Apolipoprotein C-III as a Potential Modulator of the Association Between HDL-Cholesterol and Incident Coronary Heart Disease

Background: High-density lipoproteins (HDL) are structurally and metabolically heterogeneous and subclasses with differential effects on coronary heart disease (CHD) might exist. Apolipoprotein (apo) C-III, a small proinflammatory protein that resides on the surface of lipoproteins, enhances the atherogenicity of VLDL and LDL particles, but little is known about the role apoC-III on HDL. We investigated whether the presence or absence of apoC-III differentiates HDL into subtypes with nonprotective or protective associations with risk of future CHD. Methods and Results: High-density lipoprotein cholesterol (HDL-C) levels were measured in plasma separated according to apoC-III (by immunoaffinity chromatography) in two prospective case-control studies nested within the Nurses’ Health and the Health Professionals Follow-Up Studies. Baseline was in 1990 and 1994, and 634 incident CHD cases were documented through 10 to 14 years of follow-up. The relative risk of CHD per each standard deviation of total HDL-C was 0.78 (95% confidence intervals, 0.63–0.96). The HDL-C subtypes were differentially associated with risk of CHD, HDL-C without apoC-III inversely and HDL-C with apoC-III directly (P=0.02 for a difference between the HDL types). The relative risk per standard deviation of HDL-C without apoC-III was 0.66 (0.53 to 0.93) and 1.18 (1.03 to 1.34) for HDL-C with apoC-III. HDL-C with apoC-III comprised ∼13% of the total HDL-C. Adjustment for triglycerides and apoB attenuated the risks; however, the two HDL-C subgroups remained differentially associated with risk of CHD (P=0.05). Conclusion: Separating HDL-C according to apoC-III identified two types of HDL with opposing associations with risk of CHD. The proatherogenic effects of apoC-III, as a component of VLDL and LDL, may extend to HDL. (J Am Heart Assoc. 2012;1:jah3-e000232 doi: 10.1161/JAHA.111.000232.

Interaction between Obesity and the NFKB1 - 94ins/delATTG Promoter Polymorphism in Relation to Incident Acute Coronary Syndrome: A Follow Up Study in Three Independent Cohorts

Introduction: The NF-κB transcription factor family regulates several genes encoding pro-inflammatory and anti-inflammatory proteins in adipose tissues and in atherosclerotic plaques. The deletion variant allele of the NFKB1 - 94ins/delATTG promoter polymorphism leads to lower transcript levels of the p50 subunit, and the variant allele has been associated with the risk of several inflammatory diseases as well as coronary heart disease where inflammation is important in the pathogenesis. The objective of this study was to explore the potential interaction between the NFKB1-94ins/delATTG promoter polymorphism and general, abdominal, and gluteofemoral obesity in relation to the risk of incident acute coronary syndrome (ACS) in three large independent cohorts. Methods and Results: The analyses were conducted in the Danish prospective study Diet, Cancer and Health and the two US based cohorts; Nurses’ Health Study and Health Professionals Follow-up Study. We conducted sex stratified analyses that included 1202 male and 708 female cases of incident ACS. We observed a positive association for general and abdominal obesity with risk of incident ACS, independent of genotype in both genders. Gluteofemoral obesity was negatively associated with ACS risk in women independent of genotype, whereas there was no clear association for men. We calculated the relative excess risk due to interaction (RERI) and observed a statistically significant excess risk among men jointly exposed to general or abdominal obesity and the variant allele of the NFKB1-94ATTG polymorphism, whereas there was a tendency towards sub-additivity for gluteofemoral obesity. The excess risks in all analyses were, however, small and could not clearly be demonstrated in women. Conclusion: The variant allele of the NFKB1-94ins/delATTG promoter polymorphism did not substantially modify the association between obesity and incident ACS

Renal Artery Stenting in Consecutive High-Risk Patients With Atherosclerotic Renovascular Disease:A Prospective 2-Center Cohort Study

BACKGROUND: The aim of this study was to prospectively evaluate the effects of renal artery stenting in consecutive patients with severe atherosclerotic renal artery stenosis and high‐risk clinical presentations as defined in a national protocol developed in 2015. METHODS AND RESULTS: Since the protocol was initiated, 102 patients have been referred for revascularization according to the following high‐risk criteria: severe renal artery stenosis (≥70%) with true resistant hypertension, rapidly declining kidney function, or recurrent heart failure/sudden pulmonary edema. At baseline, the mean 24‐hour ambulatory systolic blood pressure was 166.2 mm Hg (95% CI, 162.0–170.4), the defined daily dose of antihypertensive medication was 6.5 (95% CI, 5.8–7.3), and the estimated glomerular filtration rate was 41.1 mL/min per 1.73m(2) (95% CI, 36.6–45.6). In 96 patients with available 3‐month follow‐up data, mean 24‐hour ambulatory systolic blood pressure decreased by 19.6 mm Hg (95% CI, 15.4–23.8; P<0.001), the defined daily dose of antihypertensive medication was reduced by 52% (95% CI, 41%–62%; P<0.001), and estimated glomerular filtration rate increased by 7.8 mL/min per 1.73m(2) (95% CI, 4.5–11.1; P<0.001). All changes persisted after 24 month follow‐up. Among 17 patients with a history of hospitalization for acute decompensated heart failure, 14 patients had no new episodes after successful revascularization. CONCLUSIONS: In this prospective cohort study, we observed a reduction in blood pressure and antihypertensive medication, an increase in estimated glomerular filtration rate, and a decrease in new hospital admissions attributable to heart failure/sudden pulmonary edema after renal artery stenting. REGISTRATION: URL: https://clinicaltrials.gov. Identifier: NCT02770066

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

‘Friends call me racist’: Experiences of repercussions from writing comments on newspaper websites

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Necrotrophism Is a Quorum-Sensing-Regulated Lifestyle in Bacillus thuringiensis

How pathogenic bacteria infect and kill their host is currently widely investigated. In comparison, the fate of pathogens after the death of their host receives less attention. We studied Bacillus thuringiensis (Bt) infection of an insect host, and show that NprR, a quorum sensor, is active after death of the insect and allows Bt to survive in the cadavers as vegetative cells. Transcriptomic analysis revealed that NprR regulates at least 41 genes, including many encoding degradative enzymes or proteins involved in the synthesis of a nonribosomal peptide named kurstakin. These degradative enzymes are essential in vitro to degrade several substrates and are specifically expressed after host death suggesting that Bt has an active necrotrophic lifestyle in the cadaver. We show that kurstakin is essential for Bt survival during necrotrophic development. It is required for swarming mobility and biofilm formation, presumably through a pore forming activity. A nprR deficient mutant does not develop necrotrophically and does not sporulate efficiently in the cadaver. We report that necrotrophism is a highly regulated mechanism essential for the Bt infectious cycle, contributing to spore spreading

Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10$^{−35}$ and <10$^{−8}$ respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10$^{−6}$). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10$^{−20}$) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as