Absence of birth-weight lowering effect of ADCY5 and Near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians

Background: A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort.Methodology/Principal Findings: Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the ‘birth weight-lowering’ variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the ‘birth weight-lowering’ variant of ADCY5 was associated with modest increase in fasting glucose (? 0.041, p = 0.027), 2-hours glucose (? 0.127, p = 0.019), and reduced insulinogenic index (? -0.106, p = 0.050) and 2-hour insulin (? -0.058, p = 0.010).Conclusions: The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the ‘birth-weight-lowering’ variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.<br/

Neonatal anthropometry: the thin-fat Indian baby. The Pune Maternal Nutrition Study

OBJECTIVE: To examine body size and fat measurements of babies born in rural India and compare them with white Caucasian babies born in an industrialised country.DESIGN: Community-based observational study in rural India, and comparison with data from an earlier study in the UK, measured using similar methods.SUBJECTS: A total of 631 term babies born in six rural villages, near the city of Pune, Maharashtra, India, and 338 term babies born in the Princess Anne Hospital, Southampton, UK.MEASUREMENTS: Maternal weight and height, and neonatal weight, length, head, mid-upper-arm and abdominal circumferences, subscapular and triceps skinfold thicknesses, and placental weight.RESULTS: The Indian mothers were younger, lighter, shorter and had a lower mean body mass index (BMI) (mean age, weight, height and BMI: 21.4 y, 44.6 kg, 1.52 m, and 18.2 kg/m2) than Southampton mothers (26.8 y, 63.6 kg, 1.63 m and 23.4 kg/m2). They gave birth to lighter babies (mean birthweight: 2.7 kg compared with 3.5 kg). Compared to Southampton babies, the Indian babies were small in all body measurements, the smallest being abdominal circumference (s.d. score: -2.38; 95% CI: -2.48 to -2.29) and mid-arm circumference (s.d. score: -1.82; 95% CI: -1.89 to -1.75), while the most preserved measurement was the subscapular skinfold thickness (s.d. score: -0.53; 95% CI: -0.61 to -0.46). Skinfolds were relatively preserved in the lightest babies (below the 10th percentile of birthweight) in both populations.CONCLUSIONS: Small Indian babies have small abdominal viscera and low muscle mass, but preserve body fat during their intrauterine development. This body composition may persist postnatally and predispose to an insulin-resistant state

Placental phenotypes of intrauterine growth

The placenta is essential to nutrition before birth. Recent work has shown that a range of clearly defined alterations can be found in the placentas of infants with intrauterine growth restriction (IUGR). In the mouse, a placental specific knockout of a single imprinted gene, encoding IGF-2, results in one pattern of alterations in placenta structure and function which leads to IUGR. We speculate that the alterations in the human placenta can also be grouped into patterns, or phenotypes, that are associated with specific patterns of fetal growth. Identifying the placental phenotypes of different fetal growth patterns will improve the ability of clinicians to recognize high-risk patients, of laboratory scientists to disentangle the complexities of IUGR, and of public health teams to target interventions aimed at ameliorating the long-term adverse effects of inadequate intrauterine growth