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Other Original Articles: Simon M. S. Mitchell, Andrew T. Hattersley, Beatrice Knight, Tina Turner, Bradley S. Metcalf, Linda D. Voss, David Davies, Anne McCarthy, Terence J. Wilkin, George Davey Smith, Yoav Ben-Shlomo, and Timothy M. Frayling 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: 310-317 [Abstract] [Full text] [PDF]

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Letter to the Editor

Stephen W. D'Souza, G. Malcolm Taylor   (21 October 2005)

Letter to the Editor 21 October 2005
Stephen W. D'Souza, Division of Human Development University of Manchester, G. Malcolm Taylor Send letter to journal: Re: Letter to the Editor sdesouza{at}man.ac.uk Stephen W. D'Souza, et al.	Dunger and colleagues (1) suggest that birth weight and head circumference are higher in European (i.e., white UK) newborns homozygous for the insulin (INS) VNTR class III genotype compared to those with I/I or I/III genotypes. They suggest that this is due to an effect of insulin gene expression or a neighboring gene, such as IGF2, on fetal growth. However, Mitchell et al. (2) were unable to find evidence of an association between increased birth weight with INS class III homozygosity even though they took steps to ensure that their study design and analysiswere similar to Dunger et al (1). This suggests that an unrecognized confounder may explain these contrasting findings. Since maternal smoking consistently causes lower birth weight (3, 4), we advance the hypothesis that maternal smoking has a selective effect on fetal growth, depending on the INS genotype of the fetus. We analyzed birth weights in relation to INS genotypes (5) of a cross-sectional series of term newborns (n=342) of non-smoking and smoking mothers. Mothers of 208 newborns had not smoked, and mothers of 134 newborns (39%) had smoked during pregnancy. We stratified the newborns by INS genotype and compared mean birth weights (MBW), placental weights and MBW:placental weight ratios in newborns of smoking and non-smoking mothers. Maternal age, parity and social class were similar in newborns with INS class I/I, I/III and III/III genotypes, and there was no difference in INS genotype frequency in newborns of smoking (class I/I, n = 66 (49%); class I/III, n = 54 (40%); class III/III, n = 14 (11%) and non-smoking mothers (class I/I, n = 100 (48%); class I/III, n = 89 (43%); class III/III, n = 19 (9%)). However, comparison of MBW (±SD) of newborns classified by INS genotype, where mothers had or had not smoked during pregnancy, showed significant reductions in MBW of newborns with I/I (non-smoker 3504 ± 46 gm, smoker 3236 ± 57 gm, P = 0.0002, Student’s t test) or I/III genotypes (non-smoker 3480 ± 49 gm, smoker 3198 ± 64 gm, P = 0.0009) due to maternal smoking, but no significant reduction in newborns homozygous for class III genotype (non-smoker 3530 ± 107 gm, smoker 3380 ± 125 gm). There was no significant change in mean (±SD) placental weight due to INS genotype in newborns of smoking mothers (class I/I, non-smokers 642 ± 12 gm, smokers 638 ± 15 gm; class I/III, non-smoker 645 ± 13gm, smoker 626 ± 17 gm; class III/III, non-smoker 663 ± 27 gm, smoker 649 ± 32 gm) and the MBW/placental weight ratio was not significantly reduced in newborns homozygous for III genotype (class I/I, non-smoker 5.6 ± 0.1, smoker 5.2 ± 0.1, P = 0.009; class I/III, non-smoker 5.5 ± 0.1, smoker 5.2 ± 0.1, P = 0.06; class III/III, non-smoker 5.4 ± 0.2, smoker 5.2 ± 0.2, P = 0.54). These preliminary results lead us to suggest that a fetus that is INS class III homozygous may be to some extent “protected” from the growth-restricting effect of maternal smoking, whereas newborns with I/I or I/III genotypes are less so. Our results are not inconsistent with the thrifty genotype concept since maternal smoking can be regarded as an adverse environmental exposure (4) that is countered by a “protective” INS genotype. References 1. Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST, Todd JA 1998 Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 19: 98-100. 2. Mitchell SMS, Hattersley AT, Knight B, Turner T, Metcalf BS, Voss LD, Davies D, McCarthy A, Wilkin TJ, Smith GD, Ben-Shlomo Y, Frayling TM 2004 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 89: 310-317. 3. D’Souza SW, Black P, Richards B 1981 Smoking in pregnancy: associations with skin fold thickness, maternal weight gain and fetal size at birth. BMJ 282: 1661-1663. 4. Shiverick KT, Salafia C 1999 Cigarette smoking and pregnancy l: ovarian, uterine and placental effects. Placenta 20: 265-272. 5. Bell GI, Selby MJ, Rutter WJ 1982 The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295: 31-35.