Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia.

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.

Loss-of-Function CREB3L3 Variants in Patients With Severe Hypertriglyceridemia.

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.

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

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 and management considerations for vascular risks.

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.

A cross-validation Delphi method approach to the diagnosis and treatment of personality disorders in older adults.

INTRODUCTION: The Delphi method is a consensus-building technique using expert opinion to formulate a shared framework for understanding a topic with limited empirical support. This cross-validation study replicates one completed in the Netherlands and Belgium, and explores US experts' views on the diagnosis and treatment of older adults with personality disorders (PD). METHODS: Twenty-one geriatric PD experts participated in a Delphi survey addressing diagnosis and treatment of older adults with PD. The European survey was translated and administered electronically. RESULTS: First-round consensus was reached for 16 out of 18 items relevant to diagnosis and specific mental health programs for personality disorders in older adults. Experts agreed on the usefulness of establishing criteria for specific types of treatments. The majority of psychologists did not initially agree on the usefulness of pharmacotherapy. Expert consensus was reached following two subsequent rounds after clarification addressing medication use. CONCLUSIONS: Study results suggest consensus among regarding psychosocial treatments. Limited acceptance amongst US psychologists about the suitability of pharmacotherapy for late-life PDs contrasted with the views expressed by experts surveyed in Netherlands and Belgium studies.

Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment.

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.

Aberrant hetero-disulfide bond formation by the hypertriglyceridemia-associated p.Gly185Cys APOA5 variant (rs2075291).

OBJECTIVE: Apolipoprotein A-V (apoA-V) is a low-abundance plasma protein that modulates triacylglycerol homeostasis. Gene transfer studies were undertaken in apoa5 (-/-) mice to define the mechanism underlying the correlation between the single-nucleotide polymorphism c.553G>T in APOA5 and hypertriglyceridemia. APPROACH AND RESULTS: Adeno-associated virus (AAV) 2/8-mediated gene transfer of wild-type apoA-V induced a dramatic lowering of plasma triacylglycerol in apoa5 (-/-) mice, whereas AAV2/8-Gly162Cys apoA-V (corresponding to the c.553G>T single-nucleotide polymorphism: rs2075291; p.Gly185Cys when numbering includes signal sequence) had a modest effect. Characterization studies revealed that plasma levels of wild-type and G162C apoA-V in transduced mice were similar and within the physiological range. Fractionation of plasma from mice transduced with AAV2/8-G162C apoA-V indicated that, unlike wild-type apoA-V, >50% of G162C apoA-V was recovered in the lipoprotein-free fraction. Nonreducing SDS-PAGE immunoblot analysis provided evidence that G162C apoA-V present in the lipoprotein-free fraction, but not that portion associated with lipoproteins, displayed altered electrophoretic mobility consistent with disulfide-linked heterodimer formation. Immunoprecipitation followed by liquid chromatography/mass spectrometry of human plasma from subjects homozygous for wild-type APOA5 and c.553G>T APOA5 revealed that G162C apoA-V forms adducts with extraneous plasma proteins including fibronectin, kininogen-1, and others. CONCLUSIONS: Substitution of Cys for Gly at position 162 of mature apoA-V introduces a free cysteine that forms disulfide bonds with plasma proteins such that its lipoprotein-binding and triacylglycerol-modulation functions are compromised.

Stigma, social anxiety, and illness severity in bipolar disorder: Implications for treatment.

BACKGROUND: Studies indicate that comorbid anxiety disorders predict a more severe course of illness in bipolar disorder (BD). The relatively high prevalence of social anxiety in BD points to the potential role that socio-cultural factors, such as stigma, play in exacerbating the progression of this disorder. Stigma creates social anxiety in affected individuals because it essentially forces them into a vulnerable social status that is marked by public disgrace. Although the etiology of debilitating social anxiety in BD may involve multiple factors, stigma deserves particular clinical attention because research in this area indicates that it is common and its internalization is associated with poor outcome. METHODS: We conducted a literature review using search terms related to stigma, social anxiety, bipolar disorder, illness severity, and outcomes. The electronic databases searched included PsychINFO, PubMed, JSTOR, and EBSCOhost Academic Search Complete with limits set to include articles published in English. RESULTS: The literature indicates that internalized stigma often triggers the core psychological experiences of social anxiety and is highly correlated with clinical and functional outcome in BD. On a psychological level, internalized stigma and social anxiety can create distress that triggers symptoms of BD. From a biological perspective, stigma constitutes a chronic psychosocial stressor that may interact with the pathophysiology of BD in inflammatory ways. CONCLUSIONS: The connection between stigma and social anxiety, and their combined effects on people with BD, carries important implications for psychiatric care. To obtain an accurate clinical formulation, initial evaluations may seek to examine stigma-related experiences and determine their relationship to anxiety symptoms and psychosocial functioning. In addition, direct interventions for reducing the ill effects of stigma in BD deserve clinical attention, because they may carry the potential to enhance outcomes.

A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins.

Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1-597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased α-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression. GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117).

Impact of a 4q25 genetic variant in atrial flutter and on the risk of atrial fibrillation after cavotricuspid isthmus ablation.

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 < 0.001). Following catheter ablation for Afl, carrier status of rs2200733 failed to predict an increased risk of AF either among all subjects (adjusted HR: 0.94; 95% CI: 0.58-1.53, P = 0.806) or among those with isolated Afl (adjusted HR: 1.29; 95% CI: 0.51-3.26, P = 0.585). CONCLUSIONS: Our study demonstrates that Afl, whether occurring in isolation or along with AF, is associated with the rs2200733 AF risk allele. Genetic carrier status of rs2200733 failed to predict an increased risk of incident or recurrent AF following catheter ablation for Afl. These findings suggest that the causal mechanism associated with rs2200733 is germane to both AF and Afl.

Age as a predictor of cognitive decline in bipolar disorder.

OBJECTIVE: Cognitive dysfunction is a core feature of bipolar disorder (BD) in both adult and geriatric patients. However, little is known about whether cognitive functioning declines at a faster rate in patients with BD, and there are conflicting reports regarding the relationship between age and cognitive functioning in this population. This cross-sectional study examined the relationship between age and cognitive functioning in patients with BD. METHODS: Patients with BD I (N = 113) and healthy adults (N = 64) ages 18-87 completed measures of processing speed, attention, executive functioning, verbal fluency, and clinical symptomatology. Groupwise comparisons were used to examine differences between patients and the comparison group and adult and geriatric BD cohorts. A series of linear regressions was conducted to examine the relationship of age and cognitive functioning and clinical variables and cognition. RESULTS: Patients performed significantly worse than the comparison group on all neuropsychological measures. Age was a significant predictor of Trails A scores with older age associated with worse performance. CONCLUSIONS: Older age was associated with poorer performance on Trails A in patients with BD but not healthy adults. These results are suggestive of greater dysfunction in processing speed with older age in patients with BD compared with a healthy comparison group. Because cognitive functioning is associated with community outcomes, these findings suggest a need for treatments targeting cognitive symptoms across the life span. Future research exploring neurobiologic evidence for neurodegenerative processes in BD will pave the way for potential therapeutic interventions.

Evaluation of heme peripheral group interactions in extremely low-dielectric constant media and their contributions to the heme reduction potential.

In this study, we measured the contributions of the ionization of the heme propionates to the reduction potentials of heme b and heme a (bis)N-methylimidazole complexes in various low-dielectric constant conditions. Additionally, we measured the effects of H-bond to the heme a formyl group on the reduction potential of the heme. The performed electrochemical measurements show that ionization of the heme propionates lead to the largest redox change in dichloromethane with no electrolyte. The measured reduction potential changes for heme b and heme a were -55 and -47 mV (±10 mV) per ionized propionate, respectively. For heme a, the study demonstrates how the dielectric constant of the medium is important in the magnification of the ΔpKa upon redox-linked ionization of the heme propionates and their roles in the proton pump of cytochrome c oxidase.

Spiritual struggle and affective symptoms among geriatric mood disordered patients.

OBJECTIVES: We explored relationships between general religiousness, positive religious coping, negative religious coping (spiritual struggle), and affective symptoms among geriatric mood disordered outpatients, in the northeastern USA. METHODS: We assessed for general religiousness (religious affiliation, belief in God, and private and public religious activity) and positive/negative religious coping, alongside interview and self-report measures of affective functioning in a diagnostically heterogeneous sample of n = 34 geriatric mood disordered outpatients (n = 16 bipolar and n = 18 major depressive) at a psychiatric hospital in eastern Massachusetts. RESULTS: Except for a modest correlation between private prayer and lower Geriatric Depression Scale scores, general religious factors (belief in God, public religious activity, and religious affiliation) as well as positive religious coping were unrelated to affective symptoms after correcting for multiple comparisons and controlling for significant covariates. However, a large effect of spiritual struggle was observed on greater symptom levels (up to 19.4% shared variance). Further, mean levels of spiritual struggle and its observed effects on symptoms were equivalent irrespective of religious affiliation, belief, and private and public religious activity. CONCLUSIONS: Previously observed effects of general religiousness on (less) depression among geriatric mood disordered patients may be less pronounced in less religious areas of the USA. However, spiritual struggle appears to be a common and important risk factor for depressive symptoms, regardless of patients' general level of religiousness. Further research on spiritual struggle is warranted among geriatric mood disordered patients.

Prebeta-1 HDL and coronary heart disease.

PURPOSE OF REVIEW: A negative correlation between HDL cholesterol levels and risk of coronary artery disease has long been recognized. Emerging knowledge of the molecular speciation and functional properties of HDL provides an opportunity to study the atheroprotective effects of specific metabolic processes. The discovery of the quantum particle among the molecular species of HDL (prebeta-1 HDL) and its role in cholesterol efflux from the artery wall, offer a means of assessing the efficiency of efflux. This review presents observations on the structure and metabolism of this particle and its emerging role as a predictor of risk for atherosclerotic vascular disease. RECENT FINDINGS: Prebeta-1 HDL is now recognized as the primary acceptor of cholesterol effluxed by the dominant ATP-binding cassette A1 (ABCA1) transporter in arterial macrophages, a critical step in reverse cholesterol transport. Several studies have revealed an association between high levels of this particle and risk of globally defined coronary artery disease and carotid intima-media thickness. Recently, these findings have been confirmed and extended to include myocardial infarction. High levels of prebeta-1 HDL may serve as an index of functional impairment of cholesterol efflux or esterification, either of which would be expected to impede reverse cholesterol transport. SUMMARY: Recent studies underscore the critical role of prebeta-1 HDL in reverse cholesterol transport and its use as a marker of risk for structural coronary disease, myocardial infarction, and cerebral vascular disease.

APOL1 Risk Variants Associate with the Prevalence of Stroke in African American Current and Past Smokers.

Introduction: Among 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 showed APOL1 G1/G2 risk variants associate with stroke. However, the role of APOL1 variants in tobacco-related stroke is unknown. Methods: In a cross-sectional study, we examined whether APOL1 risk 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 determined APOL1 variants, smoking status, and history of stroke. Using unstratified and stratified multivariable logistic regression models we examined the association between smoking history (ever smokers vs. never smokers) and odds of stroke overall, and among carriers of risk variants and non-carriers, separately. Results: Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk 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 by APOL1 genotype status in the unstratified model (Pinteraction term=0.016). Among carriers of risk variants, ever smokers had odds ratio (OR) =2.88 for stroke compared to never smokers (P=0. 0.038). The OR for stroke comparing ever vs. never smokers 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. Conclusion: In conclusion, current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke, in particular ischemic stroke, among African Americans.

APOL1 Risk Variants Associate With the Prevalence of Stroke in African American Current and Past Smokers.

BACKGROUND: African American smokers have 2.5 times higher risk for stroke compared with nonsmokers (higher than other races). About 50% of the African American population carry 1 or 2 genetic variants (G1 and G2; rare in other races) of the apolipoprotein L1 gene (APOL1). Studies showed these variants may be associated with stroke. However, the role of the APOL1 risk variants in tobacco-related stroke is unknown. METHODS AND RESULTS: In a cross-sectional study, we examined whether APOL1 risk variants modified the relationship between tobacco smoking and stroke prevalence in 513 African American adults recruited at University of California, San Francisco. Using DNA, plasma, and questionnaires we determined APOL1 variants, smoking status, and stroke prevalence. Using logistic regression models, we examined the association between smoking (ever versus never smokers) and stroke overall, and among carriers of APOL1 risk variants (1 or 2 risk alleles), and noncarriers, separately. Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk variants, and 41 had a history of stroke. The association between smoking and stroke differed by APOL1 genotype (Pinteraction term=0.014). Among carriers, ever versus never smokers had odds ratio (OR) 2.46 (95% CI, 1.08-5.59) for stroke (P=0.034); OR 2.00 (95% CI, 0.81-4.96) among carriers of 1 risk allele, and OR 4.72 (95% CI, 0.62-36.02) for 2 risk alleles. Among noncarriers, smoking was not associated with a stroke. CONCLUSIONS: Current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke among the African American population.