Sex Differences in the Association Between Birth Weight and Adult Type 2 Diabetes

Zimmermann, Esther; Gamborg, Michael; Sørensen, Thorkild I A; Baker, Jennifer L.

doi:10.2337/db15-0494

Cited by 39 publications

(45 citation statements)

References 39 publications

(40 reference statements)

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“…Fourth, we have not investigated the potential gender difference in the associations between BW and later life traits. There is evidence that the association between BW and both T2D 48 and SBP 49 is stronger in females than males. However, to perform the MR analyses, we would require male and female-specific effect sizes for each of the exposures, which are currently not available.…”

Section: Discussionmentioning

confidence: 99%

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Warrington¹,

Beaumont²,

Horikoshi³

et al. 2018

Preprint

105

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Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

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Section: Discussionmentioning

confidence: 99%

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Warrington¹,

Beaumont²,

Horikoshi³

et al. 2018

Preprint

105

View full text Add to dashboard Cite

show abstract

“…; Zimmermann et al . ). SGA children develop glucose intolerance more frequently, and in adulthood exhibit impaired insulin secretion and a greater risk for developing Type 2 diabetes (Hales et al .…”

Section: Introductionmentioning

confidence: 97%

Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency

Limesand

Rozance

2017

The Journal of Physiology

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Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants.

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“…For example, a prospective study including three large cohorts ( n = 149 794) found that participants with low birth weight (2.00–2.75 kg) had significantly higher susceptibility to T2D than those with reference birth weight (3.25–3.75 kg). 7 A recent meta-analysis of two studies analyzed 3627 T2D cases and 12 974 control participants of European ancestry. 8 A genetic risk score was created on the basis of five low birth weight-related single nucleotide polymorphisms (SNPs).…”

Section: Introductionmentioning

confidence: 99%

Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci

Zeng

Chen

Lin

et al. 2017

Journal of Diabetes

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Background Clinical and epidemiological findings point to an association between type 2 diabetes (T2D) and low birth weight. However, the nature of the relationship is largely unknown. The aim of this study was to identify novel single nucleotide polymorphisms (SNPs) in T2D and birth weight, and their pleiotropic loci. Methods A pleiotropy-informed conditional false discovery rate (cFDR) method was applied to two independent genome-wide association studies (GWAS) summary statistics of T2D (n = 149 821) and birth weight (n = 26 836). Results A conditional Q–Q plot showed strong enrichment of genetic variants in T2D conditioned on different levels of association with birth weight. 133 T2D-associated SNPs, including 120 novel SNPs, were identified with a significance threshold of cFDR < 0.05; 13 significant birth weight-associated SNPs, including 12 novel SNPs (cFDR < 0.05) were identified. Conjunctional cFDR (ccFDR) analysis identified nine pleiotropic loci, including seven novel loci, shared by both T2D and birth weight (ccFDR < 0.05). Two novel SNPs located at the CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1; rs1012635; cFDR < 0.05) and adenylate cyclase 5 (ADCY5; rs4677887; cFDR < 0.05) genes are of note. These two genes increase the risk of T2D and low birth weight through the pathway of the “fetal insulin hypothesis.” Conclusion Several pleiotropic loci were identified between T2D and birth weight by leveraging GWAS results. The results make it possible to explain a greater proportion of trait heritability and improve our understanding of the shared pathophysiology between T2D and birth weight.

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Sex Differences in the Association Between Birth Weight and Adult Type 2 Diabetes

Cited by 39 publications

References 39 publications

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency

Increased identification of novel variants in type 2 diabetes, birth weight and their pleiotropic loci

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