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Quantile-specific heritability of high-density lipoproteins with implications for precision medicine.
J Clin Lipidol. 2020 May 29 [Online ahead of print]JC

Abstract

BACKGROUND

We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity).

OBJECTIVE

Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort).

METHODS

Quantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2βOP/(1 + rspouse) and [(8βFSrspouse + 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation.

RESULTS

HDL cholesterol heritability estimated from βOP increased significantly (P = 4.2 × 10-5) from the 10th (h2 ± SE: 0.44 ± 0.03), 25th (0.45 ± 0.03), 50th (0.47 ± 0.03), and 75th (0.56 ± 0.04) to the 90th percentiles (0.65 ± 0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P = .002), apo A1 (P = .006), HDL2 cholesterol (P = .003), and HDL3 cholesterol distribution (P = .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects.

CONCLUSION

HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.

Authors+Show Affiliations

Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Electronic address: ptwilliams@lbl.gov.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32600822

Citation

Williams, Paul T.. "Quantile-specific Heritability of High-density Lipoproteins With Implications for Precision Medicine." Journal of Clinical Lipidology, 2020.
Williams PT. Quantile-specific heritability of high-density lipoproteins with implications for precision medicine. J Clin Lipidol. 2020.
Williams, P. T. (2020). Quantile-specific heritability of high-density lipoproteins with implications for precision medicine. Journal of Clinical Lipidology. https://doi.org/10.1016/j.jacl.2020.05.099
Williams PT. Quantile-specific Heritability of High-density Lipoproteins With Implications for Precision Medicine. J Clin Lipidol. 2020 May 29; PubMed PMID: 32600822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantile-specific heritability of high-density lipoproteins with implications for precision medicine. A1 - Williams,Paul T, Y1 - 2020/05/29/ PY - 2020/01/11/received PY - 2020/05/09/revised PY - 2020/05/20/accepted PY - 2020/7/1/entrez KW - Apolipoprotein A1 KW - Gene-environment interactions KW - HDL2 KW - HDL3 KW - Heritability KW - High-density lipoprotein cholesterol JF - Journal of clinical lipidology JO - J Clin Lipidol N2 - BACKGROUND: We have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity). OBJECTIVE: Evidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort). METHODS: Quantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2βOP/(1 + rspouse) and [(8βFSrspouse + 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation. RESULTS: HDL cholesterol heritability estimated from βOP increased significantly (P = 4.2 × 10-5) from the 10th (h2 ± SE: 0.44 ± 0.03), 25th (0.45 ± 0.03), 50th (0.47 ± 0.03), and 75th (0.56 ± 0.04) to the 90th percentiles (0.65 ± 0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P = .002), apo A1 (P = .006), HDL2 cholesterol (P = .003), and HDL3 cholesterol distribution (P = .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects. CONCLUSION: HDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects. SN - 1933-2874 UR - https://www.unboundmedicine.com/medline/citation/32600822/Quantile-specific_heritability_of_high-density_lipoproteins_with_implications_for_precision_medicine L2 - https://linkinghub.elsevier.com/retrieve/pii/S1933-2874(20)30197-5 DB - PRIME DP - Unbound Medicine ER -
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