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Quantile-dependent expressivity of postprandial lipemia.
PLoS One. 2020; 15(2):e0229495.Plos

Abstract

PURPOSE

"Quantile-dependent expressivity" describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject's triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual's genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs.

RESULTS

Consistent with the phenomenon, genetic effect sizes increased (P≤0.05) with increasing triglyceride concentrations for polymorphisms associated with ABCA1, ANGPTL4, APOA1, APOA2, APOA4, APOA5, APOB, APOC3, APOE, CETP, FABP2, FATP6, GALNT2, GCKR, HL, IL1b, LEPR, LOX-1, LPL, MC4R, MTTP, NPY, SORT1, SULF2, TNFA, TCF7L2, and TM6SF2. The effect size for these polymorphisms showed a progressively increasing dose-response, with intermediate effect sizes at intermediate triglyceride concentrations. Quantile-dependent expressivity provided an alternative interpretation to their interactions with sex, drugs, disease, diet, and age, which have been traditionally ascribed to gene-environment interactions and genetic predictors of drug efficacy (i.e., personalized medicine).

CONCLUSION

Quantile-dependent expressivity applies to the majority of genetic variants affecting postprandial triglycerides, which may arise because the impaired functionalities of these variants increase at higher triglyceride concentrations. Purported gene-drug interactions may be the manifestations of quantile-dependent expressivity, rather than genetic predictors of drug efficacy.

Authors+Show Affiliations

Lawrence Berkeley National Laboratory, Berkeley, CA, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32101585

Citation

Williams, Paul T.. "Quantile-dependent Expressivity of Postprandial Lipemia." PloS One, vol. 15, no. 2, 2020, pp. e0229495.
Williams PT. Quantile-dependent expressivity of postprandial lipemia. PLoS ONE. 2020;15(2):e0229495.
Williams, P. T. (2020). Quantile-dependent expressivity of postprandial lipemia. PloS One, 15(2), e0229495. https://doi.org/10.1371/journal.pone.0229495
Williams PT. Quantile-dependent Expressivity of Postprandial Lipemia. PLoS ONE. 2020;15(2):e0229495. PubMed PMID: 32101585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantile-dependent expressivity of postprandial lipemia. A1 - Williams,Paul T, Y1 - 2020/02/26/ PY - 2019/06/04/received PY - 2020/02/09/accepted PY - 2020/2/27/entrez PY - 2020/2/27/pubmed PY - 2020/6/12/medline SP - e0229495 EP - e0229495 JF - PloS one JO - PLoS ONE VL - 15 IS - 2 N2 - PURPOSE: "Quantile-dependent expressivity" describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject's triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual's genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs. RESULTS: Consistent with the phenomenon, genetic effect sizes increased (P≤0.05) with increasing triglyceride concentrations for polymorphisms associated with ABCA1, ANGPTL4, APOA1, APOA2, APOA4, APOA5, APOB, APOC3, APOE, CETP, FABP2, FATP6, GALNT2, GCKR, HL, IL1b, LEPR, LOX-1, LPL, MC4R, MTTP, NPY, SORT1, SULF2, TNFA, TCF7L2, and TM6SF2. The effect size for these polymorphisms showed a progressively increasing dose-response, with intermediate effect sizes at intermediate triglyceride concentrations. Quantile-dependent expressivity provided an alternative interpretation to their interactions with sex, drugs, disease, diet, and age, which have been traditionally ascribed to gene-environment interactions and genetic predictors of drug efficacy (i.e., personalized medicine). CONCLUSION: Quantile-dependent expressivity applies to the majority of genetic variants affecting postprandial triglycerides, which may arise because the impaired functionalities of these variants increase at higher triglyceride concentrations. Purported gene-drug interactions may be the manifestations of quantile-dependent expressivity, rather than genetic predictors of drug efficacy. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/32101585/Quantile_dependent_expressivity_of_postprandial_lipemia_ L2 - http://dx.plos.org/10.1371/journal.pone.0229495 DB - PRIME DP - Unbound Medicine ER -