The Birth Weight Lowering C-Allele of rs900400 Near LEKR1 and CCNL1 Associates with Elevated Insulin Release following an Oral Glucose Challenge

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Ehm A Andersson, Marie N Harder, Kasper Pilgaard, Charlotta Pisinger, Alena Stancáková, Johanna Kuusisto, Niels Grarup, Kristine Færch, Pernille Poulsen, Daniel R Witte, Torben Jørgensen, Allan Vaag, Markku Laakso, Oluf Pedersen, Torben Hansen

Background and Aim
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 (ß = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (ß = 1.76% [0.04; 3.49], P = 0.05).

Conclusion
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.

Original languageEnglish
JournalP L o S One
Volume6
Issue number11
Pages (from-to)e27096
Number of pages6
ISSN1932-6203
DOIs
Publication statusPublished - Nov 2011

ID: 35311565