Obesity and diabetes genes are associated with being born small for gestational age: Results from the Auckland Birthweight Collaborative study

Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
BMC Medical Genetics (Impact Factor: 2.08). 08/2010; 11(1):125. DOI: 10.1186/1471-2350-11-125
Source: PubMed


Individuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution.
In this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA).
The results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important.

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    • "Our model also detected other SNPs in close proximity of different candidate genes; that is, SNP ss66397464 in peroxisome proliferator-activated receptor-γ gene (PPARG) on chromosome 3, SNP ss66402098 in the Wolfram syndrome 1 gene (WFSI) on chromosome 4, SNP ss66218814 in CDK5 regulatorysubunit-associated protein 1-like 1 gene (CDKAL1) on chromosome 6, and SNP ss66288005 in potassium inwardly-rectifying channel, subfamily J, member 11 gene (KCNJ11) on chromosome 12 [Frayling (2007)]. Among these four genes, PPARG and KCNJ were found to be associated with obesity [Vidal-Puig et al. (1997); Morgan et al. (2010)], while WFSI and CDKAL1 are believed to be associated with diabetes [Sandhu et al. (2007); Scott et al. (2007); Steinthorsdottir et al. (2007)]. Therefore, all these discoveries have well validated the biological relevance of the new model. "
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    ABSTRACT: Although genome-wide association studies (GWAS) have proven powerful for comprehending the genetic architecture of complex traits, they are challenged by a high dimension of single-nucleotide polymorphisms (SNPs) as predictors, the presence of complex environmental factors, and longitudinal or functional natures of many complex traits or diseases. To address these challenges, we propose a high-dimensional varying-coefficient model for incorporating functional aspects of phenotypic traits into GWAS to formulate a so-called functional GWAS or fGWAS. The Bayesian group lasso and the associated MCMC algorithms are developed to identify significant SNPs and estimate how they affect longitudinal traits through time-varying genetic actions. The model is generalized to analyze the genetic control of complex traits using subject-specific sparse longitudinal data. The statistical properties of the new model are investigated through simulation studies. We use the new model to analyze a real GWAS data set from the Framingham Heart Study, leading to the identification of several significant SNPs associated with age-specific changes of body mass index. The fGWAS model, equipped with the Bayesian group lasso, will provide a useful tool for genetic and developmental analysis of complex traits or diseases.
    Full-text · Article · Sep 2015 · The Annals of Applied Statistics
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    • "Birth weight variation has a significant genetic component with clustering of SGA births in families and recurrence in successive generations [3,4], and heritability estimates from family and twin studies range between 25-40% [5]. Recent data from genome wide association studies have found robust associations between fetal genotype and birth weight [6], and we have previously demonstrated that genetic variation in certain genes associated with obesity and or type 2 diabetes is more prevalent in those born SGA than those born appropriate for gestational age (AGA) [7]. Currently, little is known about the role of epigenetic modifications and copy number variation in determining the risk of SGA. "
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    ABSTRACT: Background There is a substantial genetic component for birthweight variation, and although there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown. The two imprinting control regions (ICRs) located on chromosome 11p15.5, involved in the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and the growth restriction disorder Silver-Russell syndrome (SRS), are prime epigenetic candidates for regulating fetal growth. We investigated whether common variation in copy number in the BWS/SRS 11p15 region or altered methylation levels at IGF2/H19 ICR or KCNQ10T1 ICR was associated with SGA. Methods We used a methylation-specific multiplex-ligation-dependent probe amplification assay to analyse copy number variation in the 11p15 region and methylation of IGF2/H19 and KCNQ10T1 ICRs in blood samples from 153 children (including 80 SGA), as well as bisulfite pyrosequencing to measure methylation at IGF2 differentially methylated region (DMR)0 and H19 DMR. Results No copy number variants were detected in the analyzed cohort. Children born SGA had 2.7% lower methylation at the IGF2 DMR0. No methylation differences were detected at the H19 or KCNQ10T1 DMRs. Conclusions We confirm that a small hypomethylation of the IGF2 DMR0 is detected in peripheral blood leucocytes of children born SGA at term. Copy number variation within the 11p15 BWS/SRS region is not an important cause of non-syndromic SGA at term.
    Full-text · Article · Jun 2014 · BMC Medical Genetics
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    • "A person from a higher socio-economic background had possibly more access to high energy foods, and probably indulged in a lower level of physical activity, making them vulnerable to increase weight gain in later life. Many studies suggest an interaction between the genetic determinants of birth weight, childhood growth, and risk of adult metabolic diseases with both the intra- and extra-uterine environments.[20] Thus, the genetic risks of obesity in the LBW individuals would have been manifested when exposed to a suitable environment as found in a family with high SES. "
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    ABSTRACT: Objective:To determine the relationship between birth weight and the evolution of obesity in adult life in women from a rural developmental block in southern India.Design:Non-concurrent cohortSetting:General community- a rural developmental block in southern India.Participants:Two hundred and seventy one young healthy females were recruited from a birth cohort. The study subjects were 98 women in the age group of 19-23 years who had been born with low birth weight (LBW) and 173 women in the same age group who had been born with normal birth weight (NBW).Materials and Methods:Data collection involved interview using a structured questionnaire and anthropometric measurements.Analysis:Chi-square test to assess significance of association, independent sample t test to assess the difference between means, odds ratios for measuring magnitude of association, stratified analysis to identify various interactions and confounders, and multiple logistic regression models to identify the relationship between birth weight and young adult obesity (BMI > 25).Results:A crude odds ratio of 0.564 (95% CI 0.262 - 1.214) was obtained for the association between LBW and development of obesity later in life. In the final logistic regression model, it was found that a young adult female with low birth weight who belonged to a higher socio-economic group had a higher risk of developing obesity (Adjusted odds for the interaction term between LBW and high SES 6.251; 95% CI 1.236 - 31.611).Conclusion:The study could not find any significant association between LBW and development of obesity later in life, but it found a higher probability of developing obesity later in life among low birth weight female children born in high socio-economic status families.
    Full-text · Article · May 2014
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