Purpose of Review
The microbiome, defined as the community of microorganisms that live on or in the human body, is involved in a variety of physiological processes. This review summarizes evidence ...that human microbial communities influence risk of cardiovascular disease (CVD) and place the microbiome in context of other –omic data layers.
Recent Findings
The most robust evidence implicating the microbiome in CVD pathogenesis involves trimethylamine-N-oxide, a moiety synthesized by gut bacteria that has been compellingly linked to the increased risk of adverse CVD events. In addition, many cross-sectional associations have been reported in humans between microbiome composition and various CVD risk factors, including impaired metabolism, hypertension, and inflammation, although interpretation of these correlations is challenging. Host genomic and other –omic variation can mediate associations between microbiome and CVD phenotypes.
Summary
In light of the complexity of –omic data, novel methods are essential to rigorously jointly analyze the role of host and microbial variation in CVD etiology. Until such methods are available, studies would benefit from narrower research questions and a renewed commitment to reproducibility.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVEDespite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in ...treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.
METHODSBiomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α) were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.
RESULTSBefore fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485) approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).
CONCLUSIONWe have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.
The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient ...interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifically dairy foods, is unexplored. Cross-sectional analyses were performed in 2 U.S. population–based samples. We evaluated interactions between dairy foods and APOA2 −265T > C (rs5082) for BMI in the Boston Puerto Rican Health Study (n = 955) and tested for replication in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1116). Dairy products were evaluated as total dairy, higher-fat dairy (>1%), and low-fat dairy (≤1%) in servings per day, dichotomized into high and low based on each population median and also as continuous variables. We identified a statistically significant interaction between the APOA2 −265T > C variant and higher-fat dairy food intake in the Boston Puerto Ricans (P-interaction = 0.028) and replicated this relation in the GOLDN study (P-interaction = 0.001). In both groups, individuals with the previously demonstrated SFA-sensitive genotype (CC) who consumed a greater amount of higher-fat dairy foods had greater BMI (P = 0.013 in Boston Puerto Ricans; P = 0.0007 in GOLDN women) compared with those consuming less of the higher-fat dairy foods. The results expand the understanding of the metabolic influence of dairy products, an important food group for which variable relations to body weight may be in part genetically based. Moreover, these findings suggest that other strongly demonstrated gene-nutrient relations might be investigated through appropriate food-based, translatable avenues and may be relevant to dietary management of obesity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of ...dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response.
We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (SORBS1) gene were associated with b-Sitosterol after correction for multiple testing (P≤4.5*10(-10)). SORBS1 has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, PRIC285, a co-activator of PPARa).
Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Obesity in pregnancy and gestational diabetes (GDM) increase cardiometabolic disease risk but are difficult to disentangle. This study aimed to test the hypothesis that 4–10 years after a ...pregnancy complicated by overweight/obesity and GDM (OB‐GDM), women and children would have greater adiposity and poorer cardiometabolic health than those with overweight/obesity (OB) or normal weight (NW) and no GDM during the index pregnancy.
Methods
In this cross‐sectional study, mother‐child dyads were stratified into three groups based on maternal health status during pregnancy (OB‐GDM = 67; OB = 76; NW = 76). Weight, height, waist and hip circumferences, and blood pressure were measured, along with fasting glucose, insulin, HbA1c, lipids, adipokines, and cytokines.
Results
Women in the OB and OB‐GDM groups had greater current adiposity and poorer cardiometabolic health outcomes than those in the NW group (p < 0.05). After adjusting for current adiposity, women in the OB‐GDM group had higher HbA1c, glucose, HOMA‐IR and triglycerides than NW and OB groups (p < 0.05). Among children, adiposity was greater in the OB‐GDM versus NW group (p < 0.05), but other indices of cardiometabolic health did not differ.
Conclusions
Poor cardiometabolic health in women with prior GDM is independent of current adiposity. Although greater adiposity among children exposed to GDM is evident at 4–10 years, differences in cardiometabolic health may not emerge until later.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In the recently published paper, “The Interplay Between the Microbiome and Cardiovascular Risk”, the last name of the lead author is listed incorrectly. The author’s name is Brè A. Minniefield.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci ...explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value≤0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1 , FLJ36070, CETP , the APOE-APOC1-APOC4-APOC2 , and CILP2 . Finally, we present strong evidence for epistasis (P-value for interaction = 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Significant controversy exists regarding the best approach for nonculprit vessel revascularization in patients with multivessel coronary artery disease presenting with ST-segment elevation myocardial ...infarction. We conducted a systematic investigation to pool data from current randomized controlled trials (RCTs) to assess optimal treatment strategies in this patient population.
A comprehensive search of SCOPUS from inception through May 2015 was performed using predefined criteria. We compared efficacy and safety outcomes of different approaches by categorizing the studies into 3 groups: (1) complete revascularization (CR) versus culprit lesion revascularization (CL) at index hospitalization, (2) CR at index hospitalization versus staged revascularization (SR) of nonculprit vessels at a separate hospitalization, and (3) comparison of SR versus CL. Eight eligible RCTs met the inclusion criteria: (1) CR versus CL (6 RCTs, n=1727) (2) CR versus SR (3 RCTs, n=311), and (3) SR versus CL (1 RCT, n=149). We observed significantly lower rates of major adverse cardiovascular events, revascularization, and repeat percutaneous coronary interventions among patients treated with CR and SR compared with a CL approach (P<0.05). The rates of all-cause mortality, cause-specific mortality, major bleeding, reinfarction, stroke, and contrast-induced nephropathy did not differ in the CR arm compared with the CL arm. The rates of these outcomes were similar in the CR and SR arms.
Results suggest that CR and SR compared with CL reduce major adverse cardiovascular event and revascularization rates primarily by lowering repeated percutaneous coronary intervention rates. We did not observe any increase in the rate of adverse events while using a CR or SR strategy compared with a CL approach. Current guidelines discouraging CR need to be reevaluated, and clinical judgment should prevail in treating multivessel coronary artery disease patients with ST-segment elevation myocardial infarction as data from larger RCTs accumulate.
GAW20 provided participants with an opportunity to comprehensively examine genetic and epigenetic variation among related individuals in the context of drug treatment response. GAW20 used data from ...188 families (
= 1105) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (clinicaltrials.gov identifier NCT00083369), which included CD4+ T-cell DNA methylation at 463,995 cytosine-phosphate-guanine (CpG) sites measured before and after a 3-week treatment with fenofibrate, single-nucleotide variation at 906,600 loci, metabolic syndrome components ascertained before and after the drug intervention, and relevant covariates. All GOLDN participants were of European descent, with an average age of 48 years. In addition, approximately half were women and approximately 40% met the diagnostic criteria for metabolic syndrome. Unique advantages of the GAW20data set included longitudinal (3 weeks apart) measurements of DNA methylation, the opportunity to explore the contributions of both genotype and DNA methylation to the interindividual variability in drug treatment response, and the familial relationships between study participants. The principal disadvantage of GAW20/GOLDN data was the spurious correlation between batch effects and fenofibrate effects on methylation, which arose because the pre- and posttreatment methylation data were generated and normalized separately, and any attempts to remove time-dependent technical artifacts would also remove biologically meaningful changes brought on by fenofibrate. Despite this limitation, the GAW20 data set offered informative, multilayered omics data collected in a large population-based study of common disease traits, which resulted in creative approaches to integration and analysis of inherited human variation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are ...population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants.
We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in
) was associated with fasting triglyceride levels (
= 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between
(
= 1.77E-07) and
(
= 7.18E-07) and triglycerides, as well as between
(
= 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved
-values of 0.04 (
), 0.08 (
), and 0.02 (
). In GOLDN, gene transcript levels of
and
were associated with fasting triglycerides (
= 0.07 and
= 0.02), highlighting functional relevance of our findings.
In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.
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