title: Absence of birth-weight lowering effect of ADCY5 and near CCNL, but association of impaired glucose-insulin homeostasis with ADCY5 in Asian Indians.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Molecular Medicine & Surgery, Karolinska Institutet, Stockholm, Sweden. vaskan@ki.se
authors.forename: Senthil K
authors.initials: SK
authors.lastname: Vasan
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Neville
authors.forename: Belavendra
authors.initials: B
authors.lastname: Antonisamy
authors.forename: Prasanna
authors.initials: P
authors.lastname: Samuel
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Fall
authors.forename: Finney S
authors.initials: FS
authors.lastname: Geethanjali
authors.forename: Nihal
authors.initials: N
authors.lastname: Thomas
authors.forename: Palany
authors.initials: P
authors.lastname: Raghupathy
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.forename: Fredrik
authors.initials: F
authors.lastname: Karpe
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000328:Adult; D000886:Anthropometry; D001724:Birth Weight / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D007194:India; D007328:Insulin / Q000378:metabolism*; D008297:Male; D044465:White People / Q000235:genetics*
chemical_list: D001786:Blood Glucose; C468873:CCNL1 protein, human; D016213:Cyclins; D007328:Insulin; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V