TY - JOUR
T1 - Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)
AU - Aslibekyan, Stella
AU - Irvin, Marguerite R.
AU - Hidalgo, Bertha A.
AU - Perry, Rodney T.
AU - Jeyarajah, Elias J.
AU - Garcia, Erwin
AU - Shalaurova, Irina
AU - Hopkins, Paul N.
AU - Province, Michael A.
AU - Tiwari, Hemant K.
AU - Ordovas, Jose M.
AU - Absher, Devin M.
AU - Arnett, Donna K.
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Background Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. Methods and results We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n = 626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n = 847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. Conclusions Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans.
AB - Background Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. Methods and results We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n = 626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n = 847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. Conclusions Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans.
KW - Atherosclerosis
KW - Cardiovascular disease
KW - Epigenetic
KW - Genetic
KW - Methylation
KW - Trimethylamine-N-oxide
UR - http://www.scopus.com/inward/record.url?scp=85015017873&partnerID=8YFLogxK
U2 - 10.1016/j.jnim.2017.03.002
DO - 10.1016/j.jnim.2017.03.002
M3 - Article
C2 - 28439531
AN - SCOPUS:85015017873
SN - 2352-3859
VL - 8
SP - 1
EP - 7
JO - Journal of Nutrition and Intermediary Metabolism
JF - Journal of Nutrition and Intermediary Metabolism
ER -