Genetic loci associated with circulating levels of very long-chain saturated fatty acids.
Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Rozenn N
RN
Lemaitre
Department of Internal Medicine, University of New Mexico, Albuquerque, NM.
Irena B
IB
King
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Edmond K
EK
Kabagambe
The George Institute for Global Health, University of Sydney, Sydney, Australia.
Jason H Y
JH
Wu
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA.
Barbara
B
McKnight
Center for Public Health Genomics University of Virginia, Charlottesville, VA Department of Public Health Sciences, Division of Biostatistics, University of Virginia, Charlottesville, VA.
Ani
A
Manichaikul
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN.
Weihua
W
Guan
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Departments of Nutrition Harvard School of Public Health, Boston, MA.
Qi
Q
Sun
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Daniel I
DI
Chasman
Institute of Molecular Medicine University of Texas Health Sciences Center-Houston, Houston, TX.
Millennia
M
Foy
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Lu
L
Wang
Key Laboratory of Nutrition and Metabolism Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate University of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
Jingwen
J
Zhu
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA Departments of Epidemiology University of Washington, Seattle, WA.
David S
DS
Siscovick
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN.
Michael Y
MY
Tsai
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Donna K
DK
Arnett
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA Departments of Epidemiology University of Washington, Seattle, WA Health Services, University of Washington, Seattle, WA Group Health Research Institute, Group Health Cooperative, Seattle, WA.
Bruce M
BM
Psaty
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Boston Veterans Healthcare System, Boston, MA.
Luc
L
Djousse
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Yii-Der I
YD
Chen
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
Weihong
W
Tang
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
Lu-Chen
LC
Weng
Departments of Nutrition Harvard School of Public Health, Boston, MA.
Hongyu
H
Wu
Departments of Nutrition Harvard School of Public Health, Boston, MA.
Majken K
MK
Jensen
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Audrey Y
AY
Chu
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
David R
DR
Jacobs
Center for Public Health Genomics University of Virginia, Charlottesville, VA.
Stephen S
SS
Rich
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Departments of Nutrition Harvard School of Public Health, Boston, MA Epidemiology, Harvard School of Public Health, Boston, MA Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA.
Dariush
D
Mozaffarian
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
Lyn
L
Steffen
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Departments of Nutrition Harvard School of Public Health, Boston, MA Epidemiology, Harvard School of Public Health, Boston, MA.
Eric B
EB
Rimm
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Departments of Nutrition Harvard School of Public Health, Boston, MA Epidemiology, Harvard School of Public Health, Boston, MA.
Frank B
FB
Hu
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Institute of Molecular Medicine University of Texas Health Sciences Center-Houston, Houston, TX.
Paul M
PM
Ridker
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA Division of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Sciences Center-Houston, Houston, TX.
Myriam
M
Fornage
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Yechiel
Y
Friedlander
D015331:Cohort Studies; D005227:Fatty Acids / Q000097:blood*; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans
D005227:Fatty Acids
arachidic acid; behenic acid; lignoceric acid; sphingolipids