LDL-cholesterol concentrations: a genome-wide association study.

BACKGROUND: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. METHODS: We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. FINDINGS: In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. INTERPRETATION: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.

Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Aorto-bronchial and aorto-pulmonary fistulation after thoracic endovascular aortic repair: an analysis from the European Registry of Endovascular Aortic Repair Complications.

OBJECTIVES: To learn upon incidence, underlying mechanisms and effectiveness of treatment strategies in patients with central airway and pulmonary parenchymal aorto-bronchial fistulation after thoracic endovascular aortic repair (TEVAR). METHODS: Analysis of an international multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2012 with a total caseload of 4680 TEVAR procedures (14 centres). RESULTS: Twenty-six patients with a median age of 70 years (interquartile range: 60-77) (35% female) were identified. The incidence of either central airway (aorto-bronchial) or pulmonary parenchymal (aorto-pulmonary) fistulation (ABPF) in the entire cohort after TEVAR in the study period was 0.56% (central airway 58%, peripheral parenchymal 42%). Atherosclerotic aneurysm formation was the leading indication for TEVAR in 15 patients (58%). The incidence of primary endoleaks after initial TEVAR was n = 10 (38%), of these 80% were either type I or type III endoleaks. Fourteen patients (54%) developed central left bronchial tree lesions, 11 patients (42%) pulmonary parenchymal lesions and 1 patient (4%) developed a tracheal lesion. The recognized mechanism of ABPF was external compression of the bronchial tree in 13 patients (50%), the majority being due to endoleak formation, further ischaemia due to extensive coverage of bronchial feeding arteries in 3 patients (12%). Inflammation and graft erosion accounted for 4 patients (30%) each. Cumulative survival during the entire study period was 39%. Among deaths, 71% were attributed to ABPF. There was no difference in survival in patients having either central airway or pulmonary parenchymal ABPF (33 vs 45%, log-rank P = 0.55). Survival with a radical surgical approach was significantly better when compared with any other treatment strategy in terms of overall survival (63 vs 32% and 63 vs 21% at 1 and 2 years, respectively), as well as in terms of fistula-related survival (63 vs 43% and 63 vs 43% at 1 and 2 years, respectively). CONCLUSIONS: ABPF is a rare but highly lethal complication after TEVAR. The leading mechanism behind ABPF seems to be a continuing external compression of either the bronchial tree or left upper lobe parenchyma. In this setting, persisting or newly developing endoleak formation seems to play a crucial role. Prognosis does not differ in patients with central airway or pulmonary parenchymal fistulation. Radical bronchial or pulmonary parenchymal repair in combination with stent graft removal and aortic reconstruction seems to be the most durable treatment strategy.

Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study.

BACKGROUND: The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. METHODS: Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. RESULTS: EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). CONCLUSIONS: In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.

Ideal Body Size as a Mediator for the Gender-Specific Association Between Socioeconomic Status and Body Mass Index: Evidence From an Upper-Middle-Income Country in the African Region.

While obesity continues to rise globally, the associations between body size, gender, and socioeconomic status (SES) seem to vary in different populations, and little is known on the contribution of perceived ideal body size in the social disparity of obesity in African countries. We examined the gender and socioeconomic patterns of body mass index (BMI) and perceived ideal body size in the Seychelles, a middle-income small island state in the African region. We also assessed the potential role of perceived ideal body size as a mediator for the gender-specific association between SES and BMI. A population-based survey of 1,240 adults aged 25 to 64 years conducted in December 2013. Participants' BMI was calculated based on measured weight and height; ideal body size was assessed using a nine-silhouette instrument. Three SES indicators were considered: income, education, and occupation. BMI and perceived ideal body size were both higher among men of higher versus lower SES (p< .001) but lower among women of higher versus lower SES (p< .001), irrespective of the SES indicator used. Multivariate analysis showed a strong and direct association between perceived ideal body size and BMI in both men and women (p< .001) and was consistent with a potential mediating role of perceived ideal body size in the gender-specific associations between SES and BMI. Our study emphasizes the importance of gender and socioeconomic differences in BMI and ideal body size and suggests that public health interventions that promote perception of healthy weight could help mitigate SES-related disparities in BMI.

A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.