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Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.
Kocarnik, JM, Pendergrass, SA, Carty, CL, Pankow, JS, Schumacher, FR, Cheng, I, Durda, P, Ambite, JL, Deelman, E, Cook, NR, et al
Circulation. Cardiovascular genetics. 2014;(2):178-88
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Abstract
BACKGROUND C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. METHODS AND RESULTS We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)). CONCLUSIONS We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
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Magnesium supplementation, metabolic and inflammatory markers, and global genomic and proteomic profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals.
Chacko, SA, Sul, J, Song, Y, Li, X, LeBlanc, J, You, Y, Butch, A, Liu, S
The American journal of clinical nutrition. 2011;(2):463-73
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Abstract
BACKGROUND Dietary magnesium intake has been favorably associated with reduced risk of metabolic outcomes in observational studies; however, few randomized trials have introduced a systems-biology approach to explore molecular mechanisms of pleiotropic metabolic actions of magnesium supplementation. OBJECTIVE We examined the effects of oral magnesium supplementation on metabolic biomarkers and global genomic and proteomic profiling in overweight individuals. DESIGN We undertook this randomized, crossover, pilot trial in 14 healthy, overweight volunteers [body mass index (in kg/m(2)) ≥25] who were randomly assigned to receive magnesium citrate (500 mg elemental Mg/d) or a placebo for 4 wk with a 1-mo washout period. Fasting blood and urine specimens were collected according to standardized protocols. Biochemical assays were conducted on blood specimens. RNA was extracted and subsequently hybridized with the Human Gene ST 1.0 array (Affymetrix, Santa Clara, CA). Urine proteomic profiling was analyzed with the CM10 ProteinChip array (Bio-Rad Laboratories, Hercules, CA). RESULTS We observed that magnesium treatment significantly decreased fasting C-peptide concentrations (change: -0.4 ng/mL after magnesium treatment compared with +0.05 ng/mL after placebo treatment; P = 0.004) and appeared to decrease fasting insulin concentrations (change: -2.2 μU/mL after magnesium treatment compared with 0.0 μU/mL after placebo treatment; P = 0.25). No consistent patterns were observed across inflammatory biomarkers. Gene expression profiling revealed up-regulation of 24 genes and down-regulation of 36 genes including genes related to metabolic and inflammatory pathways such as C1q and tumor necrosis factor-related protein 9 (C1QTNF9) and pro-platelet basic protein (PPBP). Urine proteomic profiling showed significant differences in the expression amounts of several peptides and proteins after treatment. CONCLUSION Magnesium supplementation for 4 wk in overweight individuals led to distinct changes in gene expression and proteomic profiling consistent with favorable effects on several metabolic pathways. This trial was registered at clinicaltrials.gov as NCT00737815.
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Dietary glycemic index, dietary glycemic load, blood lipids, and C-reactive protein.
Levitan, EB, Cook, NR, Stampfer, MJ, Ridker, PM, Rexrode, KM, Buring, JE, Manson, JE, Liu, S
Metabolism: clinical and experimental. 2008;(3):437-43
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Abstract
Carbohydrate quantity and quality may influence the risk of cardiovascular disease through blood lipid concentrations and inflammation. We measured dietary glycemic index (GI) and dietary glycemic load (GL) among 18137 healthy women > or = 45 years old without diagnosed diabetes using a food-frequency questionnaire. We assayed fasting total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol; LDL/HDL cholesterol ratio; triacylglycerols (TG); and C-reactive protein (CRP). We evaluated associations with dietary GI and GL using a cross-sectional design, adjusting for age, body mass index, lifestyle factors, and other dietary factors. Dietary GI was significantly associated with HDL and LDL cholesterol, LDL/HDL cholesterol ratio, TG, and CRP (comparing top to bottom quintile difference in HDL cholesterol = -2.6 mg/dL, LDL cholesterol = 2.2 mg/dL, LDL/HDL cholesterol ratio = 0.16, TG = 12 mg/dL, and CRP = 0.21 mg/L). Dietary GL was associated with HDL cholesterol, LDL/HDL cholesterol ratio, and TG (comparing top to bottom quintile HDL cholesterol = -4.9 mg/dL, LDL/HDL cholesterol ratio = 0.24, and TG = 13 mg/dL). Differences in blood lipids and CRP between extreme quintiles of dietary GI and GL were small, but may translate into a clinically meaningful difference in cardiovascular risk.
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Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women.
Liu, S, Manson, JE, Buring, JE, Stampfer, MJ, Willett, WC, Ridker, PM
The American journal of clinical nutrition. 2002;(3):492-8
Abstract
BACKGROUND Recent prospective data suggest that intake of rapidly digested and absorbed carbohydrates with a high dietary glycemic load is associated with an increased risk of ischemic heart disease. OBJECTIVE We examined whether a high dietary glycemic load was associated with elevated hs-CRP concentrations and whether this association was modified by body mass index (BMI; in kg/m(2)). DESIGN In 244 apparently healthy women, we measured plasma hs-CRP concentrations and determined average dietary glycemic loads with a validated semiquantitative food-frequency questionnaire. Using multiple regression models, we evaluated the association between dietary glycemic load and plasma hs-CRP after adjusting for age; treatment status; smoking status; BMI; physical activity level; parental history of myocardial infarction; history of hypertension, diabetes, and high cholesterol; postmenopausal hormone use; alcohol intake; and other dietary variables. RESULTS We found a strong and statistically significant positive association between dietary glycemic load and plasma hs-CRP. The median hs-CRP concentration for the lowest quintile of dietary glycemic load was 1.9 mg/L and for the highest quintile was 3.7 mg/L; corresponding multivariate-adjusted geometric means were 1.4 and 3.8 mg/L, respectively (P for trend < 0.01). This association was significantly modified by BMI. Among women with a BMI greater-than-or-equal 25, the multivariate-adjusted geometric mean hs-CRP concentration in the lowest quintile was 1.6 mg/L and in the highest quintile was 5.0 mg/L; however, among women with a BMI < 25, the corresponding means were 1.1 and 3.1 mg/L, respectively (P = 0.01 for interaction). CONCLUSIONS Dietary glycemic load is significantly and positively associated with plasma hs-CRP in healthy middle-aged women, independent of conventional risk factors for ischemic heart disease. Exacerbation of the proinflammatory process may be a mechanism whereby a high intake of rapidly digested and absorbed carbohydrates increases the risk of ischemic heart disease, especially in overweight women prone to insulin resistance.