Mindful attention is inversely associated with pain via mediation by psychological distress in orthopedic patients.

BACKGROUND: Orthopedic patients report pain as their main symptom complaint. Subjective pain experience is correlated with self-reported psychological state, such as distress. PURPOSE: This study tests whether scores from a measure of mindful attention are associated with subjective pain levels and whether psychological distress scores function as a mediation path. METHODS: During routine visits to a single orthopedic clinic in East Los Angeles, California, 525 patients were recruited to participate in the study. Participants reported on measures of pain (Universal Pain Assessment Tool [UPAT]), mindful attention (Five-Facet Mindfulness Questionnaire [FFMQ]), and psychological distress (Depression, Anxiety, Stress Scale [DASS]). We used Pearson correlations to examine relationships between FFMQ and UPAT scores and mediation analyses to test indirect effects of DASS scores as a mediation path. RESULTS: The average age of the sample was 54 years (range 18-98 years), 61% were male, and 64% were non-Hispanic White individuals. The locations of injury were the shoulder (72%), elbow (21%), and clavicle or wrist (7%). Ninety-one percent reported mild or greater pain in the prior 2 weeks (mean = 4.2 ± 2.5, range 0-10), and 49% reported mild or more severe distress symptoms (DASS: 13.0 ± 11.5). FFMQ scores inversely predicted UPAT scores (ß = -0.22, P < .01), mediated through DASS scores. DASS subscale scores for depression (ß = -0.10, P = .02) and stress (ß = -0.08, P = .04) but not anxiety (ß = -0.03, P = .33) produced significant indirect effects. FFMQ acting-with-awareness and non-judging subscales had the largest effect on depression and stress DASS subscale scores. CONCLUSIONS: We find statistical support to suggest that distress-particularly depressed mood and stress-mediates the association between mindful attention and pain intensity among orthopedic patients. A disposition of mindful attention might counter distress ailments that exacerbate subjective pain, and this has possible implications for mindfulness training interventions offered to orthopedic patients.

Oxidative stress mediates associations between preoperative psychosocial phenotype and pain-related outcomes at 6 months following total knee arthroplasty: a longitudinal cohort study.

OBJECTIVE: Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). DESIGN: A mixed between/within-subjects longitudinal cohort design. SETTING: A single academic medical center. SUBJECTS: Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. METHODS: We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6 months following TKA. RESULTS: Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (P < .05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (P < .05). Bootstrapped mediation analyses revealed significant (P < .05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (P < .05) on post-TKA outcomes that were independent of OS mechanisms. CONCLUSIONS: Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.

Perioperative opioid prescribing and iatrogenic opioid use disorder and overdose: a state-of-the-art narrative review.

BACKGROUND/IMPORTANCE: Considerable attention has been paid to identifying and mitigating perioperative opioid-related harms. However, rates of postsurgical opioid use disorder (OUD) and overdose, along with associated risk factors, have not been clearly defined. OBJECTIVE: Evaluate the evidence connecting perioperative opioid prescribing with postoperative OUD and overdose, compare these data with evidence from the addiction literature, discuss the clinical impact of these conditions, and make recommendations for further study. EVIDENCE REVIEW: State-of-the-art narrative review. FINDINGS: Nearly all evidence is from large retrospective studies of insurance claims and Veterans Health Administration (VHA) data. Incidence rates of new OUD within the first year after surgery ranged from 0.1% to 0.8%, while rates of overdose events ranged from 0.01% to 0.8%. Higher rates were seen among VHA patients, which may reflect differences in data completeness and/or risk factors. Identified risk factors included those related to substance use (preoperative opioid use; non-opioid substance use disorders; preoperative sedative, anxiolytic, antidepressant, and gabapentinoid use; and postoperative new persistent opioid use (NPOU)); demographic attributes (chiefly male sex, younger age, white race, and Medicaid or no insurance coverage); psychiatric comorbidities such as depression, bipolar disorder, and PTSD; and certain medical and surgical factors. Several challenges related to the use of administrative claims data were identified; there is a need for more granular retrospective studies and, ideally, prospective cohorts to assess postoperative OUD and overdose incidence with greater accuracy. CONCLUSIONS: Retrospective data suggest an incidence of new postoperative OUD and overdose of up to 0.8% during the first year after surgery, but prospective studies are lacking.

Preoperative Predictors of Prolonged Opioid Use in the 6 Months After Total Knee Arthroplasty.

OBJECTIVES: Prolonged postoperative opioid use increases the risk for new postsurgical opioid use disorder. We evaluated preoperative phenotypic factors predicting prolonged postoperative opioid use. METHODS: We performed a secondary analysis of a prospective observational cohort (n=108) undergoing total knee arthroplasty (TKA) for osteoarthritis with 6-week and 6-month follow-up. Current opioid use and psychosocial, pain, and opioid-related characteristics were assessed at preoperative baseline. Primary outcomes were days/week of opioid use at follow-up. RESULTS: At 6 weeks, preoperative opioid use and greater cumulative opioid exposure, depression, catastrophizing, anxiety, pain interference, sleep disturbance, and central sensitization were significantly associated with more days/week of opioid use after controlling for contemporaneous pain intensity. Prior euphoric response to opioids were also significant predictors at 6 months. All 6-week predictors except anxiety remained significant after controlling for preoperative opioid use; at 6 months, cumulative opioid exposure, catastrophizing, pain interference, and sleep disturbance remained significant after this adjustment ( P <0.05). In multivariable models, a psychosocial factor reflecting negative affect, sleep, and pain accurately predicted 6-week opioid use (area under the curve=0.84). A combined model incorporating psychosocial factor scores, opioid-related factor scores, and preoperative opioid use showed near-perfect predictive accuracy at 6 months (area under the curve=0.97). DISCUSSION: Overall, preoperative psychosocial, pain-related, and opioid-related phenotypic characteristics predicted prolonged opioid use after total knee arthroplasty.

Genetic predisposition may not improve prediction of cardiac surgery-associated acute kidney injury.

Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance (p < 5 × 10-8) threshold, however, six previously unreported variants exceeded the suggestive threshold (p < 1 × 10-6). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH. We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, p = 0.005) were significant in the full model. Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors.

Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients.

BACKGROUND: Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery. METHODS: We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants. RESULTS: The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability. CONCLUSION: The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

Patient Factors Associated With Opioid Consumption in the Month Following Major Surgery.

OBJECTIVE: The aim of this study was to determine preoperative patient characteristics associated with postoperative outpatient opioid use and assess the frequency of postoperative opioid overprescribing. SUMMARY BACKGROUND DATA: Although characteristics associated with inpatient opioid use have been described, data regarding patient factors associated with opioid use after discharge are lacking. This hampers the development of individualized approaches to postoperative prescribing. METHODS: We included opioid-naïve patients undergoing hysterectomy, thoracic surgery, and total knee and hip arthroplasty in a single-center prospective observational cohort study. Preoperative phenotyping included self-report measures to assess pain severity, fibromyalgia survey criteria score, pain catastrophizing, depression, anxiety, functional status, fatigue, and sleep disturbance. Our primary outcome measure was self-reported total opioid use in oral morphine equivalents. We constructed multivariable linear-regression models predicting opioids consumed in the first month following surgery. RESULTS: We enrolled 1181 patients; 1001 had complete primary outcome data and 913 had complete phenotype data. Younger age, non-white race, lack of a college degree, higher anxiety, greater sleep disturbance, heavy alcohol use, current tobacco use, and larger initial opioid prescription size were significantly associated with increased opioid consumption. Median total oral morphine equivalents prescribed was 600 mg (equivalent to one hundred twenty 5-mg hydrocodone pills), whereas median opioid consumption was 188 mg (38 pills). CONCLUSIONS: In this prospective cohort of opioid-naïve patients undergoing major surgery, we found a number of characteristics associated with greater opioid use in the first month after surgery. Future studies should address the use of non-opioid medications and behavioral therapies in the perioperative period for these higher risk patients.

LabWAS: Novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks.

Phenotypes extracted from Electronic Health Records (EHRs) are increasingly prevalent in genetic studies. EHRs contain hundreds of distinct clinical laboratory test results, providing a trove of health data beyond diagnoses. Such lab data is complex and lacks a ubiquitous coding scheme, making it more challenging than diagnosis data. Here we describe the first large-scale cross-health system genome-wide association study (GWAS) of EHR-based quantitative laboratory-derived phenotypes. We meta-analyzed 70 lab traits matched between the BioVU cohort from the Vanderbilt University Health System and the Michigan Genomics Initiative (MGI) cohort from Michigan Medicine. We show high replication of known association for these traits, validating EHR-based measurements as high-quality phenotypes for genetic analysis. Notably, our analysis provides the first replication for 699 previous GWAS associations across 46 different traits. We discovered 31 novel associations at genome-wide significance for 22 distinct traits, including the first reported associations for two lab-based traits. We replicated 22 of these novel associations in an independent tranche of BioVU samples. The summary statistics for all association tests are freely available to benefit other researchers. Finally, we performed mirrored analyses in BioVU and MGI to assess competing analytic practices for EHR lab traits. We find that using the mean of all available lab measurements provides a robust summary value, but alternate summarizations can improve power in certain circumstances. This study provides a proof-of-principle for cross health system GWAS and is a framework for future studies of quantitative EHR lab traits.

Patterns of Initial Opioid Prescribing to Opioid-Naive Patients.

OBJECTIVE: To determine the proportion of initial opioid prescriptions for opioid-naive patients prescribed by surgeons, dentists, and emergency physicians. We hypothesized that the percentage of such prescriptions grew as scrutiny of primary care and pain medicine opioid prescribing increased and guidelines were developed. SUMMARY OF BACKGROUND DATA: Data regarding the types of care for which opioid-naive patients are provided initial opioid prescriptions are limited. METHODS: A retrospective cross-sectional study using a nationwide insurance claims dataset to study US adults aged 18 to 64 years. Our primary outcome was a change in opioid prescription share for opioid-naive patients undergoing surgical, emergency, and dental care from 2010 to 2016; we also examined the type and amounts of opioid filled. RESULTS: From 87,941,718 analyzed lives, we identified 16,292,018 opioid prescriptions filled by opioid-naive patients. The proportion of prescriptions for patients receiving surgery, emergency, and dental care increased by 15.8% from 2010 to 2016 (P < 0.001), with the greatest increases related to surgical (18.1%) and dental (67.8%) prescribing. In 2016, surgery patients filled 22.0% of initial prescriptions, emergency medicine patients 13.0%, and dental patients 4.2%. Surgical patients' mean total oral morphine equivalents per prescription increased from 240 mg (SD 509) in 2010 to 403 mg (SD 1369) in 2016 (P < 0.001). Over the study period, surgical patients received the highest proportion of potent opioids (90.2% received hydrocodone or oxycodone). CONCLUSIONS: Initial opioid prescribing attributable to surgical and dental care is increasing relative to primary and chronic pain care. Evidence-based guideline development for surgical and dental prescribing is warranted in order to curb iatrogenic opioid morbidity and mortality.

The gender authorship gap in gynecologic oncology research.

Female first authorship and senior authorship in academic obstetrics and gynecology has increased over time but gender-specific publishing data are lacking within gynecologic oncology. We examined contribution by gender to the subspecialty's flagship journal, Gynecologic Oncology, over five decades, from 1972 to 2014, to identify trends in gender representation. Chi-square tests were used to compare gender distributions within and between the first and last years studied (1972-73 and 2014) as well as linear regression to model trends over time. Female first and senior authorship increased significantly from 1972 to 2014 (first: χ2 = 20.9, p < .01; senior: χ2 = 9.9, p < .01). The number of female first authors increased markedly after 2000. Male senior authors still outnumber female senior authors. Papers with senior female authors were more likely to have female first authors, suggesting a mentorship role. Subspecialty-wide gender equity initiatives should encourage continued mentorship of women by female colleagues.

Medial branch radiofrequency ablation outcomes in patients with centralized pain.

BACKGROUND AND OBJECTIVES: We hypothesized that patients with characteristics of centralized pain (fibromyalgia (FM)-like phenotype) would be less likely to respond to radiofrequency ablation (RFA), which may explain some of the failures of this peripherally directed therapy. METHODS: We conducted a prospective, observational study of patients undergoing RFA using a number of validated self-report measures of pain, mood and function. The 2011 Fibromyalgia Survey Criteria were used to assess for symptoms of centralized pain and was the primary predictor of interest. We constructed multivariable linear regression models to evaluate covariates independently associated with change in pain 3 months after RFA. RESULTS: 141 patients scheduled for medial branch blocks were enrolled in the study; 55 underwent RFA (51 with complete 3 months' follow-up). Patients with higher FM scores had less improvement in overall body pain; however, this was not statistically significant (adjusted mean change in pain FM+0.41, FM-1.11, p=0.396). In a secondary analysis, the FM score was not associated with change in back pain (p=0.720), with both groups improving equally. This cohort also reported significant improvement in anxiety, physical function, catastrophizing, and sleep disturbance at 3 months after RFA. CONCLUSIONS: Although patients with high baseline centralized pain exhibited less improvement in overall pain, this trend was not statistically significant, possibly due to insufficient power. The same trend was not seen with change in spine pain with both groups improving equally. Centralized pain patients may have less improvement in overall pain but may have equal improvement in their site-specific pain levels after localized interventions.

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis.

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

Genetic variants and acute kidney injury: A review of the literature.

PURPOSE: Limited data exists on potential genetic contributors to acute kidney injury. This review examines current knowledge of AKI genomics. MATERIALS AND METHODS: 32 studies were selected from PubMed and GWAS Catalog queries for original data studies of human AKI genetics. Hand search of references identified 3 additional manuscripts. RESULTS: 33 of 35 studies were hypothesis-driven investigations of candidate polymorphisms that either did not consistently replicate statistically significant findings, or obtained significant results only in few small-scale studies. Vote-counting meta-analysis of 9 variants examined in >1 candidate gene study showed ≥50% non-significant studies, with larger studies generally finding non-significant results. The remaining 2 studies were large-scale unbiased investigations: One examining 2,100 genes linked with cardiovascular, metabolic, and inflammatory syndromes identified BCL2, SERPINA4, and SIK3 variants, while a genome-wide association study (GWAS) identified variants in BBS9 and the GRM7|LMCD1-AS1 intergenic region. All studies had relatively small sample sizes (<2300 subjects). Study heterogeneity precluded candidate gene and GWA meta-analysis. CONCLUSIONS: Most studies of AKI genetics involve hypothesis-driven (rather than hypothesis-generating) candidate gene investigations that have failed to identify contributory variants consistently. A limited number of unbiased, larger-scale studies have been carried out, but there remains a pressing need for additional GWA studies.

Targeted exonic sequencing of GWAS loci in the high extremes of the plasma lipids distribution.

OBJECTIVE: Genome-wide association studies (GWAS) for plasma lipid levels have mapped numerous genomic loci, with each region often containing many protein-coding genes. Targeted re-sequencing of exons is a strategy to pinpoint causal variants and genes. METHODS: We performed solution-based hybrid selection of 9008 exons at 939 genes within 95 GWAS loci for plasma lipid levels and sequenced using next-generation sequencing technology individuals with extremely high as well as low to normal levels of low-density lipoprotein cholesterol (LDL-C, n = 311; mean low = 71 mg/dl versus high = 241 mg/dl), triglycerides (TG, n = 308; mean low = 75 mg/dl versus high = 1938 mg/dl), and high-density lipoprotein cholesterol (HDL-C, n = 684; mean low = 32 mg/dl versus high = 102 mg/dl). We identified 15,002 missense, nonsense, or splice site variants with a frequency <5%. We tested whether coding sequence variants, individually or aggregated within a gene, were associated with plasma lipid levels. To replicate findings, we performed sequencing in independent participants (n = 6424). RESULTS: Across discovery and replication sequencing, we found 6 variants with significant associations with plasma lipids. Of these, one was a novel association: p.Ser147Asn variant in APOA4 (14.3% frequency, TG OR = 0.49, P = 7.1 × 10(-4)) with TG. In gene-level association analyses where rare variants within each gene are collapsed, APOC3 (P = 2.1 × 10(-5)) and LDLR (P = 5.0 × 10(-12)) were associated with plasma lipids. CONCLUSIONS: After sequencing genes from 95 GWAS loci in participants with extremely high plasma lipid levels, we identified one new coding variant associated with TG. These results provide insight regarding design of similar sequencing studies with respect to sample size, follow-up, and analysis methodology.

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Exome sequencing in suspected monogenic dyslipidemias.

BACKGROUND: Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.

Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points.

Targeting high density lipoproteins in the prevention of cardiovascular disease?

Recent studies involving HDL-raising therapeutics have greatly changed our understanding of this field. Despite effectively raising HDL-C levels, niacin remains of uncertain clinical benefit. Synthetic niacin receptor agonists are unlikely to raise HDL-C or have other beneficial effects on plasma lipids. Despite the failure in phase 3 of 2 CETP inhibitors, 2 potent CETP inhibitors that raise HDL-C levels by >100 % (and reduce LDL-C substantially) are in late stage clinical development. Infusions of recombinant HDL containing 'wild-type' apoA-I or apoA-I Milano, as well as autologous delipidated HDL, all demonstrated promising early results, and remain in clinical development. A small molecule that causes upregulation of endogenous apoA-I production is also in clinical development. Finally, upregulation of macrophage cholesterol efflux pathways through agonism of liver X receptors or antagonism of miR-33 remains of substantial interest. The field of HDL therapeutics is poised to transition from the 'HDL-cholesterol hypothesis' to the 'HDL flux hypothesis' in which the impact on flux from macrophage to feces is deemed to be of greater therapeutic benefit than the increase in steady-state concentrations of HDL cholesterol.