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

Robert L. Hanson, Fatjon Leti, Darwin Tsinajinnie, Sayuko Kobes, Sobha Puppala, Joanne E. Curran, Laura Almasy, Donna M Lehman, John Blangero, Ravindranath Duggirala, Johanna K. DiStefano

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
JournalMolecular Genetics and Metabolism
DOIs
StateAccepted/In press - Feb 1 2016

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Angiopoietins
North American Indians
HDL Cholesterol
Alleles
Cholesterol
Association reactions
Potassium Iodide
Chromosomes
Substitution reactions
Genes
Chemical activation
Insulin
Glucose
Cohort Effect
Single Nucleotide Polymorphism
Meta-Analysis
Proteins

Keywords

  • Betatrophin
  • C19ORF80
  • Cholesterol
  • Diabetes
  • Dyslipidemias
  • Genetics
  • HDL
  • Lipasin
  • LOC55908
  • RIFL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Hanson, Robert L.; Leti, Fatjon; Tsinajinnie, Darwin; Kobes, Sayuko; Puppala, Sobha; Curran, Joanne E.; Almasy, Laura; Lehman, Donna M; Blangero, John; Duggirala, Ravindranath; DiStefano, Johanna K.

In: Molecular Genetics and Metabolism, 01.02.2016.

Research output: Contribution to journalArticle

Hanson, Robert L. ; Leti, Fatjon ; Tsinajinnie, Darwin ; Kobes, Sayuko ; Puppala, Sobha ; Curran, Joanne E. ; Almasy, Laura ; Lehman, Donna M ; Blangero, John ; Duggirala, Ravindranath ; DiStefano, Johanna K. / 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. In: Molecular Genetics and Metabolism. 2016.
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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.",
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T1 - 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

AU - Hanson, Robert L.

AU - Leti, Fatjon

AU - Tsinajinnie, Darwin

AU - Kobes, Sayuko

AU - Puppala, Sobha

AU - Curran, Joanne E.

AU - Almasy, Laura

AU - Lehman, Donna M

AU - Blangero, John

AU - Duggirala, Ravindranath

AU - DiStefano, Johanna K.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

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KW - C19ORF80

KW - Cholesterol

KW - Diabetes

KW - Dyslipidemias

KW - Genetics

KW - HDL

KW - Lipasin

KW - LOC55908

KW - RIFL

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