Abstract
Background and AimThe 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.MethodsFor 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.ResultsThe 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).ConclusionThe 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.
Highlights
Birth weight is a crude measure of the entire period of pre-natal growth
Lower birth weight was found among carriers of type 2 diabetes (T2D) risk alleles in or near HHEX-IDE, CDKAL1 and ADCY5 [5,6,7,8,9], only the latter was confirmed at genome-wide significance
This may as well be the case for the ADCY5 risk allele, but the exact mechanism by which this variant predisposes to both low birth weight and T2D is yet to be determined [12]
Summary
Birth weight is a crude measure of the entire period of pre-natal growth. It is a complex trait influenced by multiple intrauterine factors as well as the genetic disposition of both the fetus and the mother. Recent data provided proof-of-concept for the idea that the relationship between low birth weight and risk of T2D to some extent may be explained by common genetic disposition to both traits (the fetal insulin hypothesis) [4]. This hypothesis is based on insulin being an important fetal growth. Risk alleles in HHEX-IDE and CDKAL1 confer increased risk of T2D due to lower insulin secretion [10,11] and the birth weight lowering effect of these two alleles suggests that insulin secretion is diminished already in pre-natal life. We aimed to replicate the association with birth weight in the Danish Inter study and to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter study and the Finnish, Metabolic Syndrome in Men (METSIM) sample
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