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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 (β 0.041,  p  = 0.027), 2-hours glucose (β 0.127,  p  = 0.019), and reduced insulinogenic index (β -0.106,  p  = 0.050) and 2-hour insulin (β -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.

Absence of Birth-Weight Lowering Effect of ADCY5 and Near CCNL, but Association of Impaired Glucose-Insulin Homeostasis with ADCY5 in Asian Indians