Human Genetics

, Volume 133, Issue 8, pp 1049–1057 | Cite as

Metabolic heritability at birth: implications for chronic disease research

  • Kelli K. Ryckman
  • Caitlin J. Smith
  • Laura L. Jelliffe-Pawlowski
  • Allison M. Momany
  • Stanton L. Berberich
  • Jeffrey C. Murray
Original Investigation

Abstract

Recent genome-wide association studies of the adult human metabolome have identified genetic variants associated with relative levels of several acylcarnitines, which are important clinical correlates for chronic conditions such as type 2 diabetes and obesity. We have previously shown that these same metabolite levels are highly heritable at birth; however, no studies to our knowledge have examined genetic associations with these metabolites measured at birth. Here, we examine, in 743 newborns, 58 single nucleotide polymorphisms (SNPs) in 11 candidate genes previously associated with differing relative levels of short-chain acylcarnitines in adults. Six SNPs (rs2066938, rs3916, rs3794215, rs555404, rs558314, rs1799958) in the short-chain acyl-CoA dehydrogenase gene (ACADS) were associated with neonatal C4 levels. Most significant was the G allele of rs2066938, which was associated with significantly higher levels of C4 (P = 1.5 × 10−29). This SNP explains 25 % of the variation in neonatal C4 levels, which is similar to the variation previously reported in adult C4 levels. There were also significant (P < 1 × 10−4) associations between neonatal levels of C5-OH and SNPs in the solute carrier family 22 genes (SLC22A4 and SLC22A5) and the 3-methylcrotonyl-CoA carboxylase 1 gene (MCCC1). We have replicated, in newborns, SNP associations between metabolic traits and the ACADS and SLC22A4 genes observed in adults. This research has important implications not only for the identification of rare inborn errors of metabolism but also for personalized medicine and early detection of later life risks for chronic conditions.

Supplementary material

439_2014_1450_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)

References

  1. Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE et al (2009) Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African–American women. J Nutr 139(6):1073–1081PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alex S, Lange K, Amolo T, Grinstead JS, Haakonsson AK, Szalowska E et al (2013) Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor gamma. Mol Cell Biol 33(7):1303–1316PubMedCentralPubMedCrossRefGoogle Scholar
  3. Alul FY, Cook DE, Shchelochkov OA, Fleener LG, Berberich SL, Murray JC et al (2013) The heritability of metabolic profiles in newborn twins. Heredity 110(3):253–258PubMedCentralPubMedCrossRefGoogle Scholar
  4. Atzori L, Antonucci R, Barberini L, Locci E, Marincola FC, Scano P et al (2011) 1H NMR-based metabolomic analysis of urine from preterm and term neonates. Front Biosci 3:1005–1012Google Scholar
  5. Bene J, Komlosi K, Magyari L, Talian G, Horvath K, Gasztonyi B et al (2007) Plasma carnitine ester profiles in Crohn’s disease patients characterized for SLC22A4 C1672T and SLC22A5 G-207C genotypes. Br J Nutr 98(2):345–350PubMedCrossRefGoogle Scholar
  6. Bene J, Marton M, Mohas M, Bagosi Z, Bujtor Z, Oroszlan T et al (2013) Similarities in serum acylcarnitine patterns in type 1 and type 2 diabetes mellitus and in metabolic syndrome. Ann Nutr Metab 62(1):80–85PubMedCrossRefGoogle Scholar
  7. Clark RH, Chace DH, Spitzer AR, Pediatrix Amino Acid Study G (2007) Effects of two different doses of amino acid supplementation on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care unit: a randomized, controlled trial. Pediatrics 120(6):1286–1296PubMedCrossRefGoogle Scholar
  8. Corydon MJ, Vockley J, Rinaldo P, Rhead WJ, Kjeldsen M, Winter V et al (2001) Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 49(1):18–23PubMedCrossRefGoogle Scholar
  9. De Preter V, Arijs I, Windey K, Vanhove W, Vermeire S, Schuit F et al (2012) Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway. Inflamm Bowel Dis 18(6):1127–1136PubMedCrossRefGoogle Scholar
  10. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D (2000a) Fetal and childhood growth and hypertension in adult life. Hypertension 36(5):790–794PubMedCrossRefGoogle Scholar
  11. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ (2000b) Early growth, adult income, and risk of stroke. Stroke 31(4):869–874PubMedCrossRefGoogle Scholar
  12. Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ et al (2010) alpha-Hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS One 5(5):e10883PubMedCentralPubMedCrossRefGoogle Scholar
  13. Gieger C, Geistlinger L, Altmaier E, Hrabe de Angelis M, Kronenberg F, Meitinger T et al (2008) Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 4(11):e1000282PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gregersen N, Andresen BS, Corydon MJ, Corydon TJ, Olsen RK, Bolund L et al (2001) Mutation analysis in mitochondrial fatty acid oxidation defects: exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat 18(3):169–189PubMedCrossRefGoogle Scholar
  15. Hornbak M, Banasik K, Justesen JM, Krarup NT, Sandholt CH, Andersson A et al (2011) The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load. BMC Med Genet 12:4PubMedCentralPubMedCrossRefGoogle Scholar
  16. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C et al (2010) A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42(2):137–141PubMedCentralPubMedCrossRefGoogle Scholar
  17. Jung CW, Lee BH, Kim JH, Kim GH, Lee J, Choi JH et al (2012) Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations. J Hum Genet 57(1):62–64PubMedCrossRefGoogle Scholar
  18. Kelleher AS, Clark RH, Steinbach M, Chace DH, Spitzer AR, Pediatrix Amino-Acid Study G (2008) The influence of amino-acid supplementation, gestational age and time on thyroxine levels in premature neonates. J Perinatol 28(4):270–274PubMedCrossRefGoogle Scholar
  19. Kelley DE, Goodpaster B, Wing RR, Simoneau JA (1999) Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol 277(6 Pt 1):E1130–E1141PubMedGoogle Scholar
  20. la Marca G, Malvagia S, Toni S, Piccini B, Di Ciommo V, Bottazzo GF (2013) Children who develop type 1 diabetes early in life show low levels of carnitine and amino acids at birth: does this finding shed light on the etiopathogenesis of the disease? Nutr Diabetes 3:e94PubMedCentralPubMedCrossRefGoogle Scholar
  21. Lapillonne A, Griffin IJ (2013) Feeding preterm infants today for later metabolic and cardiovascular outcomes. J Pediatr 162(3 Suppl):S7–S16PubMedCrossRefGoogle Scholar
  22. Lewandowski AJ, Bradlow WM, Augustine D, Davis EF, Francis J, Singhal A et al (2013) Right ventricular systolic dysfunction in young adults born preterm. Circulation 128(7):713–720PubMedCrossRefGoogle Scholar
  23. Lowe WL Jr, Bain JR (2013) “Prediction is very hard, especially about the future”: new biomarkers for type 2 diabetes? Diabetes 62(5):1384–1385PubMedCentralPubMedCrossRefGoogle Scholar
  24. Mathai S, Derraik JG, Cutfield WS, Dalziel SR, Harding JE, Biggs J et al (2013) Increased adiposity in adults born preterm and their children. PLoS One 8(11):e81840PubMedCentralPubMedCrossRefGoogle Scholar
  25. Nagan N, Kruckeberg KE, Tauscher AL, Bailey KS, Rinaldo P, Matern D (2003) The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C(4)-acylcarnitine concentration in newborn blood spots. Mol Genet Metab 78(4):239–246PubMedCrossRefGoogle Scholar
  26. Parkinson JR, Hyde MJ, Gale C, Santhakumaran S, Modi N (2013) Preterm birth and the metabolic syndrome in adult life: a systematic review and meta-analysis. Pediatrics 131(4):e1240–e1263PubMedCrossRefGoogle Scholar
  27. Pasquali M, Monsen G, Richardson L, Alston M, Longo N (2006) Biochemical findings in common inborn errors of metabolism. Am J Med Genet C Semin Med Genet 142C(2):64–76PubMedCrossRefGoogle Scholar
  28. Pedersen CB, Bischoff C, Christensen E, Simonsen H, Lund AM, Young SP et al (2006) Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 60(3):315–320PubMedCrossRefGoogle Scholar
  29. Ryckman KK, Berberich SL, Shchelochkov OA, Cook DE, Murray JC (2013) Clinical and environmental influences on metabolic biomarkers collected for newborn screening. Clin Biochem 46(1–2):133–138PubMedCentralPubMedCrossRefGoogle Scholar
  30. Schooneman MG, Vaz FM, Houten SM, Soeters MR (2013) Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62(1):1–8PubMedCentralPubMedCrossRefGoogle Scholar
  31. Shah SH, Hauser ER, Bain JR, Muehlbauer MJ, Haynes C, Stevens RD et al (2009) High heritability of metabolomic profiles in families burdened with premature cardiovascular disease. Mol Syst Biol 5:258PubMedCentralPubMedCrossRefGoogle Scholar
  32. Shibbani K, Fahed A, Al-Shaar L, Arabi M, Nemer G, Bitar F et al (2013) Primary carnitine deficiency: novel mutations and insights into the cardiac phenotype. Clin Genet 85(2):127–137CrossRefGoogle Scholar
  33. Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B et al (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature 477(7362):54–60PubMedCrossRefGoogle Scholar
  34. Yeh CS, Wang JY, Cheng TL, Juan CH, Wu CH, Lin SR (2006) Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by microarray-bioinformatics analysis. Cancer Lett 233(2):297–308PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kelli K. Ryckman
    • 1
  • Caitlin J. Smith
    • 1
  • Laura L. Jelliffe-Pawlowski
    • 2
    • 3
  • Allison M. Momany
    • 4
  • Stanton L. Berberich
    • 5
  • Jeffrey C. Murray
    • 4
  1. 1.Department of EpidemiologyUniversity of IowaIowa CityUSA
  2. 2.Genetic Disease Screening ProgramCalifornia Department of Public HealthSacramentoUSA
  3. 3.Division of Preventive Medicine and Public Health, Department of Epidemiology and BiostatisticsUniversity of California San Francisco School of MedicineSan FranciscoUSA
  4. 4.Department of PediatricsUniversity of IowaIowa CityUSA
  5. 5.State Hygienic LaboratoryUniversity of IowaIowa CityUSA

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