Meta-analysis of loci associated with age at natural menopause in African-American women.

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Mortality in patients with premature lower extremity atherosclerosis.

OBJECTIVE: Lower extremity peripheral artery disease occurs mostly in the elderly and is associated with high mortality. Limited data are available regarding long-term mortality in patients with premature lower extremity atherosclerosis (PLEA). Our objective was to determine the all-cause mortality and its predictors in younger PLEA patients. METHODS: We studied patients with severe PLEA who were <55 years of age at diagnosis and treated at a single academic vascular center between 1998 and 2010. Data were collected prospectively at the initial evaluation for vascular care. National Death Index and hospital records were used to determine all-cause mortality. Demographic and clinical characteristics were summarized using count (%), mean (standard deviation), or median (interquartile range), and associations with aspirin use were tested using χ2 test, t-test, or Wilcoxon test. Survival times were estimated using Kaplan-Meier estimates, and associations with covariates were tested using simple and multivariable Cox proportional hazards models. RESULTS: A total of 564 patients were analyzed (46% female; 20% nonwhite; mean age 49.4 [6.4] years). Ninety-five percent of patients had ≥2 cardiovascular risk factors, 31% had coronary artery disease (CAD), and 10% had a history of cancer. During median follow-up of 5.6 years (interquartile range, 2.3-8.3 years), 108 deaths (19%) were recorded. Two-year estimated mortality (standard error) was 6% (0.01), and 5-year estimated mortality was 16% (0.02). In univariate regression analysis, patient age (P=.04), prior amputation (P<.01), history of cancer (P=.03), and established CAD (P=.04) were associated with increased risk of mortality. Aspirin use and lipid-lowering therapy at the time of first evaluation were associated with improved survival (P<.01 and P=.02, respectively). A multivariable Cox proportional hazards model identified age (hazard ratio [HR] for 5-year increase, 1.17; 95% CI, 1.01-1.36; P=.04), prior amputation (HR, 1.99; 95% CI, 1.18-3.34; P=.01), history of cancer (HR, 2.35; 95% CI, 1.36-4.07; P<.01), and CAD (HR, 1.76; 95% CI, 1.16-2.67; P<.01) as independent predictors of mortality in patients with PLEA. Importantly, history of aspirin use had a significant protective effect (HR, 0.45; 95% CI, 0.30-0.69; P<.01). The impact of lipid-lowering therapy was no longer significant in multivariable modeling. CONCLUSIONS: Patients with PLEA demonstrate high all-cause mortality. No traditional cardiovascular risk factors predicted mortality. Aspirin therapy at the time of first evaluation was a significant and independent predictor of improved survival in patients with PLEA.

Anesthesia-based evaluation of outcomes of lower-extremity vascular bypass procedures.

BACKGROUND: This report examines the effects of regional versus general anesthesia for infrainguinal bypass procedures performed in the treatment of critical limb ischemia (CLI). METHODS: Nonemergent infrainguinal bypass procedures for CLI (defined as rest pain or tissue loss) were identified using the 2005 to 2008 American College of Surgeons National Surgical Quality Improvement Program database using International Classification of Disease, ninth edition, and Current Procedure Terminology codes. Patients were classified according to National Surgical Quality Improvement Program data as receiving either general anesthesia or regional anesthesia. The regional anesthesia group included those specified as having regional, spinal, or epidural anesthesia. Demographic, medical, risk factor, operative, and outcomes data were abstracted for the study sample. Individual outcomes were evaluated according to the following morbidity categories: wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, and operative. Length of stay, total morbidity, and mortality were also evaluated. Associations between anesthesia types and outcomes were evaluated using linear or logistic regression. RESULTS: A total of 5,462 inpatient hospital visits involving infrainguinal bypasses for CLI were identified. Mean patient age was 69 ± 12 years; 69% were Caucasian; and 39% were female. In all, 4,768 procedures were performed using general anesthesia and 694 with regional anesthesia. Patients receiving general anesthesia were younger and significantly more likely to have a history of smoking, previous lower-extremity bypass, previous amputation, previous stroke, and a history of a bleeding diathesis including the use of warfarin. Patients receiving regional anesthesia had a higher prevalence of chronic obstructive pulmonary disease. Tibial-level bypasses were performed in 51% of procedures, whereas 49% of procedures were popliteal-level bypasses. Cases performed using general anesthesia demonstrated a higher rate of resident involvement, need for blood transfusion, and operative time. There was no difference in the rate of popliteal-level and infrapopliteal-level bypasses between groups. Infrapopliteal bypass procedures performed using general anesthesia were more likely to involve prosthetic grafts and composite vein. Mortality occurred in 157 patients (3%). The overall morbidity rate was 37%. Mean and median lengths of stay were 7.5 days (± 8.1) and 6.0 days (Q1: 4.0, Q3: 8.0), respectively. Multivariate analyses demonstrated no significant differences by anesthesia type in the incidence of morbidity, mortality, or length of stay. CONCLUSION: These results provide no evidence to support the systematic avoidance of general anesthesia for lower-extremity bypass procedures. These data suggest that anesthetic choice should be governed by local expertise and practice patterns.

The influence of exposure to maternal diabetes in utero on the rate of decline in ß-cell function among youth with diabetes.

Abstract We explored the influence of exposure to maternal diabetes in utero on ß cell decline measured by fasting C-peptide (FCP) among 1079 youth <20 years with diabetes, including 941 with type 1 and 138 with type 2 diabetes. Youths exposed to maternal diabetes had FCP levels that were 17% lower among youth with type 2 diabetes [95% confidence interval (CI): -34%, +6%] and 15% higher among youth with type 1 diabetes (95%CI: -14%, +55%) than their unexposed counterparts, although differences were not statistically significant (p=0.13 and p=0.35, respectively). Exposure to maternal diabetes was not associated with FCP decline in youth with type 2 (p=0.16) or type 1 diabetes (p=0.90); nor was the effect of in utero exposure on FCP modified by diabetes type. Findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term ß-cell function decline in youth with type 1 or type 2 diabetes.

Outcomes of acute intraoperative surgical conversion during endovascular aortic aneurysm repair.

PURPOSE: Outcomes and predictors of acute surgical conversion during endovascular aortic aneurysm repair (EVAR) were examined using the American College of Surgeons-National Safety and Quality Improvement Project (ACS-NSQIP) Database (2005 to 2008). METHODS: Acute intraoperative surgical conversions occurring during elective EVAR were identified using Current Procedural Terminology codes. Nonemergent EVAR and primary open surgical repairs of infrarenal aneurysms were examined for comparison. Perioperative morbidity was categorized as wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, operative, and septic. Mortality, overall morbidity, and length of stay (LOS) were examined. RESULTS: We identified 72 acute conversions, 2414 open repairs, and 6332 EVAR without acute conversion. Demographics and comorbidities were generally similar among operative groups. Mean operative time was 274 minutes for acute conversion vs 226 minutes for primary open repair and 162 minutes for EVAR (conversion vs EVAR and open repair vs EVAR P < .0001 for each; conversion vs open repair P = .0014; analysis on rank operative time). Blood transfusion was required in 69% of acute conversions (mean volume, 6.0 units) vs 73% of open repairs (mean volume, 3.3 units) and 12% of EVARs (mean volume, 2.6 units; P < .0001 for each pair-wise comparison; analysis on rank number of units among those transfused). Major morbidity was 28% for acute conversions, 28% for open repairs, and 12% for EVARs. Mortality was 4.2% for acute conversions, 3.2% for open repairs, and 1.3% for EVARs. Median (quartile 1, quartile 3) LOS was 7 (5, 9) days for acute conversion and open repair, and 2 (1, 3) days for EVAR. Morbidity and mortality were significantly higher for acute conversion and open repair vs EVAR. The OR (95% confidence interval) for morbidity was 2.9 (1.7-4.8) after conversion and 2.8 (2.5-3.2) after open repair (P < .0001 for both) and for mortality was 3.4 (1.0-10.9; P = .0437) for conversion and 2.5 (1.9-3.5; P < .0001) for open repair. Morbidity and mortality were similar between acute conversion and open repair. A similar pattern among repair groups was demonstrated for LOS, with similar LOS for acute conversions and open repair, which were significantly longer than those observed for EVAR. No significant demographic or medical risk factor predictors of acute conversion during EVAR were identified. CONCLUSION: Acute surgical conversion was a rare complication affecting 1.1% of EVAR cases, with no broadly identifiable at-risk population. When conversion did occur, morbidity and mortality rates paralleled those observed for elective open repair.

Results of endovascular aortic aneurysm repair with general, regional, and local/monitored anesthesia care in the American College of Surgeons National Surgical Quality Improvement Program database.

BACKGROUND: This study examined outcomes of endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) using general, spinal, epidural, and local/monitored anesthesia care (MAC) in a multicenter North American hospital database reflecting contemporary anesthesia and surgical practices. METHODS: Elective EVAR cases performed between 2005 and 2008 were identified from the American College of Surgeons National Surgical Quality Improvement Program database using Current Procedural Terminology codes. Excluded were emergency cases and patients with concomitant procedures requiring general anesthesia. Patient-level comorbidities, characteristics, and intraoperative and postoperative details were examined. Complications were analyzed individually and in aggregate categories, including wound, pulmonary, renal, venous thromboembolic, cardiovascular, operative, and septic. Length of stay (LOS) and 30-day mortality were examined. Characteristics and outcomes were described using mean ± standard deviation or count (%), and comparisons were evaluated for statistical significance using χ(2), Fisher exact test, and univariate linear regression. LOS was analyzed with linear regression techniques using a log transformation. Associations between anesthesia type and outcomes were examined using univariable and multivariable regression techniques. RESULTS: We identified 6009 elective EVAR procedures for analysis. General anesthesia was used in 4868 cases, spinal anesthesia in 419, epidural anesthesia in 331, and local/MAC in 391. Defined morbidity occurred in 11% of patients. Median LOS was 2 (interquartile range, 1-3) days, and mean LOS was 2.8 ± 4.3 days. The 30-day mortality rate was 1.1%. Significant multivariate associations were observed between anesthesia type, pulmonary morbidity, and log-LOS. General anesthesia was associated with an increase in pulmonary morbidity vs spinal (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.3-12.5; P = .020) and local/MAC anesthesia (OR, 2.6; 95% CI, 1.0-6.4; P = .041). Use of general anesthesia was associated with a 10% increase in LOS for general vs spinal anesthesia (95% CI, 4.8%-15.5%; P = .001) and a 20% increase for general vs local/MAC anesthesia (95% CI, 14.1%-26.2%; P < .001). Trends toward increased pulmonary morbidity and LOS were not observed for general vs epidural anesthesia. No significant association between anesthesia type and mortality was observed. CONCLUSIONS: In contemporary North American anesthetic and surgical practice, general anesthesia for EVAR was associated with increased postoperative LOS and pulmonary morbidity compared with spinal and local/MAC anesthesia. These data suggest that increasing the use of less-invasive anesthetic techniques may limit postoperative complications and decrease the overall costs of EVAR.

A vascular disease educational program in the preclinical years of medical school increases student interest in vascular disease.

BACKGROUND: New training paradigms in vascular surgery necessitate medical student interest in vascular disease. We examined the effects of incorporation of a vascular disease educational program during the second year of the medical school curriculum on student acquisition of knowledge and interest in the treatment of vascular disease. METHODS: We developed and administered a new educational program on vascular disease and delivered the program to all second-year medical students. The new program encompassed 9 didactic hours, including 7 traditional lecture hours and 2 hours of problem-based learning. After completing the program, students were surveyed regarding vascular disease-specific knowledge, interest in treating vascular disease, and career choices. Third-year students who were not exposed to the program were surveyed as a control group. We recorded the voluntary student enrollment in the vascular and endovascular surgery rotation during the following academic year. Voluntary enrollment of the students exposed to the vascular disease education program was compared with enrollment for the previous 8 years. RESULTS: Before the introduction of the new educational program, 946 total lecture hours were delivered to first- and second-year medical students, comprising 490 hours (52%) given by nonsurgeon physicians, 445 (47%) by nonphysicians, and 11 (1%) by surgeons. Survey response rate was 93% (112 of 121) for second-year students and 95% (39 of 41) for third-year students. After the vascular disease program, second-year students answered 7.1 +/- 1.4 of 9 vascular disease questions correctly, whereas unexposed third-year students answered 7.2 +/- 1.7 questions correctly (P = .96). Most second-year medical students described a "somewhat" or "much greater" interest in the medical (63%), procedural (59%), and overall (63%) management of vascular disease after exposure to the program. Most also had a "somewhat" or "much greater" interest in a vascular medicine (64%) or vascular and endovascular surgery (60%) rotation. Enrollment in the vascular surgery third-year clerkship increased significantly to a mean of 3.0 students/month from 1.16 students/month in the prior year (P = .0032, postintervention year vs 8 prior years). CONCLUSION: A vascular disease educational program administered to second-year medical students increases interest in vascular disease and interest in further training. The increased interest translates to greater student enrollment in the vascular surgery clerkship in the subsequent academic year.

Trends in vena caval interruption.

OBJECTIVE: This study examined the national use of vena cava filters (VCFs) from 1998 to 2005. METHODS: Methods for complex surveys were used to examine hospital discharge data from the Nationwide Inpatient Sample (NIS) to determine the use of VCFs for the years 1998 to 2005. VCF placement in the absence of deep venous thrombosis (DVT) or pulmonary embolus (PE) was categorized as prophylactic. RESULTS: During the study period, the estimated rate of hospitalizations per year with a diagnosis of DVT (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.019-1.032; P < .01) or PE (OR, 1.076; 95% CI, 1.069-1.083; P < .01) rose significantly. The estimated weighted frequency of VCF placement increased from 52,860 procedures in 1998 to 104,114 procedures in 2005 (0.15% and 0.27% of all discharges, respectively), representing an 80% increase. VCF placement significantly increased during hospitalizations with any diagnosis of DVT or PE, or both, and no DVT or PE (P < .01 for each). Logistic regression models revealed that the rate of prophylactic VCF placement increased at a significantly higher rate than VCF placement associated with DVT or PE (157% vs 42%; P < .01), after adjusting for age, gender, and hospital characteristics. Prophylactic VCF placement in the setting of morbid obesity (P < .01) and head injury (P = .03) rose significantly over time. CONCLUSIONS: From 1998 to 2005, the estimated rates of prophylactic VCF placement increased at a significantly higher rate than VCF placement in the setting of DVT or PE. Significant increases in the use of prophylactic VCFs were seen in the setting of morbid obesity and head injury.

Glycemic control in youth with diabetes: the SEARCH for diabetes in Youth Study.

OBJECTIVE: To assess correlates of glycemic control in a diverse population of children and youth with diabetes. STUDY DESIGN: This was a cross-sectional analysis of data from a 6-center US study of diabetes in youth, including 3947 individuals with type 1 diabetes (T1D) and 552 with type 2 diabetes (T2D), using hemoglobin A(1c) (HbA(1c)) levels to assess glycemic control. RESULTS: HbA(1c) levels reflecting poor glycemic control (HbA(1c) >or= 9.5%) were found in 17% of youth with T1D and in 27% of those with T2D. African-American, American Indian, Hispanic, and Asian/Pacific Islander youth with T1D were significantly more likely to have higher HbA(1c) levels compared with non-Hispanic white youth (with respective rates for poor glycemic control of 36%, 52%, 27%, and 26% vs 12%). Similarly poor control in these 4 racial/ethnic groups was found in youth with T2D. Longer duration of diabetes was significantly associated with poorer glycemic control in youth with T1D and T2D. CONCLUSIONS: The high percentage of US youth with HbA(1c) levels above the target value and with poor glycemic control indicates an urgent need for effective treatment strategies to improve metabolic status in youth with diabetes.

Restenosis after renal artery angioplasty and stenting: incidence and risk factors.

BACKGROUND: Management of renal artery stenosis (RAS) with primary renal artery percutaneous angioplasty and stenting (RA-PTAS) is associated with a low risk of periprocedural death and major complications; however, restenosis develops in a subset of patients and repeat intervention may be required. We examined the incidence of restenosis after RA-PTAS and associations with clinical factors. METHODS: Consecutive patients undergoing RA-PTAS for hemodynamically significant atherosclerotic RAS associated with hypertension or ischemic nephropathy, or both, between October 2003 and September 2007 were identified from a registry. Restenosis was defined using duplex ultrasound (DUS) imaging as a renal artery postintervention peak systolic velocity (PSV) >or=180 cm/s. The incidence and temporal distribution of restenosis was analyzed using survival analysis based on treated kidneys. Associations between clinical factors and recurrent stenosis were examined using proportional hazards regression. RESULTS: RA-PTAS was performed on 112 kidneys for atherosclerotic RAS during the study period. Initial postintervention renal artery DUS imaging confirming PSV <180 cm/s in 101 kidneys, which formed the basis of this analysis. Estimated restenosis-free survival was 50% at 12 months and 40% at 18 months. Decreased risk of restenosis was associated with preoperative statin use (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.16-0.74; P = .006) and increased preoperative diastolic blood pressure (DBP; HR, 0.70 per 10-mm Hg increase in preoperative DBP; 95% CI, 0.49-0.99; P = .049). No other factors assessed were associated with restenosis. CONCLUSION: Restenosis occurs in a substantial number of patients treated with RA-PTAS. Preoperative statin medication use and increased preoperative DBP are associated with reduced risk of restenosis. In the absence of contraindications, statins should be considered standard therapy for patients with atherosclerotic renal artery stenosis.

Metabolic Syndrome Derived from Principal Component Analysis and Incident Cardiovascular Events: The Multi Ethnic Study of Atherosclerosis (MESA) and Health, Aging, and Body Composition (Health ABC).

Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54-1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39-1.94), Chinese, 1.39 (1.06-1.83), African, 1.67 (1.37-2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91-2.87) for MetS-PC versus 1.79 (1.46-2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12-1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12-1.39) and African Americans (HR = 1.16, 95%CI 1.01-1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17-1.64 compared with 1.46, 95%CI 1.23-1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort.

Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.

BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, ß=-0.075±0.012 SD/allele, P=2.8×10(-10); replication ß=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave ß=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (ß=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, ß=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, ß=-0.061±0.014 SD/allele, P=9.4×10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and ß-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

Outcomes of revascularized acute mesenteric ischemia in the American College of Surgeons National Surgical Quality Improvement Program database.

This report examines outcomes of revascularization for acute arterial mesenteric ischemia (AAMI) using the American College of Surgeons National Surgical Quality Improvement Program database. Patients with International Classification of Diseases, 9th Revision and Current Procedural Terminology codes indicating AAMI with concomitant mesenteric revascularization were identified. Demographic, risk factor, procedural, morbidity, and mortality data were examined. Associations with morbidity and mortality were analyzed by logistic regression. One hundred forty-two cases of AAMI were identified. Seventy-one cases were thrombotic and 71 were embolic according to revascularization codes. Mean age was 66 years, 84 per cent of patients were white, and 54 per cent were female. Unadjusted major morbidity and mortality rates were 69 and 30 per cent, respectively. Patients with thrombotic AAMI were more likely to have a lower body mass index, greater than 10 per cent weight loss in the past 6 months, and a history of smoking. Patients with embolic AAMI were more likely to present emergently with sepsis. Unadjusted morbidity and mortality rates were 78 and 38 per cent for embolic and 61 and 23 per cent for thrombotic AAMI, respectively. Multivariable predictors of morbidity included bowel resection at the time of revascularization, transfer admission, and involvement of a surgical resident. Multivariable predictors of mortality included impaired functional status, increased age, and postoperative sepsis. Cause of AAMI was not a significant predictor of morbidity or mortality. In a large sample of AAMI cases, AAMI remained a highly lethal and morbid condition. Predictors of morbidity and mortality included indicators of advanced presentation, treatment delay, and patient-related factors specific to AAMI, including debility and advanced age. Efforts directed at prevention and increasing the speed of diagnosis and definitive treatment appear to be necessary to improve outcomes.

Depressive symptoms and diabetes self-management among rural older adults.

OBJECTIVES: To assess the association of depressive symptoms with diabetes self-management regimens among older adults with type 2 diabetes in a rural, ethnically diverse community. METHODS: Data from 696 rural older African Americans, American Indians, and whites were used to assess depressive symptoms (modified CES-D) and diabetes self-management (physical activity, blood glucose self-monitoring, self foot checks, following a healthful eating plan, and medication adherence). RESULTS: In bivariate analyses, high CES-D scores were associated with decreased adherence to a healthful eating plan and physical activity and increased foot checks; the latter 2 remained significant in multivariate analyses. CONCLUSIONS: Older adults with diabetes and depression are less likely to adhere to self-management, increasing their risk of complications.