Protective Effects of the Alcohol Dehydrogenase-ADH1B Allele in Children Exposed to Alcohol During Pregnancy

Jacobson, Sandra W.; Carr, Lucinda G.; Croxford, Julie; Sokol, Robert J.; Li, Ting Kai; Jacobson, Joseph L.

doi:10.1016/j.jpeds.2005.08.023

Cited by 84 publications

(48 citation statements)

References 28 publications

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“…Genetics has a role in determining the effects of alcohol on the developing fetus, some genotypes conferring increased risk of harm and others providing protection (Jacobson et al 2006). This factor, if unknown, contributes to the difficulty in estimating risk to the fetus in an individual pregnancy.…”

Section: Genetic Effectsmentioning

confidence: 99%

Survey of alcohol-related presentations to Australasian emergency departments

et al. 2014

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Objective: To determine the proportion of alcohol‐related presentations to emergency departments (EDs) in Australia and New Zealand, at a single time point on a weekend night shift. Design, setting and participants: A point prevalence survey of ED patients either waiting to be seen or currently being seen conducted at 02:00 local time on 14 December 2013 in 106 EDs in Australia and New Zealand. Main outcome measures: The number of ED presentations that were alcohol‐related, defined using World Health Organization ICD‐10 codes. Results: At the 106 hospitals (92 Australia, 14 New Zealand) that provided data, 395 (14.3%; 95% CI, 13.0%–15.6%) of 2766 patients in EDs at the study time were presenting for alcohol‐related reasons; 13.8% (95% CI, 12.5%–15.2%) in Australia and 17.9% (95% CI, 13.9%–22.8%) in New Zealand. The distribution was skewed left, with proportions ranging from 0 to 50% and a median of 12.5%. Nine Australian hospitals and one New Zealand hospital reported that more than a third of their ED patients had alcohol‐related presentations; the Northern Territory (38.1%) and Western Australia (21.1%) reported the highest proportions of alcohol‐related presentations. Conclusions: One in seven ED presentations in Australian and New Zealand at this 02:00 snapshot were alcohol‐related, with some EDs seeing more than one in three alcohol‐related presentations. This confirms that alcohol‐related presentations to EDs are currently underreported and makes a strong case for public health initiatives.

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Section: Genetic Effectsmentioning

confidence: 99%

Survey of alcohol-related presentations to Australasian emergency departments

et al. 2014

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“…Genetic variants that lead to altered ethanol metabolism can function to modulate the risk of adverse effects (Chernoff 1980). For instance, variants at the ADH1B (ADH1B*2 and ADH1B*3) in the mother or child are associated with more efficient ethanol metabolism, which in turn has been associated with a mild protective effect relative to those that do not possess these variants (Arfsten et al 2004;Jacobson et al 2006). Ultimately, it is likely that the interplay of various proposed mechanisms give rise to FASD (Cohen-Kerem and Koren 2003).…”

Section: Other Mechanisms Of Alcohol Teratogenesismentioning

confidence: 99%

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

Kapur

Baber

2018

Biochem. Cell Biol.

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Alcohol consumption during pregnancy remains a significant cause of preventable birth defects and developmental disabilities; however, the mechanism of toxicity remains unclear. Methanol is present as a congener in many alcoholic beverages and is formed endogenously. Because ethanol is preferentially metabolized over methanol, it has been found in the sera and cerebro-spinal fluid of alcoholics. Toxicity resulting from methanol has been attributed to formic acid. Formic acid is present in significantly higher quantities in the biofluids of alcoholics. These higher levels can be cytotoxic and cause neuronal cell death. However, the adverse effects can be mitigated by adequate levels of hepatic folic acid, because formic acid elimination depends on folic acid. During pregnancy, folate concentrations are at least 2-fold higher in cord blood then in maternal blood, owing to increased folate requirements. The reverse has been demonstrated in pregnancies with alcohol abuse, suggesting downregulation of folate transporters and low fetal folate levels. Moreover, formic acid can cross the placenta and its adverse effects can be mitigated by folic acid. Thus, the combination of low fetal folate levels and presence of formic acid form a potent cytotoxic combination that may play a significant role in the etiology of fetal alcohol spectrum disorder.Key words: formic acid, methanol, folic acid, FASD, neurotoxicity.Résumé : La consommation d'alcool pendant la grossesse demeure une cause significative de déficiences congénitales et développementales évitables, mais le mécanisme responsable de sa toxicité est encore flou. Le méthanol est présent comme congénère dans plusieurs boissons alcooliques et il est formé de manière endogène. Puisque l'éthanol est préférentiellement métabolisé par rapport au méthanol, ce dernier a été trouvé dans le sérum et le liquide céphalorachidien des personnes alcooliques. La toxicité résultant du méthanol a été attribuée à l'acide formique. L'acide formique est présent en quantité significativement plus élevée dans les liquides biologiques des patients alcooliques. Ces niveaux plus élevés peuvent être cytotoxiques et causer la mort neuronale. Cependant, ces effets nocifs peuvent être atténués par des niveaux appropriés d'acide folique hépatique, car l'élimination d'acide formique dépend de l'acide folique. Durant la grossesse, les concentrations de folate sont au moins deux fois plus élevées dans le cordon ombilical que dans le sang maternel à cause des besoins accrus en folate. L'inverse a été démontré chez les femmes enceintes qui abusent d'alcool, suggérant une régulation à la baisse des transporteurs du folate et de faibles niveaux foetaux de folate. En outre, l'acide formique peut traverser le placenta et ses effets nocifs peuvent être atténués par l'acide folique. Ainsi, de faibles niveaux foetaux de folate et la présence d'acide formique forment une combinaison cytotoxique puissante qui peut jouer un rôle significatif dans l'étiologie de troubles du spectre de l'alcoolisation foet...

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“…In this circumstance, the genotypic differences will mimic the differences in level of alcohol intake with regard to the foetal exposure to maternal circulating alcohol. Although sample sizes have been low and the analysis strategies not optimal, studies applying this approach provide some evidence to support the influence of maternal genotype, and thus of alcohol, on offspring outcomes [54][55][56]. Studies that have been able to analyse both maternal genotype and foetal genotype find that it is the maternal genotype that is related to offspring outcomes, as anticipated if the crucial exposure related to maternal alcohol intake and alcohol levels.…”

Section: Maternal Drinking the Intrauterine Environment And Offsprinmentioning

confidence: 99%

Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health

2010

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Differences in diet appear to contribute substantially to the burden of disease in populations, and therefore changes in diet could lead to major improvements in public health. This is predicated on the reliable identification of causal effects of nutrition on health, and unfortunately nutritional epidemiology has deficiencies in terms of identifying these. This is reflected in the many cases where observational studies have suggested that a nutritional factor is protective against disease, and randomized controlled trials have failed to verify this. The use of genetic variants as proxy measures of nutritional exposure-an application of the Mendelian randomization principle-can contribute to strengthening causal inference in this field. Genetic variants are not subject to bias due to reverse causation (disease processes influencing exposure, rather than vice versa) or recall bias, and if obvious precautions are applied are not influenced by confounding or attenuation by errors. This is illustrated in the case of epidemiological studies of alcohol intake and various health outcomes, through the use of genetic variants related to alcohol metabolism (in ALDH2 and ADH1B). Examples from other areas of nutritional epidemiology and of the informative nature of gene-environment interactions interpreted within the Mendelian randomization framework are presented, and the potential limitations of the approach addressed.

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Protective Effects of the Alcohol Dehydrogenase-ADH1B Allele in Children Exposed to Alcohol During Pregnancy

Cited by 84 publications

References 28 publications

Survey of alcohol-related presentations to Australasian emergency departments

Survey of alcohol-related presentations to Australasian emergency departments

FASD: folic acid and formic acid — an unholy alliance in the alcohol abusing mother

Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health

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