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Title: Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations

Abstract

"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(1 + $$\Gamma$$ spouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10-14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h2 ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).

Authors:
 [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics & Integrated Bioimaging Division
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Heart, Lung, and Blood Institute (NHLBI); Boston University; National Institutes of Health (NIH)
OSTI Identifier:
1615321
Grant/Contract Number:  
AC02-05CH11231; N01-HC-25195; HHSN268201500001I; R21ES020700
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Williams, Paul T. Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations. United States: N. p., 2020. Web. https://doi.org/10.1038/s41598-020-60965-9.
Williams, Paul T. Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations. United States. https://doi.org/10.1038/s41598-020-60965-9
Williams, Paul T. Wed . "Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations". United States. https://doi.org/10.1038/s41598-020-60965-9. https://www.osti.gov/servlets/purl/1615321.
@article{osti_1615321,
title = {Gene-environment interactions due to quantile-specific heritability of triglyceride and VLDL concentrations},
author = {Williams, Paul T.},
abstractNote = {"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(1 + $\Gamma$ spouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10-14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h2 ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).},
doi = {10.1038/s41598-020-60965-9},
journal = {Scientific Reports},
number = 1,
volume = 10,
place = {United States},
year = {2020},
month = {3}
}

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Works referenced in this record:

Contribution of Apolipoprotein C-III Gene Variants to Determination of Triglyceride Levels and Interaction With Smoking in Middle-Aged Men
journal, December 2000

  • Waterworth, Dawn M.; Talmud, Philippa J.; Bujac, Sarah R.
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 20, Issue 12
  • DOI: 10.1161/01.ATV.20.12.2663

Relationship of abdominal adiposity and dyslipemic status in women with a common mutation in the lipoprotein lipase gene
journal, May 2000


Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population
journal, June 2015

  • Justesen, Johanne M.; Allin, Kristine H.; Sandholt, Camilla H.
  • Circulation: Cardiovascular Genetics, Vol. 8, Issue 3
  • DOI: 10.1161/CIRCGENETICS.114.000637

Triglycerides and Cardiovascular Disease: A Scientific Statement From the American Heart Association
journal, May 2011


Interaction of Insulin Resistance and Related Genetic Variants With Triglyceride-Associated Genetic Variants
journal, April 2016


Polymorphism at the TNF ‐alpha gene interacts with M editerranean diet to influence triglyceride metabolism and inflammation status in metabolic syndrome patients: F rom the CORDIOPREV clinical trial
journal, April 2014

  • Gomez‐Delgado, Francisco; Alcala‐Diaz, Juan Francisco; Garcia‐Rios, Antonio
  • Molecular Nutrition & Food Research, Vol. 58, Issue 7
  • DOI: 10.1002/mnfr.201300723

The Effect of Mediterranean Diet on Metabolic Syndrome and its Components
journal, March 2011

  • Kastorini, Christina-Maria; Milionis, Haralampos J.; Esposito, Katherine
  • Journal of the American College of Cardiology, Vol. 57, Issue 11
  • DOI: 10.1016/j.jacc.2010.09.073

Biological, clinical and population relevance of 95 loci for blood lipids
journal, August 2010

  • Teslovich, Tanya M.; Musunuru, Kiran; Smith, Albert V.
  • Nature, Vol. 466, Issue 7307
  • DOI: 10.1038/nature09270

Hind III polymorphism of the lipoprotein lipase gene and plasma lipid response to low calorie diet
journal, April 1997

  • Jemaa, R.; Tuzet, S.; Betoulle, D.
  • International Journal of Obesity, Vol. 21, Issue 4
  • DOI: 10.1038/sj.ijo.0800401

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma: Management of patients on bexarotene
journal, December 2012

  • Scarisbrick, J. J.; Morris, S.; Azurdia, R.
  • British Journal of Dermatology, Vol. 168, Issue 1
  • DOI: 10.1111/bjd.12042

A Period 2 Genetic Variant Interacts with Plasma SFA to Modify Plasma Lipid Concentrations in Adults with Metabolic Syndrome
journal, May 2012

  • Garcia-Rios, Antonio; Perez-Martinez, Pablo; Delgado-Lista, Javier
  • The Journal of Nutrition, Vol. 142, Issue 7
  • DOI: 10.3945/jn.111.156968

Pharmacogenetic study of cholesteryl ester transfer protein gene and simvastatin treatment in hypercholesterolaemic subjects
journal, October 2007

  • Anagnostopoulou, Katherine; Kolovou, Genovefa; Kostakou, Peggy
  • Expert Opinion on Pharmacotherapy, Vol. 8, Issue 15
  • DOI: 10.1517/14656566.8.15.2459

Life-Style and Serum Lipids and Lipoproteins
journal, January 2000

  • Hata, Yoshiya; Nakajima, Kumiko
  • Journal of Atherosclerosis and Thrombosis, Vol. 7, Issue 4
  • DOI: 10.5551/jat1994.7.177

Sibling and parent--offspring correlation estimation with variable family size.
journal, May 1981

  • Karlin, S.; Cameron, E. C.; Williams, P. T.
  • Proceedings of the National Academy of Sciences, Vol. 78, Issue 5
  • DOI: 10.1073/pnas.78.5.2664

Effect of genetic and environmental influences on cardiometabolic risk factors: a twin study
journal, January 2011

  • Jermendy, György; Horváth, Tamás; Littvay, Levente
  • Cardiovascular Diabetology, Vol. 10, Issue 1
  • DOI: 10.1186/1475-2840-10-96

Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study
journal, August 2010

  • Wojczynski, Mary K.; Gao, Guimin; Borecki, Ingrid
  • Journal of Lipid Research, Vol. 51, Issue 11
  • DOI: 10.1194/jlr.P001834

The interaction of Apolipoprotein A5 gene promoter region T-1131C polymorphism ( rs12286037 ) and lifestyle modification on plasma triglyceride levels in Japanese
journal, January 2015

  • Yamasaki, Masayuki; Mutombo, Paulin Beya wa Bitadi; Iwamoto, Mamiko
  • Nutrition Research and Practice, Vol. 9, Issue 4
  • DOI: 10.4162/nrp.2015.9.4.379

Lipoprotein lipase gene S447X polymorphism modulates the relation between central obesity and serum lipids, a twin study
journal, March 2006

  • Huang, A. Q.; Hu, Y. H.; Zhan, S. Y.
  • International Journal of Obesity, Vol. 30, Issue 12
  • DOI: 10.1038/sj.ijo.0803332

Apolipoprotein E Polymorphisms and Postprandial Triglyceridemia Before and After Fenofibrate Treatment in the Genetics of Lipid Lowering and Diet Network (GOLDN) Study
journal, October 2010


Gender-specific interactions of MTHFR C677T and MTRR A66G polymorphisms with overweight/obesity on serum lipid levels in a Chinese Han population
journal, October 2016


Genetic association with lipids in Filipinos: waist circumference modifies an APOA5 effect on triglyceride levels
journal, September 2013

  • Wu, Ying; Marvelle, Amanda F.; Li, Jin
  • Journal of Lipid Research, Vol. 54, Issue 11
  • DOI: 10.1194/jlr.P042077

The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: Design, Recruitment, and Initial Examination
journal, April 2007

  • Splansky, G. L.; Corey, D.; Yang, Q.
  • American Journal of Epidemiology, Vol. 165, Issue 11
  • DOI: 10.1093/aje/kwm021

Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome
journal, April 2009

  • Elder, Sonya J.; Lichtenstein, Alice H.; Pittas, Anastassios G.
  • Journal of Lipid Research, Vol. 50, Issue 9
  • DOI: 10.1194/jlr.P900033-JLR200

Genetic risk score and adiposity interact to influence triglyceride levels in a cohort of Filipino women
journal, June 2014

  • Zubair, N.; Mayer-Davis, E. J.; Mendez, M. A.
  • Nutrition & Diabetes, Vol. 4, Issue 6
  • DOI: 10.1038/nutd.2014.16

Apolipoprotein E gene polymorphism alters lipids before pancreas transplantation
journal, January 2002


Physical activity modulates effects of some genetic polymorphisms affecting cardiovascular risk in men aged over 40 years
journal, August 2003


Apolipoprotein A1 genotype affects the change in high density lipoprotein cholesterol subfractions with exercise training
journal, March 2006


INSIG2 variants, dietary patterns and metabolic risk in Samoa
journal, September 2012

  • Baylin, A.; Deka, R.; Tuitele, J.
  • European Journal of Clinical Nutrition, Vol. 67, Issue 1
  • DOI: 10.1038/ejcn.2012.124

The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels
journal, February 2014


The rs2516839 Polymorphism of the USF1 Gene May Modulate Serum Triglyceride Levels in Response to Cigarette Smoking
journal, June 2015

  • Niemiec, Pawel; Nowak, Tomasz; Iwanicki, Tomasz
  • International Journal of Molecular Sciences, Vol. 16, Issue 12
  • DOI: 10.3390/ijms160613203

Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis
journal, August 1992

  • Dattilo, A. M.; Kris-Etherton, P. M.
  • The American Journal of Clinical Nutrition, Vol. 56, Issue 2
  • DOI: 10.1093/ajcn/56.2.320

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
journal, January 2019

  • de Vries, Paul S.; Brown, Michael R.; Bentley, Amy R.
  • American Journal of Epidemiology, Vol. 188, Issue 6
  • DOI: 10.1093/aje/kwz005

Triglyceride Response to an Intensive Lifestyle Intervention Is Enhanced in Carriers of the GCKR Pro446Leu Polymorphism
journal, July 2011

  • Pollin, Toni I.; Jablonski, Kathleen A.; McAteer, Jarred B.
  • The Journal of Clinical Endocrinology & Metabolism, Vol. 96, Issue 7
  • DOI: 10.1210/jc.2010-2324

Several genetic polymorphisms interact with overweight/obesity to influence serum lipid levels
journal, January 2012


Update on APOA5 Genetics: Toward a Better Understanding of Its Physiological Impact
journal, May 2017


Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1
journal, August 1995


Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin
journal, October 2018

  • Tuteja, Sony; Qu, Liming; Vujkovic, Marijana
  • Journal of the American Heart Association, Vol. 7, Issue 19
  • DOI: 10.1161/JAHA.117.008461

Gene by Smoking Interaction: Evidence for Effects on Low-Density Lipoprotein Size and Plasma Triglyceride and High-Density Lipoprotein Cholesterol Levels
journal, January 2004

  • Czerwinski, Stefan A.; Mahaney, Michael C.; Rainwater, David Luther
  • Human Biology, Vol. 76, Issue 6
  • DOI: 10.1353/hub.2005.0014

Variants Identified in a GWAS Meta-Analysis for Blood Lipids Are Associated with the Lipid Response to Fenofibrate
journal, October 2012


Apolipoprotein E polymorphism in the Tunisian population: Frequency and effect on lipid parameters
journal, August 2006


Adiposity significantly modifies genetic risk for dyslipidemia
journal, September 2014

  • Cole, Christopher B.; Nikpay, Majid; Lau, Paulina
  • Journal of Lipid Research, Vol. 55, Issue 11
  • DOI: 10.1194/jlr.P052522

Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge
journal, September 1996


Quantile-dependent expressivity of postprandial lipemia
journal, February 2020


Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study
journal, January 2018


Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner
journal, September 2001


No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population
journal, October 2013


Exercise Training-Induced Blood Pressure and Plasma Lipid Improvements in Hypertensives May Be Genotype Dependent
journal, July 1999

  • Hagberg, James M.; Ferrell, Robert E.; Dengel, Donald R.
  • Hypertension, Vol. 34, Issue 1
  • DOI: 10.1161/01.HYP.34.1.18

Interactions of the Apolipoprotein A5 Gene Polymorphisms and Alcohol Consumption on Serum Lipid Levels
journal, March 2011


A genome-wide association and gene–environment interaction study for serum triglycerides levels in a healthy Chinese male population
journal, December 2011

  • Tan, Aihua; Sun, Jielin; Xia, Ning
  • Human Molecular Genetics, Vol. 21, Issue 7
  • DOI: 10.1093/hmg/ddr587

An Investigation of Coronary Heart Disease in Families
journal, September 1979


Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia?: Findings From the GLACIER and the MDC Studies
journal, April 2016


The −1131T>C SNP of the APOA5 gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: A postprandial study
journal, September 2009


Interactions of the apolipoprotein C-III 3238C>G polymorphism and alcohol consumption on serum triglyceride levels
journal, August 2010

  • Ruixing, Yin; Yiyang, Li; Meng, Li
  • Lipids in Health and Disease, Vol. 9, Issue 1
  • DOI: 10.1186/1476-511X-9-86

Apolipoprotein E polymorphism in non-insulin-dependent diabetics of Mumbai, India and its effect on plasma lipids and lipoproteins
journal, March 2000

  • Inamdar, P. A.; Kelkar, S. M.; Devasagayam, T. P. A.
  • Diabetes Research and Clinical Practice, Vol. 47, Issue 3
  • DOI: 10.1016/S0168-8227(99)00126-6

Central obesity in males affected by a dyslipidemia-associated genetic polymorphism on APOA1/C3/A4/A5 gene cluster
journal, March 2013

  • Hsu, M-C; Chang, C-S; Lee, K-T
  • Nutrition & Diabetes, Vol. 3, Issue 3
  • DOI: 10.1038/nutd.2013.2

The Lipoprotein Lipase Hin dIII Polymorphism Modulates Plasma Triglyceride Levels in Visceral Obesity
journal, May 1995

  • Vohl, Marie-Claude; Lamarche, Benoı̂t; Moorjani, Sital
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 15, Issue 5
  • DOI: 10.1161/01.ATV.15.5.714

Novel Genetic Loci Associated with the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation
journal, January 2016

  • Vallée Marcotte, Bastien; Cormier, Hubert; Guénard, Frédéric
  • Journal of Nutrigenetics and Nutrigenomics, Vol. 9, Issue 1
  • DOI: 10.1159/000446024

Polygenic risk for hypertriglyceridemia is attenuated in Japanese men with high fitness levels
journal, March 2014


APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults
journal, November 2012

  • Carvalho-Wells, Andrew L.; Jackson, Kim G.; Lockyer, Stacey
  • The American Journal of Clinical Nutrition, Vol. 96, Issue 6
  • DOI: 10.3945/ajcn.112.043240

Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials
journal, May 2003

  • Mensink, Ronald P.; Zock, Peter L.; Kester, Arnold DM
  • The American Journal of Clinical Nutrition, Vol. 77, Issue 5
  • DOI: 10.1093/ajcn/77.5.1146

Apolipoprotein A-V Genetic Variation and Plasma Lipoprotein Response to Fibrates
journal, June 2007

  • Hegele, Robert A.; Pollex, Rebecca L.
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 27, Issue 6
  • DOI: 10.1161/ATVBAHA.107.144980

The insulin resistance syndrome and postprandial lipid intolerance in smokers
journal, February 1997


Interaction Effects of Lipoprotein Lipase Polymorphisms with Lifestyle on Lipid Levels in a Korean Population: A Cross-sectional Study
journal, January 2012

  • Pyun, Jung-A; Kim, Sunshin; Park, KyungChae
  • Genomics & Informatics, Vol. 10, Issue 2
  • DOI: 10.5808/GI.2012.10.2.88

The G972R variant of the Insulin Receptor Substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance
journal, March 2001


Quantile Regression
journal, November 2001

  • Koenker, Roger; Hallock, Kevin F.
  • Journal of Economic Perspectives, Vol. 15, Issue 4
  • DOI: 10.1257/jep.15.4.143

Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants: The GOLDN Study
journal, June 2007

  • Lai, Chao-Qiang; Arnett, Donna K.; Corella, Dolores
  • Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 27, Issue 6
  • DOI: 10.1161/ATVBAHA.107.140103

Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height
journal, January 2012