Evidence of genetic regulation of fetal longitudinal growth.

BACKGROUND: Genetic as well as environmental factors are important determinants of fetal growth but there have been few studies of the influence of paternal factors on fetal growth. AIM: To study the influence of paternal anthropometry on detailed measurements of offspring at birth. DESIGN: A prospective cohort study involving biochemistry, and anthropometry, of mothers and fathers at 28 weeks gestation, and detailed anthropometry of children within 24 h of birth. SUBJECTS: 567 White Caucasian singleton, non-diabetic, full term pregnancies recruited from central Exeter, UK. RESULTS: Paternal height, but not paternal BMI, was correlated with birth weight (r = 0.19) and with birth length (r = 0.33). This was independent of potential confounders and maternal height. All measurements of fetal skeletal growth including crown-rump, knee-heel and head circumference were associated with paternal height. Maternal height showed similar correlations with birth weight (r = 0.18) and birth length (r = 0.26). Maternal BMI was correlated with birth weight (r = 0.27) and birth length (r = 0.15). In a multifactorial analysis 38% of the variance in fetal height could be explained by gestation, sex, paternal height, maternal height, maternal glucose, maternal BMI, parity and maternal smoking. CONCLUSION: Paternal height has an independent influence on size at birth. This predominantly influences length and skeletal growth of the baby. In contrast to maternal obesity the degree of paternal obesity does not influence birth weight. This work suggests that there is genetic regulation of skeletal growth while the maternal environment predominantly alters the adiposity of the fetus.

Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population.

OBJECTIVE: To assess the association of polymorphisms in the aromatase gene (CYP19) and on the Y-chromosome, with adult height and insulin resistance in a UK Caucasian population, after a recent report indicated these variants explain 4 cm of adult male height variation. PATIENTS AND DESIGN: We performed an association study using 917 healthy UK Caucasian subjects from the Exeter Family Study, an ongoing consecutive-birth cohort. Our study had > 85% (95% for the CYP19 variant; 85% for the Y variant) power to detect the association suggested by the previous study. MEASUREMENTS: Subjects'CYP19 genotype were determined using tetra-primer PCR, and the Y-chromosome variant genotype was identified using a restriction fragment length polymorphism (RFLP) method. Trained research nurses were responsible for measurement of height. Fasting insulin concentration was determined by an immunoenzymometric assay. RESULTS: We did not find any evidence for an effect of the CYP19 polymorphism or Y-RFLP on adult height (P > 0.83 for both variants). In addition, there was no evidence for an effect on insulin resistance in a subset of 416 subjects (P > 0.46). CONCLUSION: We have not confirmed the initial observation in a larger replication cohort. Our results highlight the importance of replicating initial results from genetic association studies.

Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.