title: The birth weight lowering C-allele of rs900400 near LEKR1 and CCNL1 associates with elevated insulin release following an oral glucose challenge.
abstract: OBJECTIVE
  The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample.
  
  
  METHODS
  For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses.
  
  
  RESULTS
  The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([-41.3;-3.0], P = 0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (β = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (β = 1.76% [0.04; 3.49], P = 0.05).
  
  
  CONCLUSIONS
  The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ehm A
authors.initials: EA
authors.lastname: Andersson
authors.forename: Marie N
authors.initials: MN
authors.lastname: Harder
authors.forename: Kasper
authors.initials: K
authors.lastname: Pilgaard
authors.forename: Charlotta
authors.initials: C
authors.lastname: Pisinger
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Kristine
authors.initials: K
authors.lastname: Færch
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001724:Birth Weight / Q000235:genetics*; D016213:Cyclins / Q000235:genetics*; D055106:Genome-Wide Association Study; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics; D008875:Middle Aged
chemical_list: C468873:CCNL1 protein, human; D016213:Cyclins; D007328:Insulin
references.citation: Diabetes. 2009 Jun;58(6):1428-33
references.pmid: 19228808
references.citation: Eur J Cardiovasc Prev Rehabil. 2003 Oct;10(5):377-86
references.pmid: 14663300
references.citation: Diabetologia. 2010 Sep;53(9):1908-16
references.pmid: 20490451
references.citation: Br Med Bull. 2001;60:5-20
references.pmid: 11809615
references.citation: Diabetes Care. 2003 Aug;26(8):2335-40
references.pmid: 12882858
references.citation: Diabetologia. 2010 Dec;53(12):2526-30
references.pmid: 20859612
references.citation: J Dev Orig Health Dis. 2010 Oct;1(5):319-28
references.pmid: 25141935
references.citation: Diabetes. 2007 Dec;56(12):3105-11
references.pmid: 17827400
references.citation: Diabetologia. 2009 May;52(5):825-9
references.pmid: 19225753
references.citation: Nat Genet. 2010 Feb;42(2):105-16
references.pmid: 20081858
references.citation: Diabetes. 2009 Oct;58(10):2414-8
references.pmid: 19592620
references.citation: Am J Epidemiol. 2007 Apr 15;165(8):849-57
references.pmid: 17215379
references.citation: Lancet. 1999 May 22;353(9166):1789-92
references.pmid: 10348008
references.citation: Am J Hum Genet. 2007 Jun;80(6):1150-61
references.pmid: 17503332
references.citation: Nat Genet. 2010 May;42(5):430-5
references.pmid: 20372150
references.citation: J Pediatr Endocrinol Metab. 2011;24(3-4):187-9
references.pmid: 21648289
references.citation: Nat Genet. 2007 Jun;39(6):770-5
references.pmid: 17460697
references.citation: Am J Clin Nutr. 2011 Apr;93(4):851-60
references.pmid: 21248185