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<p>Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = −&#xa0;0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.</p>

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月25日

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  • Ryota Toki,
  • Sotaro Fushiki,
  • Shun Kojima,
  • Yoichi Sutoh,
  • Yayoi Otsuka-Yamasaki,
  • Sei Harada,
  • Miho Iida,
  • Aya Hirata,
  • Naoko Miyagawa,
  • Minako Matsumoto,
  • Shun Edagawa,
  • Atsuko Miyake,
  • Kazuyo Kuwabara,
  • Akiyoshi Hirayama,
  • Masahiro Sugimoto,
  • Asako Sato,
  • Kaori Amano,
  • Tomoyoshi Soga,
  • Masaru Tomita,
  • Kazuharu Arakawa,
  • Kengo Kinoshita,
  • Mika Sakurai-Yageta,
  • Gen Tamiya,
  • Hideki Ohmomo,
  • Atsushi Shimizu,
  • Tomonori Okamura,
  • Toru Takebayashi

摘要

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.