Is there a protective gene against alcoholism?

October 15, 2001

Numerous studies have demonstrated that genetic factors can at least partially determine vulnerability to alcohol dependence. It remains unclear, however, which genes are involved and what their roles are. Neuropeptides are peptides that are found in neural tissue. An earlier study found that a gene variant of the neuropeptide Y (NPY) was associated with a 34 percent higher average alcohol consumption among the non-alcoholic population examined. Research published in the October issue of Alcoholism: Clinical & Experimental Research investigates if the Leu(7)/Pro(7) genetic polymorphism of NPY is associated with an increased susceptibility to alcoholism.

"We were surprised to find an association between the NPY polymorphism and alcoholism that was contrary to our expectations," said Hannu Alho, a senior scientist in addiction medicine at the National Public Health Institute in Finland, and lead author of the study.

Alho and his colleagues found that the carrier status of the Pro(7) amino acid substitution in the signal peptide of NPY was associated with a decreased risk of both Type I and Type II alcoholism. Alcoholism has two distinct subgroups: Type I is late in onset, exhibited by both genders, and associated with anxiety; Type II is characterized by heavy drinking at an early age, antisocial behavior, male predominance, and thought to have a much larger genetic than environmental influence. The researchers also found a higher prevalence of the variant in the social drinkers who served as controls. They speculate that the genetic polymorphism producing the Pro(7) substitution of NPY might not predispose to alcoholism, but instead retard the transition to alcoholism.

"NPY is well characterized as a neuromodulator in the central nervous system," explained Alho. "The best known effects of NPY are stimulation of feeding among animals, and activation of a 'fat-splitting' enzyme called lipase which increases energy storage in adipose (or fatty) tissue. Central administration of NPY in mice reduces anxiety, whereas NPY-deficient mice score high on measures of anxiety. In the normal variant of the NPY gene, one Leucine (Leu) amino acid is substituted by Proline (Pro) at position seven in the coding region of the gene. Normally it is the Leu/Leu type, but after this mutation it is the Leu/Pro type. We do not completely understand the impact of the Pro mutation on the NPY function. However, contrary to the previous observations, we did not find an association between alcoholism and this Pro mutation. Our finding may indicate that this Pro type is not associated with alcoholism, or our finding may be a coincidence because our study sample was not very large."

Study participants consisted of two groups: 122 alcoholics (101 male, 21 female), and 59 social drinkers (34 male, 25 female) who served as controls. The alcoholics were further divided into two groups, based on psychiatric evaluation of their alcoholism as Type 1 or 2. DNA was extracted from saliva samples and NPY genotypes determined.

"It has long been observed that alcoholism runs in families," said Kalervo Kiianmaa, head of the Alcohol Research Centre at the Finnish National Public Health Institute. "But a well-established observation does not provide compelling evidence for a genetic or an environmental influence. The first solid evidence for a potential genetic influence came from now-famous twin and adoption studies. The adoption studies by Goodwin and colleagues, for example, helped delineate the specific genetic influence. What researchers know as the Swedish Adoption studies provided strong support for the clinical impression that there are several types of alcoholism, and offered the additional insight that genetic factors might exert a greater influence in some types of alcoholism than in others." These and other studies, said Kiianmaa, have helped establish that for a substantial number of alcoholic patients, there is a genetic predisposition to develop alcohol dependence.

"In contrast to a large number of so-called genetic disorders such as cystic fibrosis, sickle cell anemia or Huntington's chorea," Kiianmaa observed, "the development of alcoholism depends on the interaction of genetically determined predisposing factors with environmentally determined precipitating factors. While the search for genes that predispose individuals to develop alcoholism is a compelling endeavor, there are a number of caveats which must be heeded."

Both Alho and Kiianmaa commented on the complexity of alcoholism as a disorder with a number of characteristic features common to complex diseases. Both cautioned against becoming overly excited about 'a protective gene' until additional studies are carried out.

"The role of neuropeptide Y in alcohol self-administration behavior and alcoholism is far from clear," said Kiianmaa. "The results obtained from different types of studies, including the present one, seem to be varying, even conflicting, and a clear picture does not emerge from them. Therefore, anything said on the role of neuropeptide Y in alcoholism would be highly speculative. A lot of new work needs be done to clarify the situation."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Erkki Ilveskoski, Olli A. Kajander, Tarja Kunnas and Pekka J. Karhunen of the Department of Forensic Medicine in the Medical School at the University of Tempere; Terho Lehtimäki of the Laboratory of Atherosclerosis Genetics in the Department of Clinical Chemistry, Centre for Laboratory Medicine at the Tampere University Hospital; Pekka Heinälä of the Department of Mental Health and Alcohol Research at the National Public Health Institute of Finland; and Matti Virkkunen of the Department of Psychiatry at Helsinki University Central Hospital. The study was funded by the Tampere University Hospital Medical Research Fund, the Finnish Foundation of Alcohol Research, the Y. Jahnsson Foundation, the Elli and Elvi Oksanen Fund, the Pirkanmaa Region Fund of the Finnish Cultural Foundation, and the Juho Vainio Foundation.

Alcoholism: Clinical & Experimental Research

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