PVI's AUROC was 0.615 (95% confidence interval 0.521-0.708, P = 0.020), with 54.9% positive predictive value and 65.2% negative predictive value. Conclusion: PVI, PPV, and PI predicted hypotension within 5 min after general anaesthesia induction. PVI had comparatively higher accuracy, sensitivity, specificity, and positive predictive value than PI and PPV when predicting hypotension at 15 min.

Accounting for population structure in genetic studies of cystic fibrosis.

CFTR F508del (c.1521_1523delCTT, p.Phe508delPhe) is the most common pathogenic allele underlying cystic fibrosis (CF), and its frequency varies in a geographic cline across Europe. We hypothesized that genetic variation associated with this cline is overrepresented in a large cohort (N > 5,000) of persons with CF who underwent whole-genome sequencing and that this pattern could result in spurious associations between variants correlated with both the F508del genotype and CF-related outcomes. Using principal-component (PC) analyses, we showed that variation in the CFTR region disproportionately contributes to a PC explaining a relatively high proportion of genetic variance. Variation near CFTR was correlated with population structure among persons with CF, and this correlation was driven by a subset of the sample inferred to have European ancestry. We performed genome-wide association studies comparing persons with CF with one versus two copies of the F508del allele; this allowed us to identify genetic variation associated with the F508del allele and to determine that standard PC-adjustment strategies eliminated the significant association signals. Our results suggest that PC adjustment can adequately prevent spurious associations between genetic variants and CF-related traits and are therefore effective tools to control for population structure even when population structure is confounded with disease severity and a common pathogenic variant.

Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10-16 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

Diet Quality Scores Are Positively Associated with Whole Blood-Derived Mitochondrial DNA Copy Number in the Framingham Heart Study.

BACKGROUND: The association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. OBJECTIVES: We aimed to study the relation between diet quality and mtDNA-CN. METHODS: We analyzed data from 2931 Framingham Heart Study (FHS) participants (mean age of 57 y, 55% females). Whole-genome sequencing was used to calculate mtDNA-CN from whole-blood samples. We examined the cross-sectional associations between 3 diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. RESULTS: We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. A 1-SD increase in the DASH score was associated with a 0.042-SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, the mtDNA-CN SD increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for a 1-SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10-6), lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10-5), and there was no significant change in platelet number (0.1 × 1000/µL; 95% CI: -1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts and the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). CONCLUSIONS: We observed that higher diet quality is associated with a greater whole-blood derived mtDNA-CN in middle-aged to older adult FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

Risk Factors Associated with Meibomian Gland Dysfunction: A Hospital Based Study.

INTRODUCTION: Meibomian Gland Dysfunction (MGD) is a chronic diffuse abnormality of the Meibomian glands often found as a result of precipitating factors like dyslipidemia, infections, hypertension, diabetes, etc. This study aims to find the prevalence of various risk factors of Meibomian Gland Dysfunction (MGD) which will ultimately help in managing the disease and explaining the prognosis. MATERIALS AND METHODS: A hospital based cross-sectional study. A total of 400 patients with MGD over the age of 30 were examined. Patients with a history of taking lipid altering drugs, pre-existing ocular comorbidities were excluded from the study. RESULTS: Severity of MGD increased with ageing. There was a significant risk of higher grades of MGD in hypertensives, diabetics & post-menopausal women. Higher levels of LDL cholesterol showed significant risk. CONCLUSION: Blood sugar, blood pressure, blood cholesterol were seen to be the risk factors in the study and thus, should be kept within normal limits to reduce the severity of disease. Alcohol & cigarette consumption should be avoided even if they didn't show a significant relationship.

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction.

Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.

Causes of delayed presentation of pediatric cataract: A questionnaire-based prospective study at a tertiary eye care center in central rural India.

Purpose: To find out the sociodemographic, sociocultural, and socioeconomic factors leading to delay in pediatric cataract surgery and its impact on final visual outcome. Methods: A prospective interview-based analytical cohort study was conducted on 156 children aged 0-16 years with either unilateral or bilateral congenital/developmental cataracts. Caregivers were interviewed using a pretested validated questionnaire. Time intervals between recognition by a caregiver to consultation were denoted as Delay-1 and between consultations to surgical intervention as Delay-2. Spearman's rank correlation was used to determine the presence of correlation between causes of delay and visual outcome. Results: The mean age of presentation was 7.78 ± 4.34 years. Mothers were the first informant of the problem (n = 110, 70.5%). Out of 156 children, only 8 (5.1%) children presented to the hospital within 1 month by caregivers and 26 (16.7%) children underwent surgery within 2 months of advice. About 22 (14.1%) children had total cumulative delay of 1-6 months, 11 (7%) had delay of 6-12 months, and 115 (73.71%) had delay of >12 months. The most common cause identified for Delay-1 was unawareness in 41 cases (26.28%), however, for Delay-2 major factor responsible was cost (n = 38, 24.35%). The median preoperative visual acuity was 1.31 logMAR and median postoperative visual acuity at 4 weeks was 0.61 logMAR. (P < 0.001) Less age at surgery, upper socioeconomic status, less time delay, and better preoperative vision were positively correlated to better visual outcomes. Conclusion: Delay in presentation for childhood cataract surgery remains a significant problem in central rural India. Delay in surgery is multifactorial which includes unawareness, cost, misdiagnosis, self-treatment, distance from the hospital, lack of family support, and poor socioeconomic status.

Goal-directed fluid therapy using transoesophageal echocardiographic inferior venacaval index in patients with low left ventricular ejection fraction undergoing major cytoreductive surgery: A clinical trial.

BACKGROUND AND AIMS: This study aims to trans oesophageal echo cardiographically (TOE) measure inferior venacava diameter (IVCD) during inspiration and expiration in poor left ventricular ejection fraction (LVEF) patients undergoing cytoreductive oncosurgery, to ascertain if any correlation exists between, caval index (DeltaIVCD), and stroke volume variation (SVV), and to compare DeltaIVCD-guided versus SVV-guided fluid therapy. METHODS: In this prospective, parallel group, interventional study, seventy American Society of Anesthesiologists-III patients, aged 30-75 years, weighing 40-90 kg, with LVEF ≤40% undergoing cytoreductive surgery were included and randomised to group-D (DeltaIVCD-guided fluid therapy) and group-S (SVV-guided fluid therapy). Patients with oesophageal lesions were excluded. After standard endotracheal anaesthesia, arterial and internal jugular vein catheters were placed. A TOE probe was inserted in the interventional group-D. Quantification of IVCD respiratory variations was done. Heart rate (HR), arterial oxygen saturation (SPO2), mean arterial pressure, end tidal carbondioxide (EtCO2), central venous pressure, SVV, IVCD, and urine output (UO) were recorded every 30 min. Post-operative arterial blood gas analysis, lung-ultrasound, chest-radiograph, and serum creatinine were done. STATISTICAL ANALYSIS: Pearson's correlation coefficient as measure of strength of linear relationship, calculation of regression equation, and unpaired t-test for normally distributed continuous variables were used. RESULTS: A positive correlation between DeltaIVCD and SVV (r = 0.751) was observed. A regression equation was obtained for SVV (SVV = [0.317 × DeltaIVCD] + 5.877). Serum lactate, estimated glomerular filtration rate, HR, and UO were within normal limits in group-D. There was no pulmonary oedema. CONCLUSION: DeltaIVCD-guided intravenous fluid therapy is valuable in low LVEF patients where tight fluid control is essential and any fluid overload may precipitate cardiac failure.

Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1ß expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. METHODS: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala. RESULTS: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], P<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29-0.73], P<0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89-1.01], P=0.08; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036). CONCLUSIONS: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.

Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation.

Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing the pathogenicity of noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrate that this single-nucleotide alteration leads to reduced canonical splicing and increased use of an alternative splice acceptor site that causes a partial intron retention event. The resultant altered GATA1 contains a five-amino acid insertion at the C-terminus of the C-terminal zinc finger and has no observable activity. Collectively, our results demonstrate how altered splicing of GATA1, which reduces levels of the normal form of this master transcription factor, can result in distinct changes in human hematopoiesis.

Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI < 0.1), while ultra-rare missense variants were significantly overrepresented in cases only in constrained genes (pLI > 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.

Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.

BACKGROUND: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. METHODS: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations. RESULTS: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008). CONCLUSIONS: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

A Novel Mutation in Helical Domain 2 of NOD2 in Sporadic Blau Syndrome.

We report a 12-year-old girl who presented with bilateral granulomatous anterior uveitis accompanied by boggy arthritis of knee and ankle joints, intermittent fever, and nodular skin rash. She was diagnosed with sporadic Blau syndrome (early-onset sarcoidosis) based on above clinical signs and presence of non-necrotising granuloma on iris biopsy. DNA sequencing revealed a previously unreported heterozygous mutation consisting of a G>A transition in exon 4 of the NOD2 gene. This resulted in a glutamic acid to lysine substitution in helical domain 2 of the nucleotide binding and oligomerization (NACHT) region, possibly reducing efficiency of auto-inhibition in NOD2 signaling. Interestingly, the ocular inflammation resolved completely following therapeutic vitrectomy in both eyes whereas the systemic symptoms of fever and arthritis continued to wax and wane while on treatment with oral methotrexate and corticosteroids.

Utility of non-invasive haemoglobin monitoring in oncosurgery patients.

BACKGROUND AND AIMS: Oncosurgeries may incur massive blood loss demanding frequent blood sampling to assess blood loss and the need for intraoperative blood transfusions. Accuracy of non-invasive spectrophotometric haemoglobin (hereafter to be referred as SpHb) monitoring has been studied in various perioperative settings. The intraoperative use of Radical-7®, Masimo Corp., (Radical-7®) for SpHb monitoring may be useful during cancer surgery. The aim of this study is to evaluate the intraoperative utility of SpHb monitoring by the Radical-7® to guide intraoperative transfusion in oncosurgeries. METHODS: Fifty adult patients, undergoing oncosurgery with anticipated blood loss of more than 20% of blood volume, were selected. Continuous SpHb monitoring was performed intraoperatively and blood transfusion was based on SpHb values. Simultaneous laboratory haemoglobin (LabHb) samples were taken for validation. The accuracy of intraoperative blood transfusions based on SpHb was analysed using Error Grid Analysis. Paired measurements of SpHb and LabHb were compared using Bland-Altman plot analysis. RESULTS: There were 66 paired data points for blood transfusion from fifty patients with a correlation of 73% (P < 0.001) between SpHb and LabHb. In the Bland-Altman analysis, the bias was - 0.313 g/dl with ~ 95% of values within the limits of agreement of 1.81 g/dl to -2.44 g/dl. In the Error Grid Analysis, most data points were in the least error zone (Zone A). CONCLUSION: The Radical-7® has the advantage of providing SpHb value continuously to take prompt decision regarding blood transfusion intraoperatively.

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS: The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.

KSHV encoded LANA recruits Nucleosome Assembly Protein NAP1L1 for regulating viral DNA replication and transcription.

The establishment of latency is an essential for lifelong persistence and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV). Latency-associated nuclear antigen (LANA) is the most abundantly expressed protein during latency and is important for viral genome replication and transcription. Replication-coupled nucleosome assembly is a major step in packaging the newly synthesized DNA into chromatin, but the mechanism of KSHV genome chromatinization post-replication is not understood. Here, we show that nucleosome assembly protein 1-like protein 1 (NAP1L1) associates with LANA. Our binding assays revealed an association of LANA with NAP1L1 in KSHV-infected cells, which binds through its amino terminal domain. Association of these proteins confirmed their localization in specific nuclear compartments of the infected cells. Chromatin immunoprecipitation assays from NAP1L1-depleted cells showed LANA-mediated recruitment of NAP1L1 at the terminal repeat (TR) region of the viral genome. Presence of NAP1L1 stimulated LANA-mediated DNA replication and persistence of a TR-containing plasmid. Depletion of NAP1L1 led to a reduced nucleosome positioning on the viral genome. Furthermore, depletion of NAP1L1 increased the transcription of viral lytic genes and overexpression decreased the promoter activities of LANA-regulated genes. These results confirmed that LANA recruitment of NAP1L1 helps in assembling nucleosome for the chromatinization of newly synthesized viral DNA.

Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.