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Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.
Liu, CT, Raghavan, S, Maruthur, N, Kabagambe, EK, Hong, J, Ng, MC, Hivert, MF, Lu, Y, An, P, Bentley, AR, et al
American journal of human genetics. 2016;(1):56-75
Abstract
Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
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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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Effects of a low-fat dietary intervention on glucose, insulin, and insulin resistance in the Women's Health Initiative (WHI) Dietary Modification trial.
Shikany, JM, Margolis, KL, Pettinger, M, Jackson, RD, Limacher, MC, Liu, S, Phillips, LS, Tinker, LF
The American journal of clinical nutrition. 2011;(1):75-85
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Abstract
BACKGROUND Glycemic effects of the Women's Health Initiative (WHI) low-fat dietary intervention are unknown. OBJECTIVE Our objective was to analyze the effects of the WHI low-fat dietary intervention on serum glucose and insulin and insulin resistance up to 6 y after random assignment. DESIGN Postmenopausal WHI Dietary Modification trial intervention (DM-I) and comparison (DM-C) participants with blood measures at least at baseline and year 1 (n = 2263) were included. Anthropometric measures, dietary assessments, serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance (HOMA-IR) measures, and quantitative insulin sensitivity check index (QUICKI) values were obtained at baseline, year 1, year 3, and year 6. Changes in measures were compared between groups at years 1, 3, and 6 overall and within stratified analyses. RESULTS Mean (±SD) differences in changes at year 1 between the DM-I and DM-C groups were as follows: glucose, -1.7 ± 17.9 mg/dL; insulin, -0.7 ± 5.1 μIU/mL; HOMA-IR, -0.2 ± 1.9; and QUICKI, 0.004 ± 0.019 (all P < 0.05). Similar findings resulted from repeated-measures analyses comparing the intervention and comparison groups over the 6 y. Whereas normoglycemic women at baseline had a decrease in glucose at year 1 that was 1.9 ± 17.2 mg/dL greater in the DM-I than in the DM-C group, diabetic women had an increase in glucose that was 7.9 ± 20.3 mg/dL greater in the DM-I than in the DM-C group (P for interaction <0.001). CONCLUSIONS A low-fat diet was not significantly associated with adverse glycemic effects up to 6 y after random assignment in postmenopausal women. However, diabetic women experienced adverse glycemic effects of the low-fat diet. This trial is registered at clinicaltrials.gov as NCT00000611.
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Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women.
Song, Y, Manson, JE, Buring, JE, Liu, S
Diabetes care. 2004;(1):59-65
Abstract
OBJECTIVE Higher intake of magnesium appears to improve glucose and insulin homeostasis; however, there are sparse prospective data on the association between magnesium intake and incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS In the Women's Health Study, a cohort of 39,345 U.S. women aged ≥45 years with no previous history of cardiovascular disease, cancer, or type 2 diabetes completed validated semiquantitative food frequency questionnaires in 1993 and were followed for an average of 6 years. We used Cox proportional hazard models to estimate multivariate relative risks (RRs) of type 2 diabetes across quintiles of magnesium intake compared with the lowest quintile. In a sample of 349 apparently healthy women from this study, we measured plasma fasting insulin levels to examine their relation to magnesium intake. RESULTS During 222,523 person-years of follow-up, we documented 918 confirmed incident cases of type 2 diabetes. There was a significant inverse association between magnesium intake and risk of type 2 diabetes, independent of age and BMI (P = 0.007 for trend). After further adjustment for physical activity, alcohol intake, smoking, family history of diabetes, and total calorie intake, the multivariate-adjusted RRs of diabetes from the lowest to highest quintiles of magnesium intake were attenuated at 1.0, 1.06, 0.81, 0.86, and 0.89 (P = 0.05 for trend). Among women with BMI ≥25 kg/m2, the inverse trend was significant; multivariate-adjusted RRs were 1.0, 0.96, 0.76, 0.84, and 0.78 (P = 0.02 for trend). Multivariate-adjusted geometric mean insulin levels for overweight women in the lowest quartile of magnesium intake was 53.5 compared with 41.5 pmol/l among those at the highest quartile (P = 0.03 for trend). CONCLUSIONS These findings support a protective role of higher intake of magnesium in reducing the risk of developing type 2 diabetes, especially in overweight women.