Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

TY - JOUR

T1 - Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

AU - Andersson, E A

AU - Pilgaard, K

AU - Pisinger, C

AU - Harder, M N

AU - Grarup, N

AU - Faerch, K

AU - Poulsen, P

AU - Witte, D R

AU - Jørgensen, Torben

AU - Vaag, A

AU - Hansen, T

AU - Pedersen, Oluf

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Aims/hypothesis: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. Methods: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. Results: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β∈=∈-33 g [95% CI -55, -10], p∈=∈0.004) and CDKAL1 rs7756992 (β∈=∈-22 g [95% CI -43, -1], p∈=∈0.04). The association for the latter locus was confirmed in a meta-analysis (n∈=∈24,885) (β∈=∈-20 g [95% CI -29, -11], p∈=∈5∈×∈10-6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p∈=∈0.09); however, in a meta-analysis (n∈=∈25,164) this type 2 diabetes risk allele was associated with lower birthweight (β∈=∈-16 g [95% CI -24, -8], p∈= ∈8∈×∈10-5). On average, individuals with high genetic risk (≥ 25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β∈=∈-35 g [95% CI -69, -2], p∈=∈0.037). Conclusions/interpretation: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.

AB - Aims/hypothesis: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. Methods: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. Results: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β∈=∈-33 g [95% CI -55, -10], p∈=∈0.004) and CDKAL1 rs7756992 (β∈=∈-22 g [95% CI -43, -1], p∈=∈0.04). The association for the latter locus was confirmed in a meta-analysis (n∈=∈24,885) (β∈=∈-20 g [95% CI -29, -11], p∈=∈5∈×∈10-6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p∈=∈0.09); however, in a meta-analysis (n∈=∈25,164) this type 2 diabetes risk allele was associated with lower birthweight (β∈=∈-16 g [95% CI -24, -8], p∈= ∈8∈×∈10-5). On average, individuals with high genetic risk (≥ 25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β∈=∈-35 g [95% CI -69, -2], p∈=∈0.037). Conclusions/interpretation: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.

KW - Adenylate Cyclase

KW - Alleles

KW - Birth Weight

KW - Cyclin-Dependent Kinase 5

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Genome-Wide Association Study

KW - Genotype

KW - Homeodomain Proteins

KW - Humans

KW - Infant, Newborn

KW - Pregnancy

KW - Transcription Factors

U2 - 10.1007/s00125-010-1790-0

DO - 10.1007/s00125-010-1790-0

M3 - Journal article

C2 - 20490451

SN - 0012-186X

VL - 53

SP - 1908

EP - 1916

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -