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.
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.
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014, United States.
Robert L
RL
Hanson
Center for Genes, Environment, and Health, Department of Biomedical Research, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, United States.
Fatjon
F
Leti
Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, United States.
Darwin
D
Tsinajinnie
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014, United States.
Sayuko
S
Kobes
South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, 2700 E. Jackson St. Brownsville, TX 78520; 1214 W. Schunior Street, Edinburgh, TX 78541; 3463 Magic Drive San Antonio, TX 78229, United States.
Sobha
S
Puppala
South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, 2700 E. Jackson St. Brownsville, TX 78520; 1214 W. Schunior Street, Edinburgh, TX 78541; 3463 Magic Drive San Antonio, TX 78229, United States.
Joanne E
JE
Curran
South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, 2700 E. Jackson St. Brownsville, TX 78520; 1214 W. Schunior Street, Edinburgh, TX 78541; 3463 Magic Drive San Antonio, TX 78229, United States.
Laura
L
Almasy
Departments of Medicine and Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
Donna M
DM
Lehman
South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, 2700 E. Jackson St. Brownsville, TX 78520; 1214 W. Schunior Street, Edinburgh, TX 78541; 3463 Magic Drive San Antonio, TX 78229, United States.
John
J
Blangero
South Texas Diabetes and Obesity Institute (STDOI), University of Texas Rio Grande Valley (UTRGV) School of Medicine, 2700 E. Jackson St. Brownsville, TX 78520; 1214 W. Schunior Street, Edinburgh, TX 78541; 3463 Magic Drive San Antonio, TX 78229, United States.
Ravindranath
R
Duggirala
Center for Genes, Environment, and Health, Department of Biomedical Research, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, United States; Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, United States. Electronic address: distefanoj@njhealth.org.
Johanna K
JK
DiStefano
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000091303:Angiopoietin-Like Protein 3; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins / Q000235:genetics* / Q000378:metabolism*; D001120:Arginine / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D008875:Middle Aged; D036361:Peptide Hormones / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014364:Tryptophan / Q000235:genetics
C479896:ANGPTL3 protein, human; C576683:ANGPTL8 protein, human; D000091303:Angiopoietin-Like Protein 3; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D007328:Insulin; D036361:Peptide Hormones; D014364:Tryptophan; D001120:Arginine
Betatrophin; C19ORF80; Cholesterol; Diabetes; Dyslipidemias; Genetics; HDL; LOC55908; Lipasin; RIFL