title: Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis.
abstract: BACKGROUND
  Disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established.
  
  
  METHODS
  We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C→T) by instrumental variable and triangulation analysis, separately and using meta-analysis.
  
  
  RESULTS
  Median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871 g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration-PMNS: -22 g/SD [95% confidence interval (CI): (-50, 5), adjusted for gestational age and offspring gender]; Parthenon: -57 g (-92, -21); meta-analysis: -40 g (-62, -17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: -46 g (-102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: -78 g (-170, 15); meta-analysis: -61 g (-111, -10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight.
  
  
  CONCLUSIONS
  Our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth.
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK diabetes@kemdiabetes.org chandakgrc@ccmb.res.in.
authors: Chittaranjan S
authors: CS
authors: Yajnik
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK diabetes@kemdiabetes.org chandakgrc@ccmb.res.in.
authors: Giriraj R
authors: GR
authors: Chandak
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Charudatta
authors: C
authors: Joglekar
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Prachi
authors: P
authors: Katre
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Dattatray S
authors: DS
authors: Bhat
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Suraj N
authors: SN
authors: Singh
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Charles S
authors: CS
authors: Janipalli
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Helga
authors: H
authors: Refsum
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Ghattu
authors: G
authors: Krishnaveni
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Sargoor
authors: S
authors: Veena
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Clive
authors: C
authors: Osmond
authors: Diabetes Unit, King Edward Memorial Hospital and Research Centre, Pune, India, CSIR-Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India, Adjunct Group Leader, Adjunct Group, Genome Institute of Singapore, Singapore, Persistent Systems Ltd, Pune, India, Department of Nutrition, University of Oslo, Oslo, Norway, Department of Pharmacology, University of Oxford, Oxford, UK, Epidemiology Research Unit, CSI Holdsworth Memorial Hospital, Mysore, India and MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors: Caroline H D
authors: CH
authors: Fall
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001724:Birth Weight; D015331:Cohort Studies; D005260:Female; D047109:Fetal Development; D005492:Folic Acid / Q000097:blood / Q000235:genetics; D005838:Genotype; D005865:Gestational Age; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D006801:Humans; D007194:India; D057182:Mendelian Randomization Analysis; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014805:Vitamin B 12 / Q000097:blood / Q000235:genetics
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12
keywords: MTHFR variant; Maternal homocysteine; Mendelian randomization analysis; causality; folate; offspring birthweight; vitamin B12