Received 2 August 1999; in revised form 11 October 1999; accepted 26 October 1999
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ABSTRACT |
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INTRODUCTION |
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For both genders, it is likely that the mechanisms through which genes affect the predisposition toward alcoholism are complex. First, all genetic factors together probably explain only 4060% of the risk (Heath et al., 1997; Prescott and Kendler, 1999
). Thus, a variety of environmental influences, including interest in religion, marital status, peer pressures, and levels of life stress, might also contribute to the onset and clinical course of alcoholism (Lewis et al., 1995
; Neve et al., 1996
; Heath et al., 1997
). Second, the genetic influences themselves are likely to be heterogeneous, reflecting alcohol-metabolizing enzymes, personality characteristics, concomitant independent psychiatric disorders, as well as neurophysiological characteristics (Lex et al., 1993
; Ehlers et al., 1995
; Hill et al., 1998
).
An additional important genetically influenced alcoholism risk factor is the level of response (LR) to alcohol (Schuckit and Smith, 1996; Schuckit, 1998
). The intensity with which an individual reacts to a given dose of this drug is likely to reflect a combination of environmental and genetic influences, with the latter including innate sensitivity and inter-individual differences in the rate of development of both acute and intersession tolerance (Baldwin et al., 1991
; Li et al., 1993
; Heath et al., 1997
; Martin, 1988
). A low LR to alcohol has been reported to be a characteristic of sons of alcoholics, a finding which has been corroborated in most (but not all) laboratories (de Wit and McCracken, 1990
; Pollock, 1992
; Schuckit and Smith, 1996
). Furthermore, a low LR at approximately age 20 predicts the later development of alcohol abuse or dependence, explaining a significant proportion of the ability of a family history of alcoholism to predict this disorder in offspring (Schuckit and Smith, 1996
; Volavka et al., 1996
).
Most evaluations of LR have been carried out in males. These studies progressed from a comparison of family-history-positive (FHP)/family-history-negative (FHN) matched pairs, to the demonstration that the lower LR in male FHPs does not require FHNs as it can be identified within FHP groups without controls. There is, however, a paucity of data on daughters of alcoholics. This reflects a variety of considerations, including the greater difficulty in testing women because of the need to control for the phase of the menstrual cycle, the dangers of administering alcohol to a woman who might be pregnant, and a greater difficulty in scheduling women for testing because of issues of child care (Linnoila et al., 1980; Sutker et al., 1987
; Pomerleau et al., 1994
). Those evaluations of women that have been published generally report data from small samples. One study administered a 0.56 g/kg dose of alcohol to six women who were FHP for alcoholism and six FHN controls, and found significantly lower LR to alcohol in the FHP subjects as measured by standing steadiness or body sway, but not on subjective feelings of intoxication (Lex et al., 1988
). A second study used similar levels of alcohol in six FHP and six FHN women, reporting a trend for less feelings of stimulation from alcohol in the FHP subjects, although the family history differential was less marked than that observed between five FHP and seven FHN men (Savoie et al., 1988
). Other investigations have observed the effects of alcohol administration in women in general, showing responses on body sway that were similar to men, but sample sizes were generally small and these investigators did not compare family history groups (Lukas et al., 1989
; Nagoshi and Wilson, 1989
).
The present report presents data from alcohol challenges in 38 drinking, but not alcohol-dependent, women who had an alcohol-dependent parent. The intensity of response to alcohol in these subjects is compared to FHP men, a group with a well-established low alcohol response, as well as FHN controls. The goal was to determine whether similar low levels of LR are seen in FHP women and men.
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METHODS |
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The original probands and their relatives were personally interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview (Bucholz et al., 1994). The SSAGA evaluates demographic information, medical histories, and data relevant to 17 Axis I disorders, as well as the Antisocial Personality Disorder (ASPD). For inclusion, the original proband was required to meet alcohol-dependence criteria as established by the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) (American Psychiatric Association, 1987
) as well as the criteria of Feighner et al. (1972) for definite alcoholism.
From these families, non-alcohol-dependent young adult subjects were recruited for the alcohol challenge. Each appropriate FHP man or woman from the COGA families had an alcohol-dependent father or mother. In the latter instance, subjects were only selected if the SSAGA revealed no evidence of alcohol-dependence in the mother prior to the birth of the alcohol challenge subject. Personnel at all six centres regularly scanned family pedigrees for individuals who met criteria for the alcohol administration protocol. These men and women were then contacted by telephone and, after obtaining informed consent, were scheduled for testing in San Diego. Only an estimated 5% of subjects approached to participate in the challenge protocol declined.
If the study of FHP women was to parallel exactly the methods originally used in men, large samples of matched FHP and FHN subjects would be required. With three test days per subject and an estimated minimum of 25 pairs (150 sessions) before reliable data are available, this approach was felt to be prohibitively expensive. Fortunately, men and women were similar on alcohol challenges in prior work (Lukas et al., 1989; Nagoshi and Wilson, 1989
), and a recent study demonstrated that a clearly low LR score can be identified in a subgroup within FHP subjects, and does not require an FHN control group (Schuckit and Smith, 1997
). These data have allowed the San Diego component to optimize the use of resources by presenting data without an emphasis on matched pairs. In addition, it was felt that useful information could be generated by taking advantage of existing data for men (the gold standard for alcohol challenges to date) and asking a more modest question of whether FHP women more closely resembled FHP men than FHN men.
The available FHN male controls (and a small pilot group of FHN women) were identified in San Diego from an annual mailing to ~700 1830-year-old people each year at the University of California, San Diego (Schuckit and Smith, 1996). Thus, they are true FHNs with no first- or second-degree alcoholic relatives. Individuals whose responses indicated that they had no alcohol-dependent close or distant relatives and who themselves had experience with alcohol but did not fulfil criteria for DSM-III-R alcohol dependence were selected as potential FHN controls. Potential subjects were then invited to the laboratory where they were evaluated with a SSAGA interview and, if appropriate for testing, scheduled.
The alcohol challenge paradigm has been described in detail in additional publications (Schuckit and Gold, 1988; Schuckit and Smith, 1996
). All subjects participated in a three-session protocol, the first of which involved laboratory acclimatization. Subjects then received, in random order, either placebo delivered through the apparatus described by Mendelson et al. (1984), or active alcohol using 0.72 g/kg (0.9 ml/kg) of laboratory grade ethanol for men and 0.61 g/kg (0.75 ml/kg) ethanol for women, doses chosen to produce comparable breath alcohol levels (BrACs) (Breslin et al., 1997
). Women were tested at the mid-follicular phase of their menstrual cycle. Drinks were prepared as a 20% solution in a non-caffeinated, sugar-free beverage which was consumed over an 8-min period. Consistent with the laboratory procedures used over the years, the placebo and active alcohol dose sessions were separated by a minimum of 24 h, and the subjects as well as two of the three experimenters were blind to the alcohol condition.
The protocols used to evaluate LR during placebo and active alcohol sessions were similar. Subjects arrived in the laboratory at approximately 07:00, received a light breakfast, and participated in baseline testing. At approximately 09:00 they were asked to take 8 min to consume a beverage (either alcohol or placebo), after which they were presented with repetitive 30-min epochs of the tests administered at baseline. These included the Subjective High Assessment Scale (SHAS) through which they indicated their current feelings on 13 items, each of which is rated from a score of 0 (none) to 36 (extreme) (Schuckit and Gold, 1988). In addition, at similar time points, subjects were evaluated for their level of body sway, or static ataxia, using a harness attached to their upper chest from which a rope and pulley mechanism records anteriorposterior and lateral movement over three separate 1-min readings (Schuckit and Gold, 1988
).
The information from the SHAS was evaluated several ways. First, an analysis of the psychometric properties of this measure revealed that seven of the 13 items clustered together, with an overall item-to-total correlation of 0.8 or higher, and a Cronbach alpha of 0.96 overall (0.96 for men and 0.97 for women). These included feeling high, clumsy, confused, dizzy, drunk, feeling alcohol effects, and difficulty concentrating. The resulting SHAS 7 score has less error variance than the full SHAS 13 after deleting items such as sleepiness (which could be affected by environmental events such as cross-country travel) and nausea (which was most prominent early in the session and appeared to reflect the subjects' reaction to the taste of the laboratory ethanol). SHAS 7 results are analysed both as raw, unadjusted data, and for FHP versus FHN men (where BrAC values are different) also as residual scores after considering BrACs, where SHAS 7 is regressed onto BrAC values at each time point. The evaluation of residuals in this instance might be a more accurate reflection of the intensity of response to alcohol because it removes error variance related to differences between people in their rate of absorption or distribution of alcohol. Body sway data for male groups are also presented as raw and BrAC residualized values.
Statistical evaluations were carried out to address differences across the three groups of female FHP, male FHP, and male FHN control subjects. Comparisons of responses to alcohol were also made between the 38 FHP women and 11 FHN female subjects as pilot data. In addition, results for FHP women were compared with data from males to test whether FHP women resembled FHP men, rather than FHN men. These analyses, as well as those with BrAC as a dependent variable, used a group by time analysis of variance (ANOVA), with time as a repeated measure, in order to evaluate main effects of group (GP) and group-by-time (GP x T). The variable for GP varied, including family history (FH), gender, or both FH and gender. Besides GP and GP x T effects, several individual time points were evaluated for significance using ANOVA, with the prediction (based on prior data) that FHPs will show lower levels of SHAS and body sway scores at 30, 60, 90 and 120 min after consumption of the beverage (Schuckit and Gold, 1988; Schuckit and Smith, 1996
; Schuckit et al., 1996
). The 75 FHP and 68 FHN men used in the analyses include 20 individuals in each group who were reported in a prior evaluation (Schuckit et al., 1996
), and these data were analysed after excluding 17 individuals (seven FHP males, five FHN males, and five FHP women) from among the original 198 men and women whose SHAS scores were >2 SD from the mean. Exclusions were based on the total of 198 subjects and, thus, the percentages excluded per subgroup are not equal.
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RESULTS |
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Figure 1 displays BrACs for the three groups. For the FHP women compared to FHN men, these include no GP [F(1,104) = 0.01, P = 0.90], nor GP x T effects [F(7,728) = 0.64, P = 0.72]. BrAC values were significantly higher for FHP men than FHN men for GP [F(1,141) = 4.81, P = 0.03) and GP x T [F(7,987) = 2.09, P < 0.05], but not for FHP women compared to FHP men for GP [F(1,111) = 2.21, P = 0.14) nor for GP x T [F(7,777) = 0.88, P = 0.52]. The FHP men showed higher BrAC values than FHN men at both 30 min [F(1,141) = 4.01, P < 0.05] and 60 min [F(1,141) = 5.09, P < 0.03].
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Figure 3 offers the same type of data, but now focusing on a single SHAS item, Drug Effect. Similar to the SHAS 7 results, compared to FHN men, FHP women had significantly lower scores for GP [F(1,110) = 5.62, P = 0.02] and GP x T [F(7,770) = 3.06, P = 0.004]; FHP men were significantly lower than FHN men for GP x T [F(7,994) = 2.13, P < 0.04] but not GP [F(1,142) = 1.83, P = 0.18]; and there were no significant differences between FHP men and women for GP x T [F(1,118) = 1.78, P = 0.19] nor for GP x T [F(7,826) = 0.72, P = 0.65].
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DISCUSSION |
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The results on body sway are less straightforward than the data on subjective feelings of intoxication. There is a significant overall GP x T difference for FHP women and FHN men, but the lower scores for the FHPs are only seen prior to 90 min. Thus, one difference between the current results and those reported previously by our group is the possibly higher sway results for FHP women from 90 min on, although none of these later time points revealed significant group differences. A possible interpretation of these data is that the daughters of alcoholics are showing a biphasic alcohol response, with a lower intensity during rising and peak BrACs, and an enhanced level of reaction as alcohol levels fall (Conrod et al., 1997). While other authors have reported this phenomenon, none of the acute alcohol challenges emanating from the San Diego group has shown a biphasic response in the past. A second possible explanation is that women, as compared to men, show higher levels of body sway at later time points, perhaps reflecting fatigue or other factors. Unfortunately, this question cannot be answered until an adequately sized sample of FHN women is tested. It is also important to point out that, while GP x T differences exist for the body sway data, at no time point from 90 min on did the women demonstrate significantly higher values than men. A third potential explanation is that these results represent the large variability inherent in measures of body sway, and that the group differences beyond 90 min might disappear if a larger sample was gathered.
Regarding gender, while a recent report from COGA noted many similarities for men and women in the clinical course of alcoholism (Schuckit et al., 1998), the overall rate of alcohol dependence is significantly lower among women (Substance Abuse and Mental Health Administration, 1998
). At least one study noted that the gender differential in the alcoholism risk is likely to reflect environmental and social influences, rather than a difference between men and women on their genetic predisposition toward alcohol dependence (Cloninger, 1987
). The fact that a similar biologically related risk factor might be observed in both men and women might serve to stimulate additional research regarding specific environmental factors that help protect women predisposed toward alcoholism from developing their disorder. This, in turn, might lead to more effective prevention techniques.
A search is now underway to identify specific genes in both animals and humans that might contribute to LR (Schuckit et al., 1999b). The current data, supporting evidence of a similar low LR on subjective feelings in both sons and daughters of alcoholics, might facilitate this search, because it may be possible to look for the same genetic material contributing to LR in both men and women. The identification of such genes will in turn promote the identification of individuals carrying an increased risk through this mechanism in a manner that is much less time-consuming and less expensive than the alcohol challenge protocol.
These speculations aside, the current results cannot be considered conclusive. While there are marked similarities between FHP men and women on their response to alcohol, the results would have been strengthened by an adequately sized group of FHN women. However, there are several indications that the low response to alcohol in the daughters of alcoholics is likely to be valid. First, the differences between FHP women and FHN men occurred despite similarities in the usual quantity of alcohol consumed, and in spite of a lower drinking frequency in the women which would have magnified, not diminished, their response to alcohol. Second, prior studies of men and women have not indicated that women are lower responders to alcohol in general (Lukas et al., 1989; Nagoshi and Wilson, 1989
). Thus, there is no reason to expect that the lower values for women on the SHAS overall and during the first 90 min on body sway is a gender, rather than a family history, phenomenon. Third, the pilot data reported here support the contention that FHP women are likely to demonstrate lower levels of response to alcohol than FHN women.
Several additional caveats should be considered in interpreting these data. First, all subjects came from COGA families or controls, with the former representing pedigrees selected because of a high density of alcohol dependence within relatives. It is possible that the data might differ in families with less heavy loading for alcoholism, although the results reported here are similar to those noted among pairs of FHP and FHN males from families with a lower level of alcoholism density. Finally, while FHP men reached higher BrAC values than FHN men, the FHPs still demonstrated a lower LR.
In conclusion, the current results relate alcohol challenge data from one of the largest samples of daughters of alcoholics tested to date. Despite reservations generated by the lack of an adequately sized sample of FHN women, the data are consistent with prior comparisons of FHP and FHN men. The results also support the conclusion that a low LR is a characteristic of daughters of alcoholics which is similar to FHP men and significantly lower than SHAS overall and the first 90 min of body sway reactions to alcohol in FHN men.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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