Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program
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Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program. / Varga, Tibor V; Winters, Alexandra H; Jablonski, Kathleen A; Horton, Edward S; Khare-Ranade, Prajakta; Knowler, William C; Marcovina, Santica M; Renström, Frida; Watson, Karol E; Goldberg, Ronald; Florez, José C; Pollin, Toni I; Franks, Paul W.
I: Circulation. Cardiovascular genetics, Bind 9, Nr. 6, 12.2016, s. 495-503.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program
AU - Varga, Tibor V
AU - Winters, Alexandra H
AU - Jablonski, Kathleen A
AU - Horton, Edward S
AU - Khare-Ranade, Prajakta
AU - Knowler, William C
AU - Marcovina, Santica M
AU - Renström, Frida
AU - Watson, Karol E
AU - Goldberg, Ronald
AU - Florez, José C
AU - Pollin, Toni I
AU - Franks, Paul W
N1 - © 2016 American Heart Association, Inc.
PY - 2016/12
Y1 - 2016/12
N2 - BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial.METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3 for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits.CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.
AB - BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial.METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3 for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits.CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.
KW - Cholesterol, HDL/blood
KW - Cholesterol, LDL/blood
KW - Dyslipidemias/blood
KW - Gene-Environment Interaction
KW - Genetic Loci
KW - Genetic Markers
KW - Genetic Predisposition to Disease
KW - Heredity
KW - Humans
KW - Hypoglycemic Agents/therapeutic use
KW - Lipids/blood
KW - Metformin/therapeutic use
KW - Particle Size
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Prediabetic State/blood
KW - Risk Assessment
KW - Risk Factors
KW - Risk Reduction Behavior
KW - Triglycerides/blood
KW - United States/epidemiology
U2 - 10.1161/CIRCGENETICS.116.001457
DO - 10.1161/CIRCGENETICS.116.001457
M3 - Journal article
C2 - 27784733
VL - 9
SP - 495
EP - 503
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
SN - 1942-325X
IS - 6
ER -
ID: 242837079