Type 2 Diabetes TCF7L2 Risk Genotypes Alter Birth Weight: A Study of 24,053 Individuals
2007; Elsevier BV; Volume: 80; Issue: 6 Linguagem: Inglês
10.1086/518517
ISSN1537-6605
AutoresRachel M. Freathy, Michael N. Weedon, Amanda J. Bennett, Elina Hyppönen, Caroline L. Relton, Beatrice Knight, Beverley M. Shields, Kirstie Parnell, Christopher J. Groves, Susan M. Ring, Marcus Pembrey, Yoav Ben‐Shlomo, David P. Strachan, Chris Power, Marjo‐Riitta Järvelin, Mark I. McCarthy, George Davey Smith, Andrew T. Hattersley, Timothy M. Frayling,
Tópico(s)Pancreatic function and diabetes
ResumoThe role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7–29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15–45 g) increase in offspring birth weight (P=2.8×10−5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9–48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ∼0.15 standard deviation; P=1×10−4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the −30G→A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62–172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2×10−7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes–susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation. The role of genes in normal birth-weight variation is poorly understood, and it has been suggested that the genetic component of fetal growth is small. Type 2 diabetes genes may influence birth weight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. We aimed to assess the role of the recently described type 2 diabetes gene TCF7L2 in birth weight. We genotyped the polymorphism rs7903146 in 15,709 individuals whose birth weight was available from six studies and in 8,344 mothers from three studies. Each fetal copy of the predisposing allele was associated with an 18-g (95% confidence interval [CI] 7–29 g) increase in birth weight (P=.001) and each maternal copy with a 30-g (95% CI 15–45 g) increase in offspring birth weight (P=2.8×10−5). Stratification by fetal genotype suggested that the association was driven by maternal genotype (31-g [95% CI 9–48 g] increase per allele; corrected P=.003). Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested the most likely mechanism is that the risk allele reduces maternal insulin secretion (disposition index reduced by ∼0.15 standard deviation; P=1×10−4), which results in increased maternal glycemia in pregnancy and hence increased offspring birth weight. We combined information with the other common variant known to alter fetal growth, the −30G→A polymorphism of glucokinase (rs1799884). The 4% of offspring born to mothers carrying three or four risk alleles were 119 g (95% CI 62–172 g) heavier than were the 32% born to mothers with none (for overall trend, P=2×10−7), comparable to the impact of maternal smoking during pregnancy. In conclusion, we have identified the first type 2 diabetes–susceptibility allele to be reproducibly associated with birth weight. Common gene variants can substantially influence normal birth-weight variation. The role of genes in normal variation in birth weight is poorly understood, and it has been suggested that the genetic component of fetal growth in the general population is small.1van Baal CG Boomsma DI Etiology of individual differences in birth weight of twins as a function of maternal smoking during pregnancy.Twin Res. 1998; 1: 123-130Crossref PubMed Scopus (38) Google Scholar, 2Baird J Osmond C MacGregor A Snieder H Hales CN Phillips DI Testing the fetal origins hypothesis in twins: the Birmingham twin study.Diabetologia. 2001; 44: 33-39Crossref PubMed Scopus (135) Google Scholar, 3Clausson B Lichtenstein P Cnattingius S Genetic influence on birthweight and gestational length determined by studies in offspring of twins.BJOG. 2000; 107: 375-381Crossref PubMed Scopus (260) Google Scholar, 4Magnus P Gjessing HK Skrondal A Skjaerven R Paternal contribution to birth weight.J Epidemiol Community Health. 2001; 55: 873-877Crossref PubMed Scopus (122) Google Scholar In contrast, the maternal intrauterine environment, including maternal glucose tolerance, BMI, and smoking, has a large impact on birth weight.5Farmer G Russell G Hamilton-Nicol DR Ogenbede HO Ross IS Pearson DW Thom H Kerridge DF Sutherland HW The influence of maternal glucose metabolism on fetal growth, development and morbidity in 917 singleton pregnancies in nondiabetic women.Diabetologia. 1988; 31: 134-141Crossref PubMed Scopus (55) Google Scholar, 6Breschi MC Seghieri G Bartolomei G Gironi A Baldi S Ferrannini E Relation of birthweight to maternal plasma glucose and insulin concentrations during normal pregnancy.Diabetologia. 1993; 36: 1315-1321Crossref PubMed Scopus (66) Google Scholar, 7Kieffer EC Tabaei BP Carman WJ Nolan GH Guzman JR Herman WH The influence of maternal weight and glucose tolerance on infant birthweight in Latino mother-infant pairs.Am J Public Health. 2006; 96: 2201-2208Crossref PubMed Scopus (28) Google Scholar, 8Lindley AA Gray RH Herman AA Becker S Maternal cigarette smoking during pregnancy and infant ponderal index at birth in the Swedish Medical Birth Register, 1991-1992.Am J Public Health. 2000; 90: 420-423Crossref PubMed Scopus (27) Google Scholar However, the importance of these environmental factors does not negate the role of common maternal or fetal gene variants as determinants of normal fetal growth. Family, twin, and linkage studies suggest a role for common genetic variants,1van Baal CG Boomsma DI Etiology of individual differences in birth weight of twins as a function of maternal smoking during pregnancy.Twin Res. 1998; 1: 123-130Crossref PubMed Scopus (38) Google Scholar, 3Clausson B Lichtenstein P Cnattingius S Genetic influence on birthweight and gestational length determined by studies in offspring of twins.BJOG. 2000; 107: 375-381Crossref PubMed Scopus (260) Google Scholar, 4Magnus P Gjessing HK Skrondal A Skjaerven R Paternal contribution to birth weight.J Epidemiol Community Health. 2001; 55: 873-877Crossref PubMed Scopus (122) Google Scholar, 9Lindsay RS Kobes S Knowler WC Hanson RL Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of birth weight.Hum Genet. 2002; 110: 503-509Crossref PubMed Scopus (42) Google Scholar, 10Arya R Demerath E Jenkinson CP Goring HH Puppala S Farook V Fowler S Schneider J Granato R Resendez RG et al.A quantitative trait locus (QTL) on chromosome 6q influences birth weight in two independent family studies.Hum Mol Genet. 2006; 15: 1569-1579Crossref PubMed Scopus (26) Google Scholar, 11Fradin D Heath S Lepercq J Lathrop M Bougneres P Identification of distinct quantitative trait loci affecting length or weight variability at birth in humans.J Clin Endocrinol Metab. 2006; 91: 4164-4170Crossref PubMed Scopus (12) Google Scholar but, to date, specific genetic loci remain largely unknown. Diabetes-susceptibility genes or genes that alter fasting glucose are good candidates for genes that influence birth weight, since they may impact insulin secretion or insulin action in nondiabetic individuals. Altered fetal insulin secretion would alter fetal growth and hence birth weight, since insulin is a key intrauterine growth factor. A diabetes-risk allele in the mother may alter fetal growth indirectly, by altering maternal glycemia during pregnancy and thereby influencing fetal insulin secretion. Alternatively, a diabetes-risk allele in the fetus may act directly on fetal insulin secretion. Reduced birth weight is associated with an increased risk of type 2 diabetes (MIM 125853) later in life,12Hales CN Barker DJ Clark PM Cox LJ Fall C Osmond C Winter PD Fetal and infant growth and impaired glucose tolerance at age 64.BMJ. 1991; 303: 1019-1022Crossref PubMed Scopus (2084) Google Scholar, 13Barker DJ Hales CN Fall CH Osmond C Phipps K Clark PM Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.Diabetologia. 1993; 36: 62-67Crossref PubMed Scopus (2048) Google Scholar and it has been proposed under the fetal insulin hypothesis that this association could have a genetic explanation.14Hattersley AT Tooke JE The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.Lancet. 1999; 353: 1789-1792Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar There is some evidence of this from population studies.15Lindsay RS Dabelea D Roumain J Hanson RL Bennett PH Knowler WC Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes.Diabetes. 2000; 49: 445-449Crossref PubMed Scopus (159) Google Scholar, 16Hypponen E Smith GD Power C Parental diabetes and birth weight of offspring: intergenerational cohort study.BMJ. 2003; 326: 19-20Crossref PubMed Scopus (73) Google Scholar, 17Davey Smith G Sterne JA Tynelius P Rasmussen F Birth characteristics of offspring and parental diabetes: evidence for the fetal insulin hypothesis.J Epidemiol Community Health. 2004; 58: 126-128Crossref PubMed Scopus (30) Google Scholar, 18Wannamethee SG Lawlor DA Whincup PH Walker M Ebrahim S Davey-Smith G Birthweight of offspring and paternal insulin resistance and paternal diabetes in late adulthood: cross sectional survey.Diabetologia. 2004; 47: 12-18Crossref PubMed Scopus (38) Google Scholar Direct evidence that birth weight is altered by fetal and maternal inheritance of diabetes-susceptibility genes is provided by several rare subtypes of diabetes. These include mutations in monogenic diabetes genes that reduce birth weight as a result of reduced fetal insulin secretion in utero19Hattersley AT Beards F Ballantyne E Appleton M Harvey R Ellard S Mutations in the glucokinase gene of the fetus result in reduced birth weight.Nat Genet. 1998; 19: 268-270Crossref PubMed Scopus (460) Google Scholar, 20Edghill EL Bingham C Slingerland AS Minton JA Noordam C Ellard S Hattersley AT Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1β in human pancreatic development.Diabet Med. 2006; 23: 1301-1306Crossref PubMed Scopus (105) Google Scholar, 21Wright NM Metzger DL Borowitz SM Clarke WL Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.Am J Dis Child. 1993; 147: 607-609Crossref PubMed Scopus (10) Google Scholar, 22Stoffers DA Zinkin NT Stanojevic V Clarke WL Habener JF Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.Nat Genet. 1997; 15: 106-110Crossref PubMed Scopus (870) Google Scholar, 23Gloyn AL Pearson ER Antcliff JF Proks P Bruining GJ Slingerland AS Howard N Srinivasan S Silva JM Molnes J et al.Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.N Engl J Med. 2004; 350: 1838-1849Crossref PubMed Scopus (907) Google Scholar, 24Slingerland AS Hattersley AT Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes.J Clin Endocrinol Metab. 2006; 91: 2782-2788Crossref PubMed Scopus (30) Google Scholar and mutations in other monogenic diabetes genes that increase birth weight as a result of increased fetal insulin secretion.25Pearson ER Boj SF Steele AM Barrett T Stals K Shield JP Ellard S Ferrer J Hattersley AT Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.PLOS Med. 2007; 4: e118Crossref PubMed Scopus (282) Google Scholar The observations in monogenic diabetes and the general population led to the hypothesis that inheritance of type 2 diabetes–susceptibility alleles by the fetus would reduce birth weight, whereas their inheritance by the mother would increase offspring birth weight. Some studies have suggested that inheritance by the fetus of polymorphisms associated with type 2 diabetes is associated with reduced birth weight,26Lindsay RS Hanson RL Wiedrich C Knowler WC Bennett PH Baier LJ The insulin gene variable number tandem repeat class I/III polymorphism is in linkage disequilibrium with birth weight but not type 2 diabetes in the Pima population.Diabetes. 2003; 52: 187-193Crossref PubMed Scopus (57) Google Scholar, 27Vaessen N Janssen JA Heutink P Hofman A Lamberts SW Oostra BA Pols HA van Duijn CM Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight.Lancet. 2002; 359: 1036-1037Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar but these results have not been replicated.28Day IN King TH Chen XH Voropanov AM Ye S Syddall HE Sayer AA Cooper C Barker DJ Phillips DI Insulin-like growth factor-I genotype and birthweight.Lancet. 2002; 360 (author reply 945-946): 945Abstract Full Text Full Text PDF PubMed Google Scholar, 29Frayling TM Hattersley AT McCarthy A Holly J Mitchell SM Gloyn AL Owen K Davies D Davey Smith G Ben-Shlomo Y A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in UK populations.Diabetes. 2002; 51: 2313-2316Crossref PubMed Scopus (122) Google Scholar, 30Mitchell SM Hattersley AT Knight B Turner T Metcalf BS Voss LD Davies D McCarthy A Wilkin TJ Davey Smith G et al.Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations.J Clin Endocrinol Metab. 2004; 89: 310-317Crossref PubMed Scopus (43) Google Scholar, 31Hansen SK Gjesing AP Rasmussen SK Glumer C Urhammer SA Andersen G Rose CS Drivsholm T Torekov SK Jensen DP et al.Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to type 2 diabetes mellitus and insulin release.Diabetologia. 2004; 47: 1079-1087Crossref PubMed Google Scholar, 32Bennett AJ Sovio U Ruokonen A Martikainen H Pouta A Taponen S Hartikainen AL King VJ Elliott P Jarvelin MR et al.Variation at the insulin gene VNTR (variable number tandem repeat) polymorphism and early growth: studies in a large Finnish birth cohort.Diabetes. 2004; 53: 2126-2131Crossref PubMed Scopus (39) Google Scholar A maternal copy of the A allele of the common glucokinase (GCK [MIM 138079]) promoter polymorphism (GCK-30; rs1799884), which is associated with raised fasting glucose at all ages in the general population (P=1×10−9), is also associated with a 32-g (95% CI 11–53 g) increase in offspring birth weight (P=.002). However, there is no evidence of an independent effect of fetal genotype.33Weedon MN Frayling TM Shields B Knight B Turner T Metcalf BS Voss L Wilkin TJ McCarthy A Ben-Shlomo Y et al.Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.Diabetes. 2005; 54: 576-581Crossref PubMed Scopus (91) Google Scholar, 34Weedon MN Clark VJ Qian Y Ben-Shlomo Y Timpson N Ebrahim S Lawlor DA Pembrey ME Ring S Wilkin TJ et al.A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.Am J Hum Genet. 2006; 79: 991-1001Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The gene encoding transcription factor 7–like 2 (TCF7L2 [MIM 602228]) is the most important type 2 diabetes susceptibility gene found to date.35Grant SF Thorleifsson G Reynisdottir I Benediktsson R Manolescu A Sainz J Helgason A Stefansson H Emilsson V Helgadottir A et al.Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat Genet. 2006; 38: 320-323Crossref PubMed Scopus (1552) Google Scholar Since its discovery, the association has been replicated in subjects of U.K., Amish, Finnish, French, U.S., Polish, Scandinavian, Dutch, Indian, and West African origin.36Groves CJ Zeggini E Minton J Frayling TM Weedon MN Rayner NW Hitman GA Walker M Wiltshire S Hattersley AT et al.Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.Diabetes. 2006; 55: 2640-2644Crossref PubMed Scopus (228) Google Scholar, 37Damcott CM Pollin TI Reinhart LJ Ott SH Shen H Silver KD Mitchell BD Shuldiner AR Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.Diabetes. 2006; 55: 2654-2659Crossref PubMed Scopus (247) Google Scholar, 38Scott LJ Bonnycastle LL Willer CJ Sprau AG Jackson AU Narisu N Duren WL Chines PS Stringham HM Erdos MR et al.Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample.Diabetes. 2006; 55: 2649-2653Crossref PubMed Scopus (202) Google Scholar, 39Cauchi S Meyre D Dina C Choquet H Samson C Gallina S Balkau B Charpentier G Pattou F Stetsyuk V et al.Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.Diabetes. 2006; 55: 2903-2908Crossref PubMed Scopus (263) Google Scholar, 40Florez JC Jablonski KA Bayley N Pollin TI de Bakker PI Shuldiner AR Knowler WC Nathan DM Altshuler D TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program.N Engl J Med. 2006; 355: 241-250Crossref PubMed Scopus (651) Google Scholar, 41Zhang C Qi L Hunter DJ Meigs JB Manson JE van Dam RM Hu FB Variant of transcription factor 7-like 2 (TCF7L2) gene and the risk of type 2 diabetes in large cohorts of U.S. women and men.Diabetes. 2006; 55: 2645-2648Crossref PubMed Scopus (179) Google Scholar, 42Saxena R Gianniny L Burtt NP Lyssenko V Giuducci C Sjogren M Florez JC Almgren P Isomaa B Orho-Melander M et al.Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals.Diabetes. 2006; 55: 2890-2895Crossref PubMed Scopus (301) Google Scholar, 43van Vliet-Ostaptchouk JV Shiri-Sverdlov R Zhernakova A Strengman E van Haeften TW Hofker MH Wijmenga C Association of variants of transcription factor 7-like 2 (TCF7L2) with susceptibility to type 2 diabetes in the Dutch Breda cohort.Diabetologia. 2007; 50: 59-62Crossref PubMed Scopus (91) Google Scholar, 44Chandak GR Janipalli CS Bhaskar S Kulkarni SR Mohankrishna P Hattersley AT Frayling TM Yajnik CS Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population.Diabetologia. 2007; 50: 63-67Crossref PubMed Scopus (198) Google Scholar, 45Helgason A Palsson S Thorleifsson G Grant SF Emilsson V Gunnarsdottir S Adeyemo A Chen Y Chen G Reynisdottir I et al.Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.Nat Genet. 2007; 39: 218-225Crossref PubMed Scopus (358) Google Scholar In the U.K. population, the allelic odds ratio for rs7903146 (risk-allele frequency ∼30%) is 1.36 (95% CI 1.24–1.48; P=1.3×10−11), and individuals carrying two risk (T) alleles are at nearly twice the risk of type 2 diabetes as are those with none.36Groves CJ Zeggini E Minton J Frayling TM Weedon MN Rayner NW Hitman GA Walker M Wiltshire S Hattersley AT et al.Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.Diabetes. 2006; 55: 2640-2644Crossref PubMed Scopus (228) Google Scholar Studies of nondiabetic subjects indicate that TCF7L2 diabetes-risk genotypes alter insulin secretion.37Damcott CM Pollin TI Reinhart LJ Ott SH Shen H Silver KD Mitchell BD Shuldiner AR Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance.Diabetes. 2006; 55: 2654-2659Crossref PubMed Scopus (247) Google Scholar, 42Saxena R Gianniny L Burtt NP Lyssenko V Giuducci C Sjogren M Florez JC Almgren P Isomaa B Orho-Melander M et al.Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals.Diabetes. 2006; 55: 2890-2895Crossref PubMed Scopus (301) Google Scholar, 46Munoz J Lok KH Gower BA Fernandez JR Hunter GR Lara-Castro C De Luca M Garvey WT Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women.Diabetes. 2006; 55: 3630-3634Crossref PubMed Scopus (76) Google Scholar The impact of this polymorphism on birth weight has not been studied. In the present study, we hypothesized that fetal TCF7L2 type 2 diabetes–predisposing genotypes at rs7903146 and rs12255372 would be associated with reduced birth weight and that maternal genotypes would be associated with increased offspring birth weight through elevated maternal glucose. We investigated this hypothesis in >24,000 individuals from six population-based studies. In addition, we explored the role of these variants in diabetes-related intermediate traits, including beta-cell function, in >10,000 young (median age ≤45 years), nondiabetic individuals from five studies. To assess the association of fetal TCF7L2 genotypes with birth weight, we used subjects from six studies (table 1). All subjects were born at 36 full wk gestation or later and were of white European origin, either from the United Kingdom (Barry Caerphilly Growth Study [BCG],29Frayling TM Hattersley AT McCarthy A Holly J Mitchell SM Gloyn AL Owen K Davies D Davey Smith G Ben-Shlomo Y A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in UK populations.Diabetes. 2002; 51: 2313-2316Crossref PubMed Scopus (122) Google Scholar Exeter Family Study of Childhood Health [EFSOCH],47Knight B Shields BM Hattersley AT The Exeter Family Study of Childhood Health (EFSOCH): study protocol and methodology.Paediatr Perinat Epidemiol. 2006; 20: 172-179Crossref PubMed Scopus (42) Google Scholar North Cumbria Community Genetics Project [NCCGP],48Chase DS Tawn EJ Parker L Jonas P Parker CO Burn J The North Cumbria Community Genetics Project.J Med Genet. 1998; 35: 413-416Crossref PubMed Scopus (40) Google Scholar British 1958 Birth Cohort [1958BC],36Groves CJ Zeggini E Minton J Frayling TM Weedon MN Rayner NW Hitman GA Walker M Wiltshire S Hattersley AT et al.Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk.Diabetes. 2006; 55: 2640-2644Crossref PubMed Scopus (228) Google Scholar, 49Power C Elliott J Cohort profile: 1958 British Birth Cohort (National Child Development Study).Int J Epidemiol. 2006; 35: 34-41Crossref PubMed Scopus (627) Google Scholar and Avon Longitudinal Study of Parents and Children [ALSPAC]50Golding J Pembrey M Jones R ALSPAC—the Avon Longitudinal Study of Parents and Children. I. Study methodology.Paediatr Perinat Epidemiol. 2001; 15: 74-87Crossref PubMed Scopus (1031) Google Scholar) or Finland (Northern Finland 1966 Birth Cohort [NFBC1966]).51Rantakallio P The longitudinal study of the northern Finland birth cohort of 1966.Paediatr Perinat Epidemiol. 1988; 2: 59-88Crossref PubMed Scopus (295) Google Scholar, 52Jarvelin MR Sovio U King V Lauren L Xu B McCarthy MI Hartikainen AL Laitinen J Zitting P Rantakallio P et al.Early life factors and blood pressure at age 31 years in the 1966 Northern Finland Birth Cohort.Hypertension. 2004; 44: 838-846Crossref PubMed Scopus (198) Google Scholar, 53Bennett A Sovio U Ruokonen A Martikainen H Pouta A Taponen S Hartikainen AL Franks S Peltonen L Elliott P et al.No association between insulin gene variation and adult metabolic phenotypes in a large Finnish birth cohort.Diabetologia. 2005; 48: 886-891Crossref PubMed Scopus (17) Google Scholar These studies have been described in depth elsewhere, but brief details are as follows. BCG is a longitudinal study of individuals born between 1972 and 1974 whose growth was monitored from birth to age 5 years. Data for analysis of the association of rs7903146 with birth weight were available for 571 subjects. EFSOCH is a prospective study of children, born between 2000 and 2004, and their parents from a geographically defined region of Exeter, United Kingdom. Data for 792 EFSOCH babies were available for the present analysis. Maternal fasting glucose, assessed at 26–28 wk gestation, was available for these subjects. Maternal smoking status was also assessed at that time. NCCGP is a community-based DNA-banking project. Data were available for 1,096 babies born between April 1999 and March 2002. Maternal smoking status was assessed during the first 12 wk of pregnancy. The 1958BC is a national cohort of U.K. subjects born during the same week in March 1958. The 1,779 subjects included in the present analysis are from the first group of subjects from whom DNA was extracted during 2003–2005. Information about smoking during pregnancy was reported by the mothers after the birth of the child and was coded as smoking continuing after the 4th mo of pregnancy ("yes/no"). ALSPAC is a prospective study, which recruited pregnant women from Bristol, United Kingdom, with expected delivery dates between April 1991 and December 1992. We were able to include 6,893 of the ALSPAC children in the present analysis. Maternal smoking status was assessed during the first 12 wk of gestation. NFBC1966 is a study of offspring born in the two northernmost provinces of Finland to mothers with expected dates of delivery in 1966. The 4,578 subjects included in the present analysis are from a subset of individuals who had anthropometric data taken and DNA extracted at age 31 years. Maternal smoking status was assessed throughout the pregnancy and was classified as "yes/no" after the 8th gestational wk.Table 1Clinical Characteristics of Subjects Included in the Analysis of the TCF7L2 rs7903146 Genotype with Birth WeightCharacteristics by StudyCharacteristicBCGEFSOCHNCCGP1958BCNFBC1966ALSPACNaIncludes white, singleton individuals, genotyped for rs7903146, with birth weight available, born at minimum gestation of 36 wk. (% male)571 (52.2)792 (52.9)1,096 (49.9)1,779 (49.5)4,578 (47.7)6,893 (51.2)Mean (SD) birth weight, in g3,387 (496)3,504 (478)3,441 (485)3,351 (494)3,536 (490)3,489 (474)Median (IQR) gestation, in wk40.0 (39.0–41.0)40.3 (39.3–41.1)40.0 (39.0-41.0)40.3 (39.4–41.3)40.0 (38.0–42.0)40.0 (39.0–41.0)Median (IQR) maternal age, in yearsNA31.0 (27.0–34.0)28.8 (24.0–32.8)27.0 (23.0–31.0)27.2 (17.4–36.9)29.0 (26.0–32.0)Median (IQR) maternal prepregnancy BMIbCalculated as weight in kilograms divided by the square of height in meters.NA23.0 (21.1–25.7)NA22.1 (20.4–24.5)22.7 (18.9–26.5)22.2 (20.5–24.4)Primiparous births (%)NA55.366.235.230.643.3Maternal smoking during pregnancy (%)NA13.826.032.913.419.9Note.—The clinical characteristics of offspring with maternal rs7903146 genotype data available (917, 1,133, and 6,294 individuals from EFSOCH, NCCGP, and ALSPAC, respectively) were very similar (data not shown). In some cases, offspring birth weight and maternal genotype were available, whereas offspring genotype was unavailable. Therefore, for EFSOCH and NCCGP, the number of subjects in the maternal genotype analysis was larger than that included in the fetal genotype analysis. NA=not available; IQR=interquartile range.a Includes white, singleton individuals, genotyped for rs7903146, with birth weight available, born at minimum gestation of 36 wk.b Calculated as weight in kilograms divided by the square of height in meters. Open table in a new tab Note.— The clinical characteristics of offspring with maternal rs7903146 genotype data available (917, 1,133, and 6,294 individuals from EFSOCH, NCCGP, and ALSPAC, respectively) were very similar (data not shown). In some cases, offspring birth weight and maternal genotype were available, whereas offspring genotype was unavailable. Therefore, for EFSOCH and NCCGP, the number of subjects in the maternal genotype analysis was larger than that included in the fetal genotype analysis. NA=not available; IQR=interquartile range. Only singleton pregnancies were included in the analyses. In all studies, birth weight was obtained from hospital records, and gestation was inferred from the last menstrual period or ultrasound scan. In most studies, data were available on parity (dichotomized as first child or subsequent), maternal prepregnancy BMI, and maternal smoking status (smoking or nonsmoking during pregnancy). All subjects involved gave their informed consent, and ethical approval was obtained from the local institutional review board for each study. To assess the association of maternal TCF7L2 genotype
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