The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3

Authors

Robert L. Hanson
Fatjon Leti
Darwin Tsinajinnie
Sayuko Kobes
Sobha Puppala
Joanne E. Curran, The University of Texas Rio Grande ValleyFollow
Laura Almasy, The University of Texas Rio Grande Valley
Donna M. Lehman, University of Texas Health Science Center at San Antonio
John Blangero, The University of Texas Rio Grande ValleyFollow
Ravi Duggirala, The University of Texas Rio Grande Valley
Johanna K. DiStefano

Document Type

Article

Publication Date

6-2016

Abstract

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045×10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563×10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526×10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8.

Comments

Copyright © 2016 Elsevier Inc. All rights reserved.

Recommended Citation

Hanson, R. L., Leti, F., Tsinajinnie, D., Kobes, S., Puppala, S., Curran, J. E., Almasy, L., Lehman, D. M., Blangero, J., Duggirala, R., & DiStefano, J. K. (2016). The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. Molecular genetics and metabolism, 118(2), 128–137. https://doi.org/10.1016/j.ymgme.2016.04.007

Publication Title

Mol Genet Metab

DOI

10.1016/j.ymgme.2016.04.007

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics