Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study

BACKGROUND: Caffeine, 1,3,7-trimethylxanthine, is widely consumed by women of reproductive age. Although caffeine has been proposed to inhibit fetal growth, previous studies on the effects of caffeine on infant birth size have yielded inconsistent findings. This inconsistency may result from failure to account for individual differences in caffeine metabolism related to polymorphisms in the gene for CYP1A2, the major caffeine-metabolizing enzyme. METHODS: Five hundred fourteen Japanese women participated in a prospective cohort study in Sapporo, Japan, from 2002 to 2005, and 476 mother-child pairs were included for final analysis. RESULTS: Caffeine intake was not significantly associated with mean infant birth size. When caffeine intake and CYP1A2 C164A genotype were considered together, women with the AA genotype and caffeine intake of >= 300 mg per day had a mean reduction in infant birth head circumference of 0.8 cm relative to the reference group after adjusting for confounding factors. In a subgroup analysis, only nonsmokers with the AA genotype and caffeine intake of >= 300 mg per day had infants with decreased birth weight (mean reduction, 277 g) and birth head circumference (mean reduction, 1.0 cm). CONCLUSION: Nonsmokers who rapidly metabolize caffeine may be at increased risk for having infants with decreased birth size when consuming >= 300 mg of caffeine per day.This is the author's accepted version of their manuscript of the following article: Sasaki, et al. Pediatric Research (2017) 82, 19–28. The final publication is available at: http://dx.doi.org/10.1038/pr.2017.7

Considering Trauma Exposure in the Context of Genetics Studies of Posttraumatic Stress Disorder: A Systematic Review

Background: Posttraumatic stress disorder (PTSD) is a debilitating anxiety disorder. Surveys of the general population suggest that while 50-85% of Americans will experience a traumatic event in their lifetime, only 2-50% will develop PTSD. Why some individuals develop PTSD following trauma exposure while others remain resilient is a central question in the field of trauma research. For more than half a century, the role of genetic influences on PTSD has been considered as a potential vulnerability factor. However, despite the exponential growth of molecular genetic studies over the past decade, limited progress has been made in identifying true genetic variants for PTSD. Methods: In an attempt to aid future genome wide association studies (GWAS), this paper presents a systematic review of 28 genetic association studies of PTSD. Inclusion criteria required that 1) all participants were exposed to Criterion A traumatic events, 2) polymorphisms of relevant genes were genotyped and assessed in relation to participants’ PTSD status, 3) quantitative methods were used, and 4) articles were published in English and in peer-reviewed journals. In the examination of these 28 studies, particular attention was given to variables related to trauma exposure (e.g. number of traumas, type of trauma). Results: Results indicated that most articles did not report on the GxE interaction in the context of PTSD or present data on the main effects of E despite having data available. Furthermore, some studies that did consider the GxE interaction had significant findings, underscoring the importance of examining how genotypes can modify the effect of trauma on PTSD. Additionally, results indicated that only a small number of genes continue to be studied and that there were marked differences in methodologies across studies, which subsequently limited robust conclusions. Conclusions: As trauma exposure is a necessary condition for the PTSD diagnosis, this paper identifies gaps in the current literature as well as provides recommendations for how future GWAS studies can most effectively incorporate trauma exposure data in both the design and analysis phases of studies

Evolutionism and genetics of posttraumatic stress disorder

The authors discuss, from the evolutionary concept, how flight and fight responses and tonic immobility can lead to a new understanding of posttraumatic stress disorder. Through the analysis of symptom clusters (revivals, avoidance and hyperexcitation), neurobiological and evolutionary findings are correlated. The current discoveries on posttraumatic stress disorder genetics are summarized and analyzed in this evolutionary perspective, using concepts to understand the gene-environment interaction, such as epigenetic. The proposal is that the research of susceptibility factors in posttraumatic stress disorder must be investigated from the factorial point of view, where their interactions increase the risk of developing the disorder, preventing a unique search of the cause of this disorder. The research of candidate genes in posttraumatic stress disorder must take into consideration all the systems associated with processes of stress response, such as the hypothalamus-pituitary-adrenal and sympathetic axes, mechanisms of learning, formation and extinguishing of declarative memories, neurogenesis and apoptosis, which involve many systems of neurotransmitters, neuropeptides and neurohormones.Os autores discutem, a partir do conceito evolutivo, como a resposta de estresse, nas suas possibilidades de fuga e luta e de imobilidade tônica, pode levar a uma nova compreensão etiológica do transtorno de estresse pós-traumático. Através da análise dos agrupamentos de sintomas desse diagnóstico - revivência, evitação e hiperexcitação -, procuram correlacionar os achados neurobiológicos e evolutivos. As descobertas atuais sobre a genética do transtorno de estresse pós-traumático são resumidas e colocadas nessa perspectiva evolutiva, dentro de conceitos que possibilitam o entendimento da interação gene/ambiente, como a epigenética. Propõem que a pesquisa dos fatores de risco do transtorno de estresse pós-traumático deva ser investigada do ponto de vista fatorial, onde a somatória destes aumenta o risco de desenvolvimento do quadro, não sendo possível a procura da causa do transtorno de forma única. A pesquisa de genes candidatos no transtorno de estresse pós-traumático deve levar em consideração todos os sistemas associados aos processos de respostas ao estresse, sistemas dos eixos hipotálamo-hipofisário-adrenal e simpático, mecanismos de aprendizado, formação de memórias declarativas, de extinção e esquecimento, da neurogênese e da apoptose, que envolvem vários sistemas de neurotransmissores, neuropeptídeos e neuro-hormônios.Universidade Federal de São Paulo (UNIFESP)(UNIFESP)UNIFESP Departamento de PsiquiatriaUniversidade de São Paulo Faculdade de Medicin Hospital de ClínicasUNIFESP, Depto. de PsiquiatriaSciEL

Antenatal Mental Health and Retinal Vascular Caliber in Pregnant Women

10.1167/tvst.2.2.2Translational Vision Science and Technology221-1

Transcriptome changes affecting Hedgehog and cytokine signalling in the umbilical cord: implications for disease risk

BACKGROUND: Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA.METHODS: The gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698-4151 g) and gestational ages (35-41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity.RESULTS: We found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome.CONCLUSIONS: We studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk

The glutathione transferase Mu null genotype leads to lower 6-MMPR levels in patients treated with azathioprine but not with mercaptopurine

The conversion of azathioprine (AZA) to mercaptopurine (MP) is mediated by glutathione transferase Mu1 (GSTM1), alpha1 (GSTA1) and alpha2 (GSTA2). We designed a case-control study with data from the TOPIC trial to explore the effects of genetic variation on steady state 6-methylmercaptopurine ribonucleotide (6-MMPR) and 6-thioguanine nucleotide (6-TGN) metabolite levels. We included 199 patients with inflammatory bowel disease (126 on AZA and 73 on MP). GSTM1-null genotype carriers on AZA had two-fold lower 6-MMPR levels than AZA users carrying one or two copies of GSTM1 (2239 (1006-4587) versus 4371 (1897-7369) pmol/8 × 10(8) RBCs; P<0.01). In patients on MP (control group) 6-MMPR levels were comparable (6195 (1551-10712) versus 6544 (1717-11600) pmol/8 × 10(8) RBCs; P=0.84). The 6-TGN levels were not affected by the GSTM1 genotype. The presence of genetic variants in GSTA1 and GSTA2 was not related to the 6-MMPR and 6-TGN levels.The Pharmacogenomics Journal advance online publication, 3 January 2017; doi:10.1038/tpj.2016.87

Association of birthweight and head circumference at birth to cognitive performance in 9- to 10-year-old children in South India: prospective birth cohort study

To examine whether birthweight and head circumference at birth are associated with childhood cognitive ability in South India, cognitive function was assessed using three core tests from the Kaufman Assessment Battery for children and additional tests measuring long-term retrieval/storage, attention and concentration, and visuospatial and verbal abilities among 505 full-term born children (mean age 9.7 y). In multiple linear regression adjusted for age, sex, gestation, socioeconomic status, parent's education, maternal age, parity, body mass index, height, rural/urban residence, and time of testing, Atlantis score (learning ability/long-term storage and retrieval) rose by 0.1 SD per SD increase in newborn weight and head circumference, respectively (p &lt; 0.05 for all), and Kohs' block design score (visuospatial ability) increased by 0.1 SD per SD increase in birthweight (p &lt; 0.05). The associations were reduced after further adjustment for current head circumference. There were no associations of birthweight and/or head circumference with measures of short-term memory, fluid reasoning, verbal abilities, and attention and concentration. In conclusion, higher birthweight and larger head circumference at birth are associated with better childhood cognitive ability. The effect may be specific to learning, long-term storage and retrieval, and visuospatial abilities, but this requires confirmation by further research