Predictors of lack of glycemic control in persons with type 2 diabetes.

BACKGROUND: Professional guidelines recommend an HbA1c < 7% for most people with diabetes and < 8.5% for those with relaxed glycemic goals. However, many people with type 2 diabetes mellitus (T2DM) are unable to achieve the desired HbA1c goal. This study evaluated factors associated with lack of improvement in HbA1c over 3 years. METHODS: All patients with T2DM treated within a major academic healthcare system during 2015-2020, who had at least one HbA1c value > 8.5% within 3 years from their last HbA1c were included in analysis. Patients were grouped as improved glycemic control (last HbA1c ≤ 8.5%) or lack of improvement (last HbA1c > 8.5%). Multivariate logistic regression analysis was performed to assess independent predictors of lack of improvement in glycemic control. RESULTS: Out of 2,232 patients who met the inclusion criteria, 1,383 had an improvement in HbA1c while 849 did not. In the fully adjusted model, independent predictors of lack of improvement included: younger age (odds ratio, 0.89 per 1-SD [12 years]; 95% CI, 0.79-1.00), female gender (1.30, 1.08-1.56), presence of hypertension (1.29, 1.08-1.55), belonging to Black race (1.32, 1.04-1.68, White as reference), living in low income area (1.86,1.28-2.68, high income area as reference), and insurance coverage other than Medicare (1.32, 1.05-1.66). Presence of current smoking was associated with a paradoxical improvement in HbA1c (0.69, 0.47-0.99). In a subgroup analysis, comparing those with all subsequent HbA1c values > 8.5% (N = 444) to those with all subsequent HbA1c values < 8.5% (N = 341), similar factors were associated with lack of improvement, but smoking was no longer significant. CONCLUSION: We conclude that socioeconomic factors like race, type of insurance coverage and living in low-income areas are associated with lack of improvement in HbA1c over a period of 3-years in people with T2DM. Intervention strategies focused on low-income neighborhoods need to be designed to improve diabetes management.

Prediction of Future Medical Costs by Modifiable Measures of Health.

Introduction: Strategies to mitigate rising health-care costs are a priority for patients, employers, and health insurers. Yet gaps currently exist in whether health risk assessment can forecast medical claims costs. This study examined the ability of a health quotient (HQ) based on modifiable risk factors, age, sex, and chronic conditions to predict future medical claims spending. Methods: The study included 18,695 employees and adult dependents who participated in health assessments and were enrolled in an employer-sponsored health plan. Linear mixed effect models stratified by chronic conditions and adjusted for age and sex were utilized to evaluate the relationship between the health quotient (score of 0-100) and future medical claims spending. Results: Lower baseline health quotient was associated with higher medical claims cost over 2 years of follow up. For participants with chronic condition(s), costs were $3628 higher for those with a low health quotient (<73; N = 2673) compared to those with high health quotient (>85; N = 1045), after adjustment for age and sex (P value = 0.004). Each one-unit increase in health quotient was associated with a decrease of $154 (95% CI: 87.4, 220.3) in average yearly medical claims costs during follow up. Discussion: This study used a large employee population with 2 years of follow-up data, which provides insights that are applicable to other large employers. Results of this analysis contribute to our ability to predict health-care costs using modifiable aspects of health, objective laboratory testing and chronic condition status.

The relationship between insulin resistance and ion mobility lipoprotein fractions.

Objective: Insulin resistance (IR) increases risk of type 2 diabetes and atherosclerotic cardiovascular disease and is associated with lipid and lipoprotein abnormalities including high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C). Lipoprotein size and lipoprotein subfractions (LS) have also been used to assist in identifying persons with IR. Associations of LS and IR have not been validated using both direct measures of IR and direct measures of LS. We assessed the usefulness of fasting lipoprotein subfractions (LS) by ion mobility to identify individuals with IR. Methods: Lipid panel, LS by ion mobility (LS-IM), and IR by steady-state plasma glucose (SSPG) concentration were assessed in 526 adult volunteers without diabetes. IR was defined as being in the highest tertile of SSPG concentration. LS-IM score was calculated by linear combination of regression coefficients from a stepwise regression analysis with SSPG concentration as the dependent variable. Improvement in prediction of IR was evaluated after combining LS-IM score with TG/HDL-C, TG/HDL-C and BMI as well as with TG/HDL-C, BMI, sex, race and ethnicity. IR prediction was evaluated by area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV) considering the highest 5% of scores as positive test. Results: Prediction of IR was similar by LS-IM score and TG/HDL-C (AUC=0.68; PPV=0.59 and AUC=0.70; PPV=0.59, respectively) and prediction was improved when LS-IM was combined with TG/HDL-C (AUC=0.73; PPV=0.70), TG/HDL-C and BMI (AUC=0.82; PPV=0.81) and with TG/HDL-C, BMI, sex, race and ethnicity (AUC=0.84; PPV=0.89). Conclusion: For identifying individuals with IR, LS-IM score and TG/HDL-C are comparable and their combination further improves IR prediction by TG/HDL-C alone. Among patients who have undergone IM testing, the LS-IM score may assist prioritization of subjects for further evaluation and interventions to reduce IR.

Workplace Outreach Program Improves Management of Chronic Kidney Disease.

OBJECTIVE: Assess whether an employee outreach program improved management of chronic kidney disease (CKD). METHODS: Participants with suspected CKD (eGFR <60 mL/min/1.73m 2 ) identified in employee health assessments in 2017 and 2018 were contacted by phone and offered physician consultation. Subsequent nephrologist visits at 11 months of follow up were compared between those who were (outreach group) and were not (control group) successfully contacted. RESULTS: Most CKD risk factors at baseline were similar in outreach and control groups. At the end of the follow-up, outreach participants had more than 2-fold greater incidence of visiting a nephrologist compared with controls (HR = 2.3; 95% CI 1.2-4.2, P = 0.01), after adjusting for potential confounders. Conclusions: Employee outreach program increased utilization of nephrologist care.

Association of changes in lipid levels with changes in vitamin D levels in a real-world setting.

In clinical trials, vitamin D supplementation has been reported to reduce serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) but not high-density lipoprotein cholesterol (HDL-C). In this cohort study we evaluated the association between changes in vitamin D (25-hydroxyvitamin D) and changes in lipid levels in a real-world setting. Changes in lipid levels over a 1-year period were evaluated among individuals whose vitamin D levels increased (group 1) or decreased (group 2) by ≥ 10 ng/mL in year 2018 versus 2017 (cohort 1; n = 5580), in 2019 versus 2018 (cohort 2, n = 6057), or in 2020 versus 2019 (cohort 3, n = 7249). In each cohort, levels of TC, LDL-C, and TG decreased in group 1 and increased in group 2. Between-group differences in average changes in the 3 cohorts ranged from 10.71 to 12.02 mg/dL for TC, from 7.42 to 8.95 mg/dL for LDL-C, and from 21.59 to 28.09 mg/dL for TG. These differences were significant after adjusting for age, sex, race, education, body mass index, blood pressure, smoking status, geographical location, and baseline levels of vitamin D and lipids (P < 0.001). Changes in vitamin D levels were not significantly associated with changes in HDL-C levels.

Intact Fasting Insulin Identifies Nonalcoholic Fatty Liver Disease in Patients Without Diabetes.

CONTEXT: Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies. OBJECTIVE: We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD. METHODS: Patients underwent a 2-hour oral glucose tolerance test (OGTT), a liver magnetic resonance spectroscopy (1H-MRS), and a percutaneous liver biopsy if they had a diagnosis of NAFLD. Mass spectrometry was used to measure intact molecules of insulin and C-peptide. RESULTS: A total of 180 patients were recruited (67% male; 52 ± 11 years of age; body mass index [BMI] 33.2 ± 5.7 kg/m2; 46% with diabetes and 65% with NAFLD). Intact fasting insulin was higher in patients with NAFLD, irrespective of diabetes status. Patients with NAFLD without diabetes showed ~4-fold increase in insulin secretion during the OGTT compared with all other subgroups (P = 0.008). Fasting intact insulin measurements predicted NAFLD in patients without diabetes (area under the receiver operating characteristic curve [AUC] of 0.90 [0.84-0.96]). This was significantly better than measuring insulin by radioimmunoassay (AUC 0.80 [0.71-0.89]; P = 0.007). Intact fasting insulin was better than other clinical variables (eg, aspartate transaminase, triglycerides, high-density lipoprotein, glucose, HbA1c, and BMI) to predict NAFLD. When combined with alanine transaminase (ALT) (intact insulin × ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and positive and negative predictive values of 93% and 88%, respectively. This newly described approach was significantly better than previously validated noninvasive scores such as NAFLD-LFS (P = 0.009), HSI (P < 0.001), and TyG index (P = 0.039). CONCLUSION: In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and noninvasive strategy to predict presence of NAFLD.

Arginine to ornithine ratio as a diagnostic marker in patients with positive newborn screening for hyperargininemia.

Arginase deficiency is a rare inborn error of metabolism that interrupts the final step of the urea cycle. Untreated individuals often present with episodic hyperammonemia, developmental delay, cognitive impairment, and spasticity in early childhood. The newborn screening (NBS) algorithms for arginase deficiency vary between individual states in the US but often include hyperargininemia and elevated arginine to ornithine (Arg/Orn) ratio. Here, we report 14 arginase deficiency cases, including two patients with positive NBS for hyperargininemia in whom the diagnosis of arginase deficiency was delayed owing to normal or near normal plasma arginine levels on follow-up testing. To improve the detection capability for arginase deficiency, we evaluated plasma Arg/Orn ratio as a secondary diagnostic marker in positive NBS cases for hyperargininemia. We found that plasma Arg/Orn ratio combined with plasma arginine was a better marker than plasma arginine alone to differentiate patients with arginase deficiency from unaffected newborns. In fact, elevated plasma arginine in combination with an Arg/Orn ratio of ≥1.4 identified all 14 arginase deficiency cases. In addition, we examined the impact of age on plasma arginine and ornithine levels. Plasma arginine increased 0.94 µmol/L/day while ornithine was essentially unchanged in the first 31 days of life, which resulted in a similar increasing trend for the Arg/Orn ratio (0.01/day). This study demonstrated that plasma Arg/Orn ratio as a secondary diagnostic marker improved the detection capability for arginase deficiency in newborns with hyperargininemia, which will allow timely detection of arginase deficiency and hence initiation of treatment before developing symptoms.

Concordance of Cardiovascular Risk Factors and Behaviors in a Multiethnic US Nationwide Cohort of Married Couples and Domestic Partners.

Importance: Married couples and domestic partners have been reported to share similar environmental exposures, adopt similar behavior patterns, and have similar transferable characteristics. However, the degree to which couples share similar levels of cardiovascular risk factors and behaviors is uncertain. Objective: To assess within-couple concordance of the American Heart Association-defined Life's Simple 7 (LS7). Design, Setting, and Participants: Cross-sectional study with a longitudinal substudy of employees and spouses (or domestic partners) who participated in an employer-sponsored health assessment program throughout the United States between October 2014 and December 2018. Data were analyzed from November 1, 2019, to August 4, 2020. Exposures: Having a spouse or domestic partner. Main Outcomes and Measures: The LS7 risk factors and behaviors (smoking status, body mass index, exercise, diet, total cholesterol, blood pressure, and fasting glucose) were assessed by questionnaires, examinations, and laboratory tests. LS7 categories were scored as 2 for ideal, 1 for intermediate, or 0 for poor and summed to generate a CV health score. Results: The study included 10 728 participants (5364 couples): 7% were African American, 11% Hispanic, 21% Asian, and 54% White (median [interquartile range] age, 50 [41-57] years for men and 47 [39-55] for women). For most couples, both members were in the ideal category or both were in a nonideal category. Concordance ranged from 53% (95% CI, 52%-54%) for cholesterol to 95% (95% CI, 94%-95%) for diet. For the CV health score, in 79% (95% CI, 78%-80%) of couples both members were in a nonideal category, which was associated mainly with unhealthy diet (94% [95% CI, 93%-94%] of couples) and inadequate exercise (53% [95% CI, 52%-55%] of couples). However, in most couples, both members were in the ideal category for smoking status (60% [95% CI, 59%-61%] of couples) and glucose (56% [95% CI, 55%-58%]). Except for total cholesterol, when 1 member of a couple was in the ideal category, the other member was likely also to be in the ideal category: the adjusted odds ratios for also being in the ideal category ranged from 1.3 (95% CI, 1.1-1.5; P ≤ .001) for blood pressure to 10.6 (95% CI, 7.4-15.3; P ≤ .001) for diet. Concordance differed by ethnicity, socioeconomic status, and geographic location. A 5-year longitudinal analysis of 2186 couples found modest changes in concordance of blood pressure (from 55% [95% CI, 53%-57%] to 59% [95% CI, 57%-61%]; P < .001 for trend) and fasting glucose (from 64% [95% CI, 62%-66%] to 59% [95% CI, 57%-61%]; P < .001 for trend) with no change in other factors. Conclusions and Relevance: In this study, high concordance of nonideal behaviors was found within couples; behavioral modification programs may benefit both the targeted and the nontargeted member of a couple.

Detection of SARS-CoV-2 IgG Targeting Nucleocapsid or Spike Protein by Four High-Throughput Immunoassays Authorized for Emergency Use.

A total of 1,200 serum samples that were tested for SARS-CoV-2 IgG antibody using the Abbott Architect immunoassay targeting the nucleocapsid protein were run in 3 SARS-CoV-2 IgG immunoassays targeting spike proteins (DiaSorin Liaison, Ortho Vitros, and Euroimmun). Consensus-positive and consensus-negative interpretations were defined as qualitative agreement in at least 3 of the 4 assays. Agreement of the 4 individual assays with a consensus-negative interpretation (n = 610) ranged from 96.7% to 100%, and agreement with a consensus-positive interpretation (n = 584) ranged from 94.3% to 100%. Laboratory-developed inhibition assays were utilized to evaluate 49 consensus-negative samples that were positive in only one assay; true-positive reactivity was confirmed in only 2 of these 49 (4%) samples. These findings demonstrate very high levels of agreement among 4 SARS-CoV-2 IgG assays authorized for emergency use, regardless of antigen target or assay format. Although false-positive reactivity was identified, its occurrence was rare (no more than 1.7% of samples for a given assay).

Performance of Plasma Biomarkers and Diagnostic Panels for Nonalcoholic Steatohepatitis and Advanced Fibrosis in Patients With Type 2 Diabetes.

OBJECTIVE: The 2019 Standards of Medical Care in Diabetes suggested that patients with nonalcoholic fatty liver disease (NAFLD) should be evaluated for liver fibrosis. However, the performance of noninvasive clinical models/scores and plasma biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and advanced fibrosis has not been carefully assessed in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In this cross-sectional study, patients (n = 213) had a liver MRS, and those with a diagnosis of NAFLD underwent a percutaneous liver biopsy. Several noninvasive clinical models/scores and plasma biomarkers were measured to identify NASH and advanced fibrosis (NASH: ALT, cytokeratin-18, NashTest 2, HAIR, BARD, and OWLiver; advanced fibrosis: AST, fragments of propeptide of type III procollagen [PRO-C3], FIB-4, APRI, NAFLD fibrosis score, and FibroTest). RESULTS: None of the noninvasive tools assessed for the diagnosis of NASH in patients with T2DM had an optimum performance (all areas under the curve [AUCs] <0.80). Of note, none of the panels or biomarkers was able to outperform plasma ALT (AUC 0.78 [95% CI 0.71-0.84]). Performance was better to diagnose advanced fibrosis, in which plasma PRO-C3, AST, and APRI showed better results than the other approaches (AUC 0.90 [0.85-0.95], 0.85 [0.80-0.91], and 0.86 [0.80-0.91], respectively). Again, none of the approaches did significantly better than plasma AST. Sequential use of plasma AST and other noninvasive tests may help in limiting the number of liver biopsies required to identify patients with advanced fibrosis. CONCLUSIONS: Performance of noninvasive clinical models/scores and plasma biomarkers for the diagnosis of NASH or advanced fibrosis was suboptimal in patients with T2DM. Combination of multiple tests may provide an alternative to minimize the need for liver biopsies to detect fibrosis in these patients.

Association of cardiovascular events and lipoprotein particle size: Development of a risk score based on functional data analysis.

BACKGROUND: Functional data is data represented by functions (curves or surfaces of a low-dimensional index). Functional data often arise when measurements are collected over time or across locations. In the field of medicine, plasma lipoprotein particles can be quantified according to particle diameter by ion mobility. GOAL: We wanted to evaluate the utility of functional analysis for assessing the association of plasma lipoprotein size distribution with cardiovascular disease after adjustment for established risk factors including standard lipids. METHODS: We developed a model to predict risk of cardiovascular disease among participants in a case-cohort study of the Malmö Prevention Project. We used a linear model with 311 coefficients, corresponding to measures of lipoprotein mass at each of 311 diameters, and assumed these coefficients varied smoothly along the diameter index. The smooth function was represented as an expansion of natural cubic splines where the smoothness parameter was chosen by assessment of a series of nested splines. Cox proportional hazards models of time to a first cardiovascular disease event were used to estimate the smooth coefficient function among a training set consisting of one half of the participants. The resulting model was used to calculate a functional risk score for the remaining half of the participants (test set) and its association with events was assessed in Cox models that adjusted for traditional cardiovascular risk factors. RESULTS: In the test set, participants with a functional risk score in the highest quartile were found to be at increased risk of cardiovascular events compared with the lowest quartile (Hazard ratio = 1.34; 95% Confidence Interval: 1.05 to 1.70) after adjustment for established risk factors. CONCLUSION: In an independent test set of Malmö Prevention Project participants, the functional risk score was found to be associated with cardiovascular events after adjustment for traditional risk factors including standard lipids.

Prenatal cell-free DNA screening for fetal aneuploidy in pregnant women at average or high risk: Results from a large US clinical laboratory.

BACKGROUND: We evaluated the performance of a cell-free DNA (cfDNA) prenatal screening assay for trisomies 21, 18, and 13, and sex chromosome aneuploidies (SCAs) among a population of pregnant women that included both those at average and high risk. METHODS: Specimen collection, cfDNA extraction, massively parallel sequencing, and bioinformatics analysis were conducted per laboratory protocol. Assay results, concordance with pregnancy outcomes, and performance characteristics were evaluated. RESULTS: A total 75,658 specimens from 72,176 individual pregnant women were received. Technical reasons accounted for 288 (0.4% of all received samples) tests not performed. In the final analysis cohort (N = 69,794), 13% of pregnancies were considered at average risk and 87% at high risk. Mean gestational age at specimen collection was 15.1 weeks. Of the 69,794 unique pregnancies, 1,359 (1.9%) had positive test results. Among the results with confirmed outcomes, PPV for trisomies 21, 18, and 13 was 98.1%, 88.2%, and 59.3%, respectively; the PPV was 69.0% for SCAs and 75.0% for microdeletions. Overall, PPV was 87.2%, sensitivity was 97.9%, and specificity was 99.9%. CONCLUSION: This cfDNA prenatal screening assay provides highly accurate discrimination between affected and unaffected pregnancies among a population of pregnant women at average and high risk for fetal genetic abnormalities.

KIF6 719Arg Genetic Variant and Risk for Thoracic Aortic Dissection.

BACKGROUND: Carriers of the 719Arg variant in KIF6, compared with noncarriers, have been reported to be at greater risk for coronary heart disease (CHD) in six prospective studies. Because CHD, thoracic aortic dissection, and nondissection thoracic aortic aneurysm share some risk factors and aspects of pathophysiology, we investigated whether carriers of the 719Arg variant also have greater odds of thoracic aortic dissection or nondissected thoracic aortic aneurysm than noncarriers. METHODS: We genotyped 140 thoracic aortic dissection cases, 497 nondissection thoracic aortic aneurysm cases, and 275 disease-free controls collected in the United States, Hungary, and Greece and investigated the association between KIF6 719Arg carrier status and thoracic aortic dissection, and between KIF6 719Arg carrier status and nondissection thoracic aortic aneurysm, using logistic regression models adjusted for age, sex, hypertension, smoking, and country. RESULTS: The odds of aortic dissection were two-fold greater in KIF6 719Arg carriers compared with noncarriers (odds ratio (OR) 2.14, 95% confidence interval (CI) 1.18-3.9). To account for the potential of concomitant CHD to confound the association between the KIF6 719Arg and thoracic aortic dissection, we repeated the analysis after removing subjects with concomitant CHD; the estimates for association of KIF6 719Arg carrier status remained essentially the same (OR 2.04, 95% CI 1.11-3.77). In contrast, KIF6 719Arg carrier status was not associated with risk for nondissection thoracic aortic aneurysm. CONCLUSIONS: We observed an association of the KIF6 719Arg genetic variant with thoracic aortic dissection in this multicenter case-control study. This association may enhance our management of patients with thoracic aortic disease.

Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history.

AIMS: Genetic risk scores (GRSs) have been associated with coronary heart disease (CHD) in large studies. We asked whether expanding an established 27-variant GRS (GRS27) to a 50-variant GRS (GRS50) improved CHD prediction and whether GRSs are independent of self-reported family history of CHD. METHODS AND RESULTS: The association between GRSs and incident CHD was assessed in Cox models adjusting for established risk factors in 23 595 participants of the Malmö Diet and Cancer study--a prospective, population-based study. During a median follow-up of 14.4 years, 2213 participants experienced a first CHD event. After adjustment for established risk factors, both GRS27 and GRS50 were associated with incident CHD [hazard ratio (HR) = 1.70 for high (top quintile) vs. low (bottom quintile) of GRS27; 95% confidence interval (CI): 1.48-1.94; Ptrend = 1.6 × 10(-15) and HR = 1.92 for GRS50; 95% CI: 1.67-2.20; Ptrend = 6.2 × 10(-22)]. Adding 23 single nucleotide polymorphisms (SNPs) to GRS27 improved risk prediction (P = 3 × 10(-6)). Further adjustment for self-reported family history did not appreciably change the risk estimates of either GRS27 (HR = 1.65; 95% CI: 1.45-1.89) or GRS50 (HR = 1.87; 95% CI: 1.63-2.14). The addition of GRS50 to established risk factors, including self-reported family history, improved discrimination (P < 0.0001) and reclassification (continuous net reclassification improvement index = 0.17, P < 0.0001). In young participants (below median age), those with high GRS50 had 2.4-fold greater risk (95% CI: 1.85-3.12) than those with low GRS50. CONCLUSION: The addition of 23 SNPs to an existing GRS27 improved CHD risk prediction and was independent of self-reported family history. Coronary heart disease risk assessment by GRS could be particularly useful in young individuals.

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

BACKGROUND: Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo. METHODS AND RESULTS: In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk. CONCLUSIONS: In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND.

Although albuminuria and subsequent advanced stage chronic kidney disease are common among patients with diabetes, the rate of increase in albuminuria varies among patients. Since genetic variants associated with estimated glomerular filtration rate (eGFR) were identified in cross sectional studies, we asked whether these variants were also associated with rate of increase in albuminuria among patients with diabetes from ONTARGET and TRANSCEND-randomized controlled trials of ramipril, telmisartan, both, or placebo. For 16 genetic variants associated with eGFR at a genome-wide level, we evaluated the association with annual rate of increase in albuminuria estimated from urine albumin:creatinine ratio (uACR). One of the variants (rs267734) was associated with rate of increase in albuminuria. The annual rate of increase in albuminuria among risk homozygotes (69% of the study population) was 11.3% (95%CI; 7.5% to 15.3%), compared with 5.0% (95%CI; 3.3% to 6.8%) for heterozygotes (27% of the population), and 1.7% (95%CI; -1.7% to 5.3%) for non-risk homozygotes (4% of the population); P = 0.0015 for the difference between annual rates in the three genotype groups. These estimates were adjusted for age, sex, ethnicity, and principal component of genetic heterogeneity. Among patients without albuminuria at baseline (uACR<30 mg/g), each risk allele was associated with 50% increased risk of incident albuminuria (OR = 1.50; 95%CI 1.15 to 1.95; P = 0.003) after further adjustment for traditional risk factors including baseline uACR and eGFR. The rs267734 variant is in almost perfect linkage-disequilibrium (r2 = 0.94) with rs267738, a single nucleotide polymorphism encoding a glutamic acid to alanine change at position 115 of the ceramide synthase 2 (CERS2) encoded protein. However, it is unknown whether CERS2 function influences albuminuria. In conclusion, we found that rs267734 in CERS2 is associated with rate of increase in albuminuria among patients with diabetes and elevated risk of cardiovascular disease.

Genetic variants in FBN-1 and risk for thoracic aortic aneurysm and dissection.

OBJECTIVES: A recent genome wide association study (GWAS) by LeMaire et al. found that two single nucleotide polymorphisms (SNPs), rs2118181 and rs10519177 in the FBN-1 gene (encoding Fibrillin-1), were associated with thoracic aortic dissection (TAD), non-dissecting thoracic aortic aneurysm (TAA), and thoracic aortic aneurysm or dissection (TAAD); the largest effect was observed for the association of rs2118181 with TAD. We investigated whether rs2118181 and rs10519177 were associated with TAD, TAA, and TAAD in the Yale study. METHODS: The genotypes of rs2118181 and rs10519177 were determined for participants in the Yale study: 637 TAAD cases (140 TAD, 497 TAA) and 275 controls from the United States, Hungary, and Greece. The association of the genotypes with TAD, TAA and TAAD were assessed using logistic regression models adjusted for sex, age, study center and hypertension. RESULTS AND CONCLUSIONS: In the Yale study, rs2118181 was associated with TAD: compared with non-carriers, carriers of the risk allele had an unadjusted odds ratio for TAD of 1.80 (95% CI 1.15-2.80) and they had odds ratio for TAD of 1.87 (95% CI 1.09-3.20) after adjusting for sex, age, study center and hypertension. We did not find significant differences in aortic size, a potential confounder for TAD, between rs2118181 risk variant carriers and non-carriers: mean aortic size was 5.56 (95% CI: 5.37-5.73) for risk variant carriers (CC+CT) and was 5.48 (95% CI: 5.36-5.61) for noncarriers (TT) (p = 0.56). rs2118181 was not associated with TAA or TAAD. rs10519177 was not associated with TAD, TAA, or TAAD in the Yale study. Thus, the Yale study provided further support for the association of the FBN-1 rs2118181SNP with TAD.