Journal Digest

Genetics

• People with a polymorphism in one of the genes coding for alcohol dehydrogenase (ADH) enzymes, known as ADH1B*3, have been shown in previous research to have a lower risk of developing alcohol use disorders than individuals without this mutation. Now researchers from the University of Missouri, Washington University in St. Louis, and the University of California, San Diego have conducted an experiment to explain the protective effect of ADH1B*3.

The authors enrolled 91 African-American young adults and gave them an alcohol-challenge test. About one-third of the study subjects carried at least one ADH1B*3 allele, and the rest carried two ADH1B*1 alleles. The ADH1B*3 carriers reported a greater degree of sleepiness and a sharper increase in pulse rate immediately after drinking a moderate dose of alcohol than other subjects did.

ADH enzymes in the liver are the main pathway for metabolizing ethanol to acetaldehyde. The protein generated from the ADH1B*3 gene, found primarily in people of African descent, appears to turn ethanol rapidly into acetaldehyde, resulting in a “burst” of acetaldehyde in the body. The researchers suggested that this high level of acetaldehyde may explain the polymorphism carriers' uncomfortable physiological response to drinking and, in turn, leads to a lower risk of alcohol dependence.

McCarthy DM, Pedersen SL, Lobos EA, et al.: ADH1B*3 and Response to Alcohol in African Americans. Alcohol Clin Exp Res. Published online May 4, 2010

• A single nucleotide polymorphism (SNP) at the rs10473984 position in the CRHBP gene, one of the genes in the corticotrophin-releasing system, was significantly associated with remission and symptom reduction in patients with major depression treated with citalopram.

The study was a new analysis of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study sponsored by the National Institute of Mental Health. The authors analyzed known SNPs in 10 genes involved in the regulation of the corticotropin-releasing hormone (CRH) and arginine vasopressin neuronal systems, both of which are a part of the hypothalamic-pituitary-adrenocortical (HPA) system and play an important role in stress response. The CRHBP gene codes for the CRH binding protein, which binds CRH in circulation and prevents CRH binding to receptors.

Patients who carry the T allele in the CRHBP gene had poorer response to citalopram treatment. This association was statistically significant in African-American and Hispanic patients and more pronounced in patients with anxious features. In addition, patients who carry the T allele had higher plasma corticotropin levels of free CRH.

Binder EB, Owens MJ, Liu W, et al.: Association of Polymorphisms in Genes Regulating the Corticotropin-Releasing Factor System With Antidepressant Treatment Response. Arch Gen Psychiatry. 2010; 67(4):369-379

• A polymorphism in the OPRM1 gene, which encodes the mu-opioid receptor in the brain, accounts for different levels of dopamine released in response to alcohol consumption in the ventral striatum, according to a new study. This finding may explain why some people derive a great sense of pleasure from drinking while others do not, which predisposes the former group to a higher risk of alcohol dependence.

Dopamine release in the ventral striatum is a key part of drug- and alcohol-induced reward response. Using positron emission tomography, researchers observed that the brains of men who carry one copy of the 118G allele (n=12) had a higher amount of striatal dopamine release after the men were given a standard dose of an intravenous infusion of alcohol compared with men carrying two copies of the 118A allele (n=16). Homozygous 118G carriers are rare, but 15 percent of the Caucasian population are heterozygous carriers (that is, they carry an A allele and a G allele).

To confirm that the genetic variation is the cause of the brain response, the researchers used a mouse model in which the human OPRM1 gene was inserted. As expected, mice that carried the human OPRM1 gene with two copies of the G allele released four times as much dopamine in the brain as mice that carried two copies of the A allele after receiving a dose of alcohol.

Ramchandani VA, Umhau J, Pavon FJ, et al.: A Genetic Determinant of the Striatal Dopamine Response to Alcohol in Men. Molecular Psychiatry. Published online May 18, 2010

Case Reports

• A case of eosinophilic hepatitis associated with the use of lisdexamfetamine dimesylate in an adolescent patient was reported in Pediatrics last month. A 14-year-old boy had been taking lisdexamfetamine dimesylate (marketed as Vyvanse) 30 mg per day for treatment of attention-deficit/hyperactivity disorder (ADHD) for five months before presenting to his primary care physician with abdominal pain, nausea, vomiting, and generalized jaundice. Biochemical tests indicated a diagnosis of hepatitis. Viral causes were ruled out with serological tests. He had not been taking any other drugs. The patient was hospitalized because of worsening signs of hepatitis. A liver biopsy was performed and led to the diagnosis of drug-induced eosinophilic hepatitis.

After discontinuation of the medication and treatment with steroids, the patient's aminotransferase levels normalized in two months. A second liver biopsy, four months after the initial one, showed no abnormalities. The authors concluded that the ADHD drug was the probable cause of the hepatitis.

Hood B, Nowicki MJ: Eosinophilic Hepatitis in an Adolescent During Lisdexamfetamine Dimesylate Treatment for ADHD. Pediatrics. Published online May 10, 2010

• A retrospective case study of children who were referred to a pediatric ophthalmological service in Glasgow, Scotland, suggested that infants born to women who were on methadone replacement therapy during pregnancy may be at risk for visual problems. Twenty children aged 3 months to 7 years who had in utero exposure to methadone, underwent electrophysiological examinations at the specialty service because of suspected visual impairment. Nineteen of these children were found to have reduced visual acuity; 14 had nystagmus; 10 had delayed visual maturation; seven had strabismus; and six had refractive errors. Twelve of these children showed abnormal visual electrophysiology. A majority of these children were exposed to other illicit drugs in utero in addition to methadone, including benzodiazepines and heroin, the authors commented. Thus, the contribution of methadone on their visual problems needs further attention and research.

Hamilton R, McGlone L, MacKinnon JR, et al.: Opthalmic, Clinical, and Visual Electrophysiological Findings in Children Born to Mothers Prescribed Substitute Methadone in Pregnancy. Br J Ophthalmol. Published online April 21, 2010

Longitudinal Observation

• Watching more television at about age 2 was associated with several unhealthy trends at age 10, a prospective, longitudinal study shows. More than 2,000 children born in 1997 or 1998 in Quebec, Canada, were followed periodically by researchers at the Institut de la Statistique du Quebec to document their physical and psychosocial health status. A total of 1,314 of the children had parent-reported data on weekly hours of television viewing during early childhood.

After adjusting for potential confounding factors, the authors found that higher amounts of television exposure at 29 months was associated at age 10 with significantly lower classroom engagement and math achievement, increased likelihood of being bullied by classmates, less time spent on weekend physical activities, more intake of soft drinks and snacks, and a higher body mass index. These behavioral observations were reported by parents and teachers. Reading achievement was not significantly associated with television exposure at 29 months. The authors noted that the associations between early television exposure and developmental outcomes were “modest, yet nontrivial.”

Pagani LS, Fitzpatrick C, Barnett TA, et al.: Prospective Associations Between Early Childhood Television Exposure and Academic, Psychosocial, and Physical Well-Being by Middle Childhood. Arch Pediatr Adolesc Med. 2010;164(5):425-431.