The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene

AbstractInflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3−/− mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.

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Effects of Full-Fat and Fermented Dairy Products on Cardiometabolic Disease: Food Is More Than the Sum of Its Parts

Advances in Nutrition ◽

10.1093/advances/nmz069 ◽

2019 ◽

Vol 10 (5) ◽

pp. 924S-930S ◽

Cited By ~ 14

Author(s):

Arne Astrup ◽

Nina Rica Wium Geiker ◽

Faidon Magkos

Keyword(s):

Cardiovascular Disease ◽

Dairy Products ◽

Disease Risk ◽

Saturated Fat ◽

Dietary Guidelines ◽

Blood Cholesterol ◽

Weight Of Evidence ◽

Cardiometabolic Disease ◽

Increased Risk ◽

Cardiometabolic Disease Risk

ABSTRACT Current dietary recommendations to limit consumption of saturated fat are largely based on early nutrition studies demonstrating a direct link between dietary saturated fat, elevated blood cholesterol levels, and increased risk of cardiovascular disease. As full-fat dairy products are rich in saturated fat, these dietary guidelines recommend consumption of fat-free or low-fat dairy products in place of full-fat dairy. However, dairy products vary greatly in both their nutrient content and their bioactive ingredients, and research increasingly highlights the importance of focusing on whole foods (i.e., the food matrix) as opposed to single nutrients, such as saturated fat. In fact, the weight of evidence from recent large and well-controlled studies, systematic reviews, and meta-analyses of both observational studies and randomized controlled trials indicates that full-fat dairy products, particularly yogurt and cheese, do not exert the detrimental effects on insulin sensitivity, blood lipid profile, and blood pressure as previously predicted on the basis of their sodium and saturated fat contents; they do not increase cardiometabolic disease risk and may in fact protect against cardiovascular disease and type 2 diabetes. Although more research is warranted to adjust for possible confounding factors and to better understand the mechanisms of action of dairy products on health outcomes, it becomes increasingly clear that the recommendation to restrict dietary saturated fat to reduce risk of cardiometabolic disease is getting outdated. Therefore, the suggestion to restrict or eliminate full-fat dairy from the diet may not be the optimal strategy for reducing cardiometabolic disease risk and should be re-evaluated in light of recent evidence.

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C-Reactive Protein and All-Cause Mortality in a Large Hospital-Based Cohort

Clinical Chemistry ◽

10.1373/clinchem.2007.091959 ◽

2008 ◽

Vol 54 (2) ◽

pp. 343-349 ◽

Cited By ~ 62

Author(s):

Claudia Marsik ◽

Lili Kazemi-Shirazi ◽

Thomas Schickbauer ◽

Stefan Winkler ◽

Christian Joukhadar ◽

...

Keyword(s):

Hospital Admission ◽

Acute Phase ◽

Cox Regression ◽

Disease Risk ◽

C Reactive Protein ◽

Reactive Protein ◽

Increased Risk ◽

All Cause Mortality ◽

Low Sensitivity

Abstract Background: C-reactive protein (CRP), an acute-phase protein, is a sensitive systemic marker of inflammation and acute-phase reactions. Testing CRP concentrations at hospital admission may provide information about disease risk and overall survival. Methods: All first-ever transmittals to the department of medical and chemical laboratory diagnostics for determination of low-sensitivity CRP (n = 274 515, 44.5% male, median age 51 years) between January 1991 and July 2003 were included [median follow-up time: 4.4 years (interquartile range, 2.3–7.4 years)]. The primary endpoint was all-cause mortality. Multivariate Cox regression adjusted for sex and age was applied for analysis. Results: Compared to individuals within the reference category (CRP <5 mg/L), hazard ratios (HR) for all-cause mortality increased from 1.4 (5–10 mg/L category) to 3.3 in the highest category (>80 mg/L, all P <0.001). CRP was associated with various causes of death. The relation of CRP to cancer death was stronger than to vascular death. Younger patients with increased CRP had relatively far worse outcome than older patients (maximal HR: ≤30 years: 6.7 vs >60 years: 1.7–3.7). Interestingly, both short- and long-term mortality were associated with increasing CRP concentrations (>80 mg/L: HR 22.8 vs 1.4). Conclusion: Measurement of low-sensitivity CRP at hospital admission allowed for the identification of patients at increased risk of unfavorable outcome. Our findings indicate that close attention should be paid to hospitalized patients with high CRP not only because of very substantial short-term risk, but also long-term excess risk, the basis for which needs to be determined.

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Abstract 288: Novel Mechanisms of Non-coding Genomic Regulation Identified in Cardiac Disease-in-a-dish Models

Circulation Research ◽

10.1161/res.119.suppl_1.288 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Aditya Kumar ◽

Stephanie Thomas ◽

Kirsten Wong ◽

Kevin Tenerelli ◽

Valentina Lo Sardo ◽

...

Keyword(s):

Heart Attack ◽

Connexin 43 ◽

Disease Risk ◽

Association Studies ◽

Correlation Coefficients ◽

Induced Pluripotent Stem Cell ◽

Genome Wide Association Studies ◽

Isogenic Line ◽

Nucleotide Polymorphisms ◽

Increased Risk

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) at gene loci that affect cardiovascular function, and while mechanisms in protein-coding loci are obvious, those in non-coding loci are difficult to determine. 9p21 is a recently identified locus associated with increased risk of coronary artery disease (CAD) and myocardial infarction. Associations have implicated SNPs in altering smooth muscle and endothelial cell properties but have not identified adverse effects in cardiomyocytes (CMs) despite enhanced disease risk. Using induced pluripotent stem cell-derived CMs from patients that are homozygous risk/risk (R/R) and non-risk/non-risk (N/N) for 9p21 SNPs and either CAD positive or negative, we assessed CM function when cultured on hydrogels capable of mimicking the fibrotic stiffening associated with disease post-heart attack, i.e. “heart attack-in-a-dish” stiffening from 11 kiloPascals (kPa) to 50 kPa. While all CMs independent of genotype and disease beat synchronously on soft matrices, R/R CMs cultured on dynamically stiffened hydrogels exhibited asynchronous contractions and had significantly lower correlation coefficients versus N/N CMs in the same conditions. Dynamic stiffening reduced connexin 43 expression and gap junction assembly in R/R CMs but not N/N CMs. To eliminate patient-to-patient variability, we created an isogenic line by deleting the 9p21 gene locus from a R/R patient using TALEN-mediated gene editing, i.e. R/R KO. Deletion of the 9p21 locus restored synchronous contractility and organized connexin 43 junctions. As a non-coding locus, 9p21 appears to repress connexin transcription, leading to the phenotypes we observe, but only when the niche is stiffened as in disease. These data are the first to demonstrate that disease-specific niche remodeling, e.g. a “heart attack-in-a-dish” model, can differentially affect CM function depending on SNPs within a non-coding locus.

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Interethnic Differences in Serum Lipids and Implications for Cardiometabolic Disease Risk in African Ancestry Populations

Global Heart ◽

10.1016/j.gheart.2017.01.011 ◽

2017 ◽

Vol 12 (2) ◽

pp. 141 ◽

Cited By ~ 20

Author(s):

Amy R. Bentley ◽

Charles N. Rotimi

Keyword(s):

Serum Lipids ◽

Disease Risk ◽

African Ancestry ◽

Cardiometabolic Disease ◽

Interethnic Differences ◽

Cardiometabolic Disease Risk

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Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors – ERRATUM

Psychological Medicine ◽

10.1017/s0033291719000291 ◽

2019 ◽

Vol 49 (10) ◽

pp. 1758-1758

Author(s):

Ragni H. Mørch ◽

Ingrid Dieset ◽

Ann Færden ◽

Elina J. Reponen ◽

Sigrun Hope ◽

...

Keyword(s):

Risk Factors ◽

Mental Disorders ◽

Inflammatory Markers ◽

Disease Risk ◽

Cardiometabolic Disease ◽

Severe Mental Disorders ◽

Cardiometabolic Disease Risk

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Distinct phenotypic characteristics of normal-weight adults at risk of developing cardiovascular and metabolic diseases

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa194 ◽

2020 ◽

Vol 112 (4) ◽

pp. 967-978

Author(s):

Abishek Stanley ◽

John Schuna ◽

Shengping Yang ◽

Samantha Kennedy ◽

Moonseong Heo ◽

...

Keyword(s):

Health Risk ◽

Body Shape ◽

Metabolic Diseases ◽

Disease Risk ◽

White Men ◽

Normal Weight ◽

Cardiometabolic Disease ◽

Men And Women ◽

Distinct Phenotype ◽

Cardiometabolic Disease Risk

ABSTRACT Background The normal-weight BMI range (18.5–24.9 kg/m2) includes adults with body shape and cardiometabolic disease risk features of excess adiposity, although a distinct phenotype developed on a large and diverse sample is lacking. Objective To identify demographic, behavioral, body composition, and health-risk biomarker characteristics of people in the normal-weight BMI range who are at increased risk of developing cardiovascular and metabolic diseases based on body shape. Methods Six nationally representative waist circumference index (WCI, weight/height0.5) prediction formulas, with BMI and age as covariates, were developed using data from 17,359 non-Hispanic (NH) white, NH black, and Mexican-American NHANES 1999–2006 participants. These equations were then used to predict WCI in 5594 NHANES participants whose BMI was within the normal weight range. Men and women in each race/Hispanic-origin group were then separated into high, medium, and low tertiles based on the difference (residual) between measured and predicted WCI. Characteristics were compared across tertiles; P values for significance were adjusted for multiple comparisons. Results Men and women in the high WCI residual tertile, relative to their BMI and age-equivalent counterparts in the low tertile, had significantly lower activity levels; higher percent trunk and total body fat (e.g. NH white men, X ± SE, 25.3 ± 0.2% compared with 20.4 ± 0.2%); lower percent appendicular lean mass (skeletal muscle) and bone mineral content; and higher plasma insulin and triglycerides, higher homeostatic model assessment of insulin resistance (e.g. NH white men, 1.45 ± 0.07 compared with 1.08 ± 0.06), and lower plasma HDL cholesterol. Percent leg fat was also significantly higher in men but lower in women. Similar patterns of variable statistical significance were present within sex and race/ethnic groups. Conclusions Cardiometabolic disease risk related to body shape in people who are normal weight according to BMI is characterized by a distinct phenotype that includes potentially modifiable behavioral health risk factors.

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Genetically Determined Physical Activity and Its Association with Circulating Blood Cells

Genes ◽

10.3390/genes10110908 ◽

2019 ◽

Vol 10 (11) ◽

pp. 908 ◽

Cited By ~ 2

Author(s):

Femke M. Prins ◽

M. Abdullah Said ◽

Yordi J. van de Vegte ◽

Niek Verweij ◽

Hilde E. Groot ◽

...

Keyword(s):

Physical Activity ◽

Blood Cells ◽

Fixed Effects ◽

Mendelian Randomization ◽

P Value ◽

Nucleotide Polymorphisms ◽

Increased Risk ◽

Inflammatory State ◽

The Uk ◽

Genetically Determined

Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p < 1.85 × 10−3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (β = –0.03, SE = 0.008, p = 1.35 × 10−3) and decreased eosinophils (β = –0.008, SE = 0.002, p = 1.36 × 10−3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.

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