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Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women.

ABSTRACT: BACKGROUND/OBJECTIVES:Individually, genetic variants only moderately influence cardiometabolic (CM) traits, such as lipid and inflammatory markers. In this study we generated genetic risk scores from a combination of previously reported variants influencing CM traits, and used these scores to explore how adiposity levels could mediate genetic contributions to CM traits. SUBJECTS/METHODS:Participants included 1649 women from the 2005 Cebu Longitudinal Health and Nutrition Survey. Three genetic risk scores were constructed for C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs). We used linear regression models to assess the association between each genetic risk score and its related trait. We also tested for interactions between each score and measures of adiposity. RESULTS:Each genetic risk score explained a greater proportion of variance in trait levels than any individual genetic variant. We found an interaction between the TG genetic risk score (2.29-14.34 risk alleles) and waist circumference (WC) (Pinteraction=1.66 × 10(-2)). Based on model predictions, for individuals with a higher TG genetic risk score (75th percentile=12), having an elevated WC (?80?cm) increased TG levels from 1.32 to 1.71?mmol?l(-1). However, for individuals with a lower score (25th percentile=7), having an elevated WC did not significantly change TG levels. CONCLUSIONS:The TG genetic risk score interacted with adiposity to synergistically influence TG levels. For individuals with a genetic predisposition to elevated TG levels, our results suggest that reducing adiposity could possibly prevent further increases in TG levels and thereby lessen the likelihood of adverse health outcomes such as cardiovascular disease.

SUBMITTER: Zubair N

PROVIDER: S-EPMC4079926 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women.

Zubair N N Mayer-Davis E J EJ Mendez M A MA Mohlke K L KL North K E KE Adair L S LS

Nutrition & diabetes 20140616

<h4>Background/objectives</h4>Individually, genetic variants only moderately influence cardiometabolic (CM) traits, such as lipid and inflammatory markers. In this study we generated genetic risk scores from a combination of previously reported variants influencing CM traits, and used these scores to explore how adiposity levels could mediate genetic contributions to CM traits.<h4>Subjects/methods</h4>Participants included 1649 women from the 2005 Cebu Longitudinal Health and Nutrition Survey. T ...[more]

PMID: 24932782

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Project description:BackgroundInformation about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on serum lipid profiles is still scarce. The present study was undertaken to detect ten SNPs and their interactions with overweight/obesity on serum lipid levels.MethodsA total of 978 normal weight and 751 overweight/obese subjects of Bai Ku Yao were randomly selected from our previous stratified randomized cluster samples. Normal weight, overweight and obesity were defined as a body mass index (BMI) < 24, 24-28, and > 28 kg/m(2); respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1 and ApoB levels were measured. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions were detected by factorial design covariance analysis.ResultsThe genotypic and allelic frequencies of LIPC and PCSK9 were different between normal weight and overweight/obese subjects, the genotypic frequency of LIPG and allelic frequency of MYLIP were also different between normal weight and overweight/obese subjects (P < 0.05-0.001). The levels of TC, ApoA1 (ABCA-1); TC, LDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TG, HDL-C, and ApoA1 (LIPG); TC, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); HDL-C and ApoA1 (MYLIP) in normal weight subjects were different among the genotypes (P < 0.01-0.001). The levels of LDL-C, ApoB and ApoA1/ApoB (ABCA-1); HDL-C, ApoA1, ApoB and ApoA1/ApoB (LIPC); TC, HDL-C, ApoA1 and ApoB (LIPG); TC, TG, HDL-C, LDL-C, ApoA1 and ApoB (MTHFR); TC, TG and ApoB (MYLIP); TG (PCSK9); TG, ApoA1 and ApoB (PPARD); and TC, HDL-C, LDL-C, ApoA1 and ApoB (SCARB1) in overweight/obese subjects were different among the genotypes (P < 0.01-0.001). The SNPs of ABCA-1 (LDL-C and ApoA1/ApoB); LIPC (TC, LDL-C, ApoA1 and ApoB); LIPG (ApoB); MTHFR (TC, TG and LDL-C); MYLIP (TC and TG); PCSK9 (TG, HDL-C, ApoB and ApoA1/ApoB); PPARD (TG and ApoA1/ApoB); and SCARB1 (TG, ApoA1 and ApoB) interacted with overweight/obesity to influence serum lipid levels (P < 0.05-0.001).ConclusionsThe differences in serum lipid levels between normal weight and overweight/obese subjects might partly result from different genetic polymorphisms and the interactions between several SNPs and overweight/obesity.

Project description:BACKGROUNDInsulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODSA hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTSInsulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSIONHyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver's maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.

Dataset Information

Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women.

Publications

Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women.

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