Real-World Clinical and Economic Outcomes in Selected Immune-Related Adverse Events Among Patients with Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND: With increased use of immune checkpoint inhibitors (ICIs) among patients with cancer, there is substantial interest in understanding clinical and economic outcomes and management of immune-related adverse events (irAEs). PATIENTS, MATERIALS, AND METHODS: A retrospective study was conducted using Premier Healthcare Database, a U.S. national hospital discharge database, from March 1, 2015, through December 31, 2017. The database comprises more than 880 million inpatient and hospital-based outpatient encounters, with more than 200 million unique patients reported by 966 hospitals. Patients with four solid tumors known to benefit from ICI therapy were included. The list of irAEs assessed was defined a priori per American Society of Clinical Oncology clinical guidelines for irAE management. Baseline irAE-related inpatient and outpatient visits were defined as the first inpatient or hospital-based outpatient visit with discharge diagnosis of any irAE of interest following confirmed ICI usage within 90 days prior to the baseline visit. Patients were followed for 90 days after baseline irAE-related inpatient discharge date or outpatient visit date to assess irAE-related inpatient admissions, all-cause in-hospital mortality, ICI reinitiation, and to determine costs and health care resource utilization. RESULTS: Records from 673,957 patients with four tumor types were reviewed for ICI therapy. Of 13,030 patients receiving ICIs, approximately 40% experienced at least one irAE, with a total of 10,121 irAEs occurring within 90 days of the ICI visit. The most frequent (>1,000 events) irAEs were anemia, impaired ventricular function with heart failure and vasculitis, thrombocytopenia, thyroid conditions, and peripheral edema. As might be expected, compared with those with baseline irAE-related outpatient visits, patients with baseline irAE-related inpatient visits had a significantly higher percentage of irAE-related inpatient admissions (23% vs. 14%) and all-cause in-hospital mortality (22% vs. 6%) and lower reinitiation of ICI therapy (31% vs. 71%). Baseline irAE-related inpatient visits had significantly higher mean costs ($29,477 vs. $5,718) with longer hospital stays (12.6 vs. 7.8 days). CONCLUSION: Findings from a U.S. national hospital discharge database suggest that irAEs in patients treated with ICIs are common, occur in multiples and with greater frequency in those with pre-existing comorbidities. Those with inpatient admissions have poorer outcomes. IMPLICATIONS FOR PRACTICE: The present work addressed the knowledge gap in understanding real-world outcomes of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). Patients who experienced irAEs had significantly higher baseline comorbidities and were more likely to have immune-related or immune-compromised comorbid conditions. Patients with baseline irAE-related hospitalizations were more likely to be rehospitalized and to experience in-hospital mortality and less likely to reinitiate ICI treatment. Real-world patients are more diverse than clinical trials, and clinicians should consider both the efficacy and safety profile of ICI treatments, especially for patients with comorbidity conditions. Close monitoring is needed after patients have experienced an irAE.

APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

BACKGROUND: Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.

Risk of readmissions, mortality, and hospital-acquired conditions across hospital-acquired pressure injury (HAPI) stages in a US National Hospital Discharge database.

Pressure injuries are one of the most common and costly complications occurring in US hospitals. With up to 3 million patients affected each year, hospital-acquired pressure injuries (HAPIs) place a substantial burden on the US healthcare system. In the current study, US hospital discharge records from 9.6 million patients during the period from October 2009 through September 2014 were analysed to determine the incremental cost of hospital-acquired pressure injuries by stage. Of the 46 108 patients experiencing HAPI, 16.3% had Stage 1, 41.0% had Stage 2, 7.0% had Stage 3, 2.8% had Stage 4, 7.3% had unstageable, 14.6% had unspecified, and 10.9% had missing staging information. In propensity score-adjusted models, increasing HAPI severity was significantly associated with higher total costs and increased overall length of stay when compared with patients not experiencing a HAPI at the index hospitalisation. The average incremental cost for a HAPI was $21 767. Increasing HAPI severity was significantly associated with greater risk of in-hospital mortality at the index hospitalisation compared with patients with no HAPI, as well as 1.5 to 2 times greater risk of 30-, 60-, and 90-day readmissions. Additionally, increasing HAPI severity was significantly associated with increasing risk of other hospital-acquired conditions, such as pneumonia, urinary tract infections, and venous thromboembolism during the index hospitalisation. By preventing pressure injuries, hospitals have the potential to reduce unreimbursed treatment expenditures, reduce length of stay, minimise readmissions, prevent associated complications, and improve overall outcomes for their patients.

Increased hepatocyte growth factor levels over 2 years are associated with coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA)

Hepatocyte growth factor (HGF) is associated with subclinical and clinical atherosclerosis. However, the significance of change in HGF and development of atherosclerotic disease is unknown. In a large and diverse population-based cohort, we report that change in the biomarker HGF is an independent predictor of incident CHD.

Racial/Ethnic Differences in Diabetes Screening and Hyperglycemia Among US Women After Gestational Diabetes.

INTRODUCTION: Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and is associated with an increased risk for type 2 diabetes. Racial/ethnic minority populations are at a higher risk than non-Hispanic white populations of developing type 2 diabetes after GDM. The aim of this study was to describe racial/ethnic differences in hyperglycemia and receipt of screening services in a nationally representative sample of women with a history of GDM. METHODS: Our sample included 765 women from the US National Health and Nutrition Examination Survey (2007-2016) with a history of GDM. We used logistic, multinomial, linear, and proportional hazards regression to evaluate racial/ethnic differences in development of diabetes after GDM, hyperglycemia (measured by HbA1c), and receipt of diabetes screening services. RESULTS: Non-Hispanic black women had 63% higher risk and Hispanic women and "other" racial/ethnic women had more than double the risk for diabetes compared with non-Hispanic white women. Among women with a GDM history who did not receive a diagnosis of diabetes by the time of the study examination, both non-Hispanic black women and Hispanic women were more likely than non-Hispanic white women to be in the prediabetes or diabetes range (measured HbA1c ≥5.7%). However, non-Hispanic black women had 2.07 (95% confidence interval, 1.29-3.81) times the odds of being screened for diabetes compared with non-Hispanic white women (P = .02). CONCLUSION: Delays in identification of hyperglycemia and diagnosis of diabetes in racial/ethnic minority women may reflect differential delivery of guideline-based care or poor follow-up of abnormal screening test results.

Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study.

Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10-8) for the NOX4 locus (lead variant rs2289125, ß = -0.15, p = 5.3 × 1011). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.

Relationship of femoral artery ultrasound measures of atherosclerosis with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown. METHODS: We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m2 (binary) were evaluated as outcomes. RESULTS: Mean age was 70 ± 10 years, mean eGFR was 78 ± 17 mL/min/1.73 m2, and 156 (15%) individuals had eGFR <60 mL/min/1.73 m2; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m2 lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m2 (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors. CONCLUSIONS: Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course.

Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10-4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10-7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC).

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.

Hepatocyte Growth Factor Is Positively Associated With Risk of Stroke: The MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND AND PURPOSE: Hepatocyte growth factor (HGF) is positively associated with ischemic and hemorrhagic stroke risk factors. However, understanding the relation between HGF and stroke is in its infancy. Therefore, we sought to examine the association of circulating HGF with incident stroke using data from the MESA (Multi-Ethnic Study of Atherosclerosis). We hypothesized that circulating HGF would be positively associated with an increased risk of stroke. METHODS: Participants aged 45 to 84 years (n=6711) had HGF measured between 2000 and 2002 and were followed for incident stroke through 2013 (n=233). Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for incident stroke. A secondary analysis stratified results by adjudicated stroke type (n=183 ischemic; n=39 hemorrhagic; n=11 other). RESULTS: After adjustment for potential confounding variables, risk of stroke was 17% higher with each standard deviation increase in HGF (hazard ratio, 1.17; 95% confidence interval, 1.03-1.34). This association was mainly driven by ischemic stroke and did not change on exclusion of cardioembolic strokes, although the number of excluded cases was small. The few hemorrhagic and other types of stroke were not associated with HGF. CONCLUSIONS: Circulating HGF was positively associated with the incidence of stroke in a diverse, population-based cohort of men and women from the United States. Our findings support the hypothesis that circulating HGF is a marker of endothelial damage and suggest that HGF may have utility as a prognostic marker of stroke risk.

Blood group antigen loci demonstrate multivariate genetic associations with circulating cellular adhesion protein levels in the Multi-Ethnic Study of Atherosclerosis.

The cellular adhesion pathway is critical in the pathophysiology of atherosclerosis, and genetic factors contributing to regulation of circulating levels of related proteins may be relevant to risk prediction of cardiovascular disease. In contrast to conducting separate genome-wide protein quantitative trait loci (pQTL) mapping analyses of each individual protein, joint genetic association analyses of multiple quantitative traits can leverage cross-trait co-variation and identify simultaneous regulatory effects on protein levels across the pathway. We conducted a multi-pQTL (mpQTL) analysis of 15 proteins related to cellular adhesion assayed on 2313 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We applied the MQFAM multivariate association analysis method in PLINK on normalized protein level residuals derived from univariate linear regression, adjusting for age, sex, and principal components of ancestry. Race/ethnicity-stratified analyses identified nine genome-wide significant (P < 5e-08) loci associated with co-variation of protein levels. Although the majority of these SNPs were in proximity to structural genes of the assayed proteins, we discovered multiple loci demonstrating co-association with the circulation of at least two proteins. Of these, two significant loci specific to non-Hispanic white participants, rs17074898 at ALOX5AP (P = 1.78E-08) and rs7521237 at KIAA1614 (P = 2.2E-08), would not have met statistical significance using univariate analyses. Moreover, common patterns of multi-protein associations were discovered at the ABO locus across race/ethnicity. These results indicate the biological relevance of blood group antigens on regulation of circulating cellular adhesion pathway proteins while also demonstrating race/ethnicity-specific co-regulatory effects.

Ankle-brachial index predicts change over time in functional status in the San Diego Population Study.

BACKGROUND: Peripheral artery disease (PAD) affects millions of people, both in the U.S. and worldwide. Even when asymptomatic, PAD and the ankle-brachial index (ABI), the major clinical diagnostic criterion for PAD, are associated with decreased functional status and quality of life, as well as mobility impairment. Whether the ABI or change in the ABI predicts decline in functional status over time has not been previously assessed in a population-based setting. METHODS: Participants were 812 non-Hispanic white, African American, Hispanic, and Asian men and women from the San Diego Population Study (SDPS) who attended a baseline examination (1994-1998), and follow-up clinic examination approximately 11 years later. The Medical Outcomes Study 36-Item Short Form (SF-36) was obtained at both the baseline and follow-up examinations, and the summary performance score (SPS) at the follow-up examination. Associations of the baseline ABI and clinically relevant change in the ABI (<-0.15 vs ≥-0.15) with change in SF-36 scores over time were assessed using growth curve models, a type of mixed model that accounts for within participant correlation of measurements over time, and using linear regression for SPS. Models were adjusted for baseline age, sex, race/ethnicity, body mass index, ever smoking, physical activity, hypertension, diabetes, and dyslipidemia. RESULTS: Mean ± standard deviation (SD) for the baseline ABI was 1.11 ± 0.10, and 50.8 ± 9.0 for the baseline Physical Component Score (PCS), 50.1 ± 9.5 for the baseline Mental Component Score (MCS), and 11.2 ± 1.9 for the SPS at the follow-up examination. In fully adjusted models, each SD lower of the baseline ABI was significantly associated with an average decrease over time of 0.6 (95% confidence interval [CI], -1.1 to -0.1; P = .02) units on SF-36 PCS. Each SD lower of the baseline ABI was also significantly associated with an average decrease over time of 1.2 units (95% CI, -2.3 to -0.2; P = .02) on the SF-36 physical functioning subscale, and a decrease of 1.3 units (95% CI, -2.3 to -0.3; P = .01) on the SF-36 energy/vitality subscale in fully adjusted models. Baseline ABI was not significantly associated with change in the SF-36 MCS over time, or the SPS at the follow-up examination. Change in the ABI was not associated with SF-36 PCS, MCS, or the SPS. CONCLUSIONS: In this multiethnic population of healthy middle-aged community-living men and women, we showed that participants with a lower baseline ABI had declines in functional status over 11 years. Findings suggest that small differences in the ABI, even within the normal range, may identify subclinical lower extremity PAD, which in turn may help to identify individuals at risk for declining functional status with age.

Group-Based Trajectory Modeling of Suppression Ratio After Cardiac Arrest.

BACKGROUND: Existing studies of quantitative electroencephalography (qEEG) as a prognostic tool after cardiac arrest (CA) use methods that ignore the longitudinal pattern of qEEG data, resulting in significant information loss and precluding analysis of clinically important temporal trends. We tested the utility of group-based trajectory modeling (GBTM) for qEEG classification, focusing on the specific example of suppression ratio (SR). METHODS: We included comatose CA patients hospitalized from April 2010 to October 2014, excluding CA from trauma or neurological catastrophe. We used Persyst®v12 to generate SR trends and used semi-quantitative methods to choose appropriate sampling and averaging strategies. We used GBTM to partition SR data into different trajectories and regression associate trajectories with outcome. We derived a multivariate logistic model using clinical variables without qEEG to predict survival, then added trajectories and/or non-longitudinal SR estimates, and assessed changes in model performance. RESULTS: Overall, 289 CA patients had ≥36 h of EEG yielding 10,404 h of data (mean age 57 years, 81 % arrested out-of-hospital, 33 % shockable rhythms, 31 % overall survival, 17 % discharged to home or acute rehabilitation). We identified 4 distinct SR trajectories associated with survival (62, 26, 12, and 0 %, P < 0.0001 across groups) and CPC (35, 10, 4, and 0 %, P < 0.0001 across groups). Adding trajectories significantly improved model performance compared to adding non-longitudinal data. CONCLUSIONS: Longitudinal analysis of continuous qEEG data using GBTM provides more predictive information than analysis of qEEG at single time-points after CA.

Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant association analysis and trans-ethnic meta-analysis of 6201 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low-frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity-specific gene-level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low-frequency/rare variants, while meta-analysis of gene-level results identified a significant association for HGFAC. However, identified single-variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate that genetic factors influencing circulating HGF levels may be complex and ethnically diverse.

Multi-ethnic analysis reveals soluble L-selectin may be post-transcriptionally regulated by 3'UTR polymorphism: the Multi-Ethnic Study of Atherosclerosis (MESA).

L-Selectin is constitutively expressed on leukocytes and mediates their interaction with endothelial cells during inflammation. Previous studies on the association of soluble L-selectin (sL-selectin) with cardiovascular disease (CVD) are inconsistent. Genetic variants associated with sL-selectin levels may be a better surrogate of levels over a lifetime. We explored the association of genetic variants and sL-selectin levels in a race/ethnicity stratified random sample of 2,403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Through a genome-wide analysis with additive linear regression models, we found that rs12938 on the SELL gene accounted for a significant portion of the protein level variance across all four races/ethnicities. To evaluate potential additional associations, elastic net models were used for variants located in the SELL/SELP/SELE genetic region and an additional two SNPs, rs3917768 and rs4987361, were associated with sL-selectin levels in African Americans. These variants accounted for a portion of protein variance that ranged from 4 % in Hispanic to 14 % in African Americans. To investigate the relationship of these variants with CVD, 6,317 subjects were used. No significant association was found between any of the identified SNPs and carotid intima-media thickness or presence of carotid plaque using linear and logistic regression, respectively. Similarly no significant results were found for coronary artery calcium or coronary heart disease events. In conclusion, we found that variants within the SELL gene are associated with sL-selectin levels. Despite accounting for a significant portion of the protein level variance, none of the variants was associated with clinical or subclinical CVD.

Associations of Abdominal Muscle Area with 4-Year Change in Coronary Artery Calcium Differ by Ethnicity Among Post-Menopausal Women.

OBJECTIVE: To examine the association of abdominal muscle area with coronary artery calcium (CAC) presence, extent, and progression in a multi-ethnic cohort of older, community-dwelling post-menopausal women. DESIGN AND SETTING: Cross-sectional and longitudinal population-based cohort. PARTICIPANTS: The sample comprised 179 non-Hispanic White women, 116 Filipina women and 144 African American women, all without known CVD, who underwent chest and abdominal computed tomography (CT) scans twice about four years apart for abdominal muscle and fat, as well as CAC. MAIN OUTCOME MEASURES: CAC presence, extent and progression. RESULTS: There was a significant interaction of ethnicity with baseline oblique muscle area (p-for-interaction .01), and marginally significant interactions with baseline total and paraspinal muscle for change in CAC (p-for-interactions both .09). Among Filipina women, each standard deviation (SD) greater total muscle area was associated with a 26% (95% CI (-43%, -4%), P=.02) reduced rate of change in CAC; higher paraspinal and oblique muscle area were associated with a 24% (-38%, -6%, P=.01) and a 37% (-53%, -16%, P=.0002) reduced rate of change in CAC, respectively. These associations were not significant in African American or non-Hispanic White women. There were no significant associations of abdominal muscle with CAC presence or extent, nor were there significant ethnicity by muscle interactions in these models. CONCLUSIONS: Among Filipina women, greater abdominal muscle mass is associated with a decreased rate of CAC progression. Higher muscle mass may be important for this group in reducing CVD outcomes.

Urine creatinine-based estimates of fat-free mass in community-dwelling older persons: the Rancho Bernardo study.

OBJECTIVES: To determine whether a previously developed and externally validated equation using common variables (demographics and weight) that are important determinants of muscle mass to estimate 24-hour urine creatinine excretion rate (eCER) is associated with muscle mass and whether spot urine creatinine (UCr) provides similar estimates of muscle mass. DESIGN: Observational cross-sectional cohort study. SETTING: The Rancho Bernardo Study, San Diego, California. SUBJECTS: A total of 1,371 Caucasian, middle class, community-dwelling older adults. INTERVENTION: Morning spot UCr and fat-free mass (FFM) by dual-energy x-ray absorptiometry were measured. eCER was calculated: eCER (mg/day) = 879.89 + 12.51 × weight (kilogram) - 6.19 × age + 34.51 if black - 379.42 if female. Pearson correlation coefficients and linear regression were used to determine strengths of association of eCER and spot UCr with FFM. RESULTS: Mean age was 70 years, and 58% were women. eCER was strongly correlated with FFM (r = 0.95, P < .001), a correlation that was superior to that of spot UCr (r = 0.40, P < .001). CONCLUSIONS: An equation incorporating age, weight, sex, and race to estimate eCER is highly correlated with FFM in community-dwelling older persons and provides a more precise estimate than spot UCr. A simple screening tool for sarcopenia in older persons may allow interventions to maintain or improve muscle mass. Future studies should evaluate whether eCER predicts sarcopenia-related frailty and mortality in older persons.