title: Insulin family polymorphisms in pregnancies complicated by small for gestational age infants.
abstract: Being born small for gestational age (SGA) increases the risk for adverse perinatal outcomes and later life vascular and metabolic disorders. The insulin family plays a vital role in intrauterine growth. We investigated the association of functional SNPs in insulin (INS), insulin receptor (INSR) and insulin receptor substrate 2 (IRS2) with small for gestational age (SGA) pregnancies, uterine and umbilical artery Doppler and plasma insulin level. We conducted a nested case-control study of 1401 nulliparous Caucasian women, their partners and babies (216 SGA and 1185 uncomplicated). SGA was defined as a birthweight less than the 10th customized birthweight percentile adjusted for maternal height, weight, parity, ethnicity, gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 ± 1 week gestation. The SNPs in the parent infant trios were genotyped using Sequenom MassARRAY. Plasma insulin was measured by double antibody RIA in 188 healthy non-pregnant adults to assess correlations between SNP genotypes and circulating insulin. Paternal [odds ratio (OR) (95% CI) = 2.2 (1.3-3.9), P = 0.005] and infant [OR (95% CI) = 3.3 (1.7-6.2), P = 0.0001] INSR rs2059806 AA genotype was associated with SGA. Infant INSR rs2059806 A allele was associated with abnormal umbilical artery Doppler [OR (95% CI) = 1.3(1.0-1.7), P = 0.04]. INSR rs2059806 AA homozygous individuals had lower plasma insulin compared with heterozygotes (P = 0.03) and GG homozygotes (P = 0.03). The INSR rs2059806 SNP previously associated with adult vascular and metabolic diseases is also associated with SGA pregnancies. This polymorphism may associate with the risk of vascular and metabolic disorders across the life course.
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Prabha H
authors.initials: PH
authors.lastname: Andraweera
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Gatford
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia Women's and Children's Division, Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia.
authors.forename: Gustaaf A
authors.initials: GA
authors.lastname: Dekker
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Shalem
authors.initials: S
authors.lastname: Leemaqz
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Darryl
authors.initials: D
authors.lastname: Russell
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
authors.forename: Lesley
authors.initials: L
authors.lastname: McCowan
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, Australia claire.roberts@adelaide.edu.au.
authors.forename: Claire T
authors.initials: CT
authors.lastname: Roberts
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D001724:Birth Weight / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005865:Gestational Age; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007328:Insulin / Q000097:blood / Q000235:genetics; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D009520:New Zealand; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D011446:Prospective Studies; D011972:Receptor, Insulin / Q000235:genetics*; D012039:Regional Blood Flow; D012307:Risk Factors; D013021:South Australia; D018608:Ultrasonography, Doppler; D014469:Umbilical Arteries / Q000000981:diagnostic imaging; D055988:Uterine Artery / Q000000981:diagnostic imaging; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C435941:INSR protein, human; D011972:Receptor, Insulin
keywords: SGA; SNP; insulin receptor; polymorphism; rs2059806