Lynda Rose

Cardiovascular risks associated with incident and prevalent periodontal disease

AIMnWhile prevalent periodontal disease associates with cardiovascular risk, little is known about how incident periodontal disease influences future vascular risk. We compared effects of incident versus prevalent periodontal disease in developing major cardiovascular diseases (CVD), myocardial infarction (MI), ischaemic stroke and total CVD.nnnMATERIAL AND METHODSnIn a prospective cohort of 39,863 predominantly white women, age ≥45xa0years and free of cardiovascular disease at baseline were followed for an average of 15.7xa0years. Cox proportional hazard models with time-varying periodontal status [prevalent (18%), incident (7.3%) versus never (74.7%)] were used to assess future cardiovascular risks.nnnRESULTSnIncidence rates of all CVD outcomes were higher in women with prevalent or incident periodontal disease. For women with incident periodontal disease, risk factor adjusted hazard ratios (HRs) were 1.42 (95% CI, 1.14-1.77) for major CVD, 1.72 (1.25-2.38) for MI, 1.41 (1.02-1.95) for ischaemic stroke and 1.27 (1.06-1.52) for total CVD. For women with prevalent periodontal disease, adjusted HRs were 1.14 (1.00-1.31) for major CVD, 1.27 (1.04-1.56) for MI, 1.12 (0.91-1.37) for ischaemic stroke and 1.15 (1.03-1.28) for total CVD.nnnCONCLUSIONnNew cases of periodontal disease, not just those that are pre-existing, place women at significantly elevated risks for future cardiovascular events.

Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies

Objective To examine the interactions between genetic predisposition and consumption of fried food in relation to body mass index (BMI) and obesity. Design Prospective cohort study. Setting Health professionals in the United States. Participants 9623 women from the Nurses’ Health Study, 6379 men from the Health Professionals Follow-up Study, and a replication cohort of 21u2009421 women from the Women’s Genome Health Study. Main outcome measure Repeated measurement of BMI over follow-up. Results There was an interaction between fried food consumption and a genetic risk score based on 32 BMI-associated variants on BMI in both the Nurses’ Health Study and Health Professionals Follow-up Study (P≤0.001 for interaction). Among participants in the highest third of the genetic risk score, the differences in BMI between individuals who consumed fried foods four or more times a week and those who consumed fried foods less than once a week amounted to 1.0 (SE 0.2) in women and 0.7 (SE 0.2) in men, whereas the corresponding differences were 0.5 (SE 0.2) and 0.4 (SE 0.2) in the lowest third of the genetic risk score. The gene-diet interaction was replicated in the Women’s Genome Health Study (P<0.001 for interaction). Viewed differently, the genetic association with adiposity was strengthened with higher consumption of fried foods. In the combined three cohorts, the differences in BMI per 10 risk alleles were 1.1 (SE 0.2), 1.6 (SE 0.3), and 2.2 (SE 0.6) for fried food consumption less than once, one to three times, and four or more times a week (P<0.001 for interaction); and the odds ratios (95% confidence intervals) for obesity per 10 risk alleles were 1.61 (1.40 to 1.87), 2.12 (1.73 to 2.59), and 2.72 (2.12 to 3.48) across the three categories of consumption (P=0.002 for interaction). In addition, the variants in or near genes highly expressed or known to act in the central nervous system showed significant interactions with fried food consumption, with the FTO (fat mass and obesity associated) variant showing the strongest result (P<0.001 for interaction). Conclusion Our findings suggest that consumption of fried food could interact with genetic background in relation to obesity, highlighting the particular importance of reducing fried food consumption in individuals genetically predisposed to obesity.

A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women

AIMSnTo assess the joint influence of inflammatory biomarkers on the risk of incident atrial fibrillation (AF) in women.nnnMETHODS AND RESULTSnWe performed a prospective cohort study among women participating in the Womens Health Study. All women were free of AF at study entry and provided a baseline blood sample assayed for high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen. To evaluate the joint effect of these three biomarkers, an inflammation score was created that ranged from 0 to 3 and reflected the number of biomarkers in the highest tertile per individual. During a median follow-up of 14.4 years, 747 of 24,734 women (3.0%) experienced a first AF event. Assessed individually, all three biomarkers were associated with incident AF, even after adjustment for traditional risk factors. When combined into an inflammation score, a strong and independent relationship between inflammation and incident AF emerged. Across increasing inflammation score categories, there were 1.66, 2.22, 2.73, and 3.25 AF events per 1000 person-years of follow-up. The corresponding hazard ratios (95% confidence intervals) across inflammation score categories were 1.0, 1.22 (1.00-1.49), 1.32 (1.06-1.65), and 1.59 (1.22-2.06) (P for linear trend 0.0006) after multivariable adjustment.nnnCONCLUSIONnIn this large-scale prospective study among women without a history of cardiovascular disease, markers of systemic inflammation were significantly related to AF even after controlling for traditional risk factors.

Novel locus including FGF21 is associated with dietary macronutrient intake

Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10(-5)) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10(-9)). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake.

Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents

AIMSnCurrent statin guidelines in Europe and Canada advocate achieving a fixed LDL target or the attainment of a ≥50% reduction in low-density lipoprotein cholesterol (LDLC), while current US guidelines advocate the use of statin therapies that reduce LDLC by <50% (moderate intensity) or ≥50% (high intensity). Data are limited, however, linking the achievement of these % reduction thresholds to subsequent cardiovascular outcomes particularly for contemporary high-intensity regimens.nnnMETHODS AND RESULTSnIn a randomized trial of 17 082 initially healthy men and women with median baseline LDLC of 108 mg/dL (interquartile range 94-119), we (i) used waterfall plots to assess the variability in LDLC response to rosuvastatin 20 mg daily and (ii) evaluated the impact of reaching ≥50% reductions in LDLC on risk of developing the first cardiovascular events. Among rosuvastatin allocated participants, 3640 individuals (46.3%) experienced an LDLC reduction ≥50%; 3365 individuals (42.8%) experienced an LDLC reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDLC compared with baseline. These % LDLC reductions directly related to the risks of first cardiovascular events; at trial completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1000 person-years for those in the placebo, no LDLC reduction, LDLC reduction <50%, and LDLC reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment per cent reductions in LDLC were 0.91 (95%CI 0.54-1.53), 0.61 (95%CI 0.44-0.83), and 0.43 (95%CI 0.30-0.60) (P < 0.00001). Similar relationships between % reduction and clinical outcomes were observed in analyses focusing on non-HDLC or apolipoprotein B.nnnCONCLUSIONSnAs documented for low- and moderate-intensity regimens, variability in % LDLC reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors should these agents prove broadly effective for cardiovascular event reduction.

Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Womens Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, Pu200a=u200a5.4×10−9), PNPLA3 (rs738409, Pu200a=u200a5.8×10−9), RELA (rs1049728, Pu200a=u200a2.7×10−16), and SH2B3 (rs3184504, Pu200a=u200a2.9×10−17). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

Genome-wide Linkage and Association Analyses Implicate FASN in Predisposition to Uterine Leiomyomata

Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scoresxa0> 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05xa0× 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.

Large-Scale Candidate Gene Analysis of HDL Particle Features

Background HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: pu200a=u200a5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: pu200a=u200a8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: pu200a=u200a6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: pu200a=u200a1.7*10−8) and FBLN5 (fibulin-5; rs2246416: pu200a=u200a6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (nu200a=u200a3,078) and/or the Womens Genome Health Study (nu200a=u200a23,170). Conclusions We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C.

Association of Adiposity Genetic Variants With Menarche Timing in 92,105 Women of European Descent

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events.

AIMSnProprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that enhances degradation of the LDL receptor. While agents that inhibit PCSK9 markedly reduce atherogenic lipoproteins and show great promise for event reduction, it is unknown whether plasma PCSK9 levels predict incident cardiovascular events.nnnMETHODS AND RESULTSnIn a nested case-control evaluation conducted in a prospective cohort of >28 000 initially healthy American women, we measured plasma concentrations of PCSK9 at baseline among 358 participants who subsequently developed major cardiovascular events (cases) and among 358 age, smoking, and hormone replacement therapy matched participants who remained free of disease during 17 years of follow-up (controls). Proprotein convertase subtilisin/kexin type 9 level was not significantly related to smoking status, hypertension, obesity, or a family history of premature cardiovascular disease but was positively associated with apolipoprotein B-100 (r = 0.20, P< 0.001), and triglycerides (r = 0.13, P = 0.004). No associations were observed between PCSK9 and apo A1, HDLC, lipoprotein(a), or high-sensitivity C-reactive protein. Despite modest positive association with atherogenic lipids, baseline levels of PCSK9 did not predict the first cardiovascular events; the odds ratios (ORs) for future vascular events for the lowest (referent) to highest baseline quartiles of PCSK9 were 1.0, 0.94, 0.98, and 1.15 (P-trend = 0.53). In contrast, the corresponding ORs for baseline apo B levels were 1.0, 1.14, 1.34, and 1.94 (P-trend = 0.002).nnnCONCLUSIONSnIn a large-scale primary prevention cohort, plasma levels of PCSK9 measured at baseline did not predict future cardiovascular events.