Genetic and environmental contributions to serum retinol and alpha-tocopherol concentrations: the Stanislas Family Study

BACKGROUND: Although numerous environmental factors are documented to influence serum retinol and alpha-tocopherol concentrations, little is known about the genetic versus the environmental contributions to variations in these traits. OBJECTIVE: The aim of this study was to estimate additive genetic heritability and household effects for serum retinol and alpha-tocopherol concentrations in a variance component analysis. DESIGN: In a sample of 387 French families, information on serum retinol and alpha-tocopherol concentrations, usual dietary intake, lifestyle, and serum lipid profiles and related polymorphisms (apolipoprotein E, apolipoprotein C-III, apolipoprotein B, cholesteryl ester transfer protein, and lipoprotein lipase) was obtained. RESULTS: For serum retinol--after adjustment for sex, age, body mass index, alcohol consumption, oral contraceptive use, and serum albumin, triacylglycerol, and apolipoprotein A-I concentrations--additive genetic effects and shared common environment contributed 30.5% and 14.2% of the total variance, respectively. For serum alpha-tocopherol, approximately 22.1% of the total variance was due to the additive effects of genes and 18.7% to those of household environment, after adjustment for the covariates sex, age, vitamin E intake, oral contraceptive use, and cholesterol, triacylglycerol, and apolipoprotein A-I concentrations. For both vitamins, the influence of measured polymorphisms was not significant. Moreover, heritability and household effect estimates were not significantly different between the 4 classes of relatives and did not vary significantly when families shared more meals at home. CONCLUSIONS: The results show that serum retinol and alpha-tocopherol concentrations are under genetic control in healthy families.     

Erythrocyte aldehyde dehydrogenase activity: lack of association with alcohol use and dependence or alcohol reactions in Australian twins

AIM: Aldehyde dehydrogenase 1 (ALDH1) has been advocated as a marker of alcohol intake. The absence or low levels of ALDH1 may be associated with alcohol-induced flushing or other reactions to alcohol in Europeans and therefore, with reduced alcohol use. This study tested whether variation in erythrocyte ALDH1 activity was associated with alcohol use, alcohol dependence or reactions to alcohol in unselected subjects of European descent, and whether variation in ALDH1 activity was subject to genetic influences. METHODS: ALDH activity was measured in erythrocytes from 677 men and women who had participated in a twin study of alcohol use and dependence. RESULTS: There were no significant effects of sex, alcohol consumption or alcohol dependence on ALDH activity. Subjects who reported reactions to alcohol did not have low activity. Women aged below 45 years had lower ALDH activity than men or older women. The heritability of ALDH activity was 56% (95% confidence interval = 42-67%). CONCLUSIONS: Previous reports that erythrocyte ALDH activity is low in alcoholics were not substantiated in this community-based sample. Associations with alcohol reactions were not found. ALDH activity varies widely between subjects, largely because of genetic factors.     

Sources of variability of human plasma apolipoprotein A-IV levels and relationships with lipid metabolism

Plasma apolipoprotein (apo) A-IV concentration was determined by immunoelectrophoretic assay (EIA) in 119 nuclear families. No significant effect of concomitants such as age, weight, height, body mass index, tobacco, and alcohol consumption was observed on apo A-IV levels in men and in boys. In women, contraceptive use and hormonal status affected apo A-IV levels. In girls, only age influenced the quantitative phenotype. After adjusting by specific concomitants significant correlations were observed between apo A-IV levels and triglycerides, apolipoprotein A-I and apo B levels, suggesting a role of apolipoprotein A-IV in the hepatic lipid metabolism. Intrafamilial correlations were estimated to investigate the plausibility of a common family factor. The results obtained in this study showed a significant correlation between family members with the exception of mother-daughter pairs. Using a variance components model, the contribution of genetic and environmental factors was then investigated. Different statistical models were used and two major hypotheses were statistically acceptable: the first hypothesis supports that shared and specific environmental factors explain 35 and 65%, respectively, of the total adjusted plasma apo A-IV variation. The fraction of apo A-IV variability attributable to genetic factors was null. The second hypothesis supports that the fraction of variability attributable to apo A-IV genetic variation is 67% and the common spouse environmental factors are responsible for 33% of the total variability and no specific environmental effect was found. Among the two hypotheses, taking account of the metabolism function, we support the first one without excluding gene- environment interactions which could mask the genetic influence. © 1994 Wiley-Liss, Inc.     

儿童青少年双生子瘦素遗传度估计及影响因素分析

目的 分析影响儿童青少年瘦素的遗传因素和环境因素,探讨性别、年龄和体质量指数(BMI)的作用,为儿童肥胖早期预防提供依据.方法 选择6～18岁同性别双生子337对,平均年龄(12.3±3.5)岁,其中同卵双生子257对,异卵双生子80对.采用DNA微卫星多态性鉴定卵性.应用Mx结构方程模型分别计算年龄和BMI调整前后瘦素的遗传度,并检验性别、年龄和BMI对于模型的作用.结果 不同性别间身高、体重和瘦素水平差异均有统计学意义(P值均＜0.05).相关分析显示,瘦素水平与性别、年龄和BMI相关(P值均＜0.0l).遗传分析发现,调整前年龄方差在女生中影响较大,而男生则受共同环境方差影响较大.调整后男生特异性性别方差降低,最适模型为ACE(scale)模型.男、女生瘦素遗传模型一致,遗传度为20％.结论 儿童青少年人群中瘦素水平与性别、年龄和BMI相关.瘦素受遗传和环境因素共同影响.调整年龄及BMI后,瘦素遗传度不受性别影响.     

Genetic and environmental contributions to serum ascorbic acid concentrations: the Stanislas Family Study

Although numerous environmental factors are documented to influence serum ascorbic concentrations, little is known about the genetic versus environmental contributions to variation of this trait. The aim of this study was to estimate family correlation and, additive genetic heritability and household effects in a variance component analysis for serum ascorbic acid concentrations. In a sample of ninety French families, information was obtained regarding serum ascorbic acid concentrations, usual dietary intake, lifestyle, and other related covariates. Spouse, parent-offspring and offspring-offspring significant correlation coefficients for serum ascorbic acid concentrations, adjusted for age, cigarette consumption and oral contraceptive use, were 0.432, 0.298 and 0.485, respectively, and for adjusted values for additional diet covariates (vitamin C intake and fruit and vegetable consumption), were 0.362, 0.154 and 0.348, respectively. Variance component analysis for serum ascorbic concentrations showed no significant genetic contribution to variability of this trait. Conversely, household common environment accounted for 27.7 and 42.6% in parents and offspring, respectively, after adjustment for age, cigarette consumption and oral contraceptive use. After adjustment for the two additional diet covariates (vitamin C intake and fruit and vegetable consumption) household common variance decreased to 13.6 and 30.5% in parents and offspring, respectively. These results show that serum ascorbic acid concentrations aggregate within healthy families partly due to diet intake but without a significant genetic component.     

Sex differences in genetic and environmental determinants of pulse pressure

Pulse pressure (PP) is an independent risk factor for cardiovascular disease. PP rises with age, more so in women. We examined sex differences in the correlations and variance components of PP in adult subjects from 767 nuclear families, enriched with those containing twins, from the Victorian Family Heart Study. After adjusting for age, we found no significant differences in the means or variances of PP in males and females. Under the assumption of no sex differences, the proportions of variance due to shared genes, shared environment, and individual-specific environment were 20%, 23% and 57%, respectively. However, same-sex relative pairs had significantly higher correlations than opposite-sex pairs (P = 0.005), implying the existence of sex-dependent effects. Extensions to the simple variance components model suggested three possible explanations for these differences: smaller genetic correlation between opposite-sex pairs (rhoG,MF = 0.45, P = 0.007); smaller environmental correlation between opposite-sex pairs (P = 0.0003); or different environmental and genetic correlations obtained by estimating genetic, environmental, and individual variance components separately for males and females (not nested, Akaike's Information Criterion (AIC) smaller by 6.69). Under the last model, the genetic component of PP variance is greater for males (1.62 vs 0.33) while the environmental component is greater for females (1.84 vs 0), which would have implications for the planning of gene discovery studies, since heritability would be higher in males. However, the second (environmental) approach best fits the data according to the AIC. Genetic explanations for sex differences in phenotypic correlations may be misleading unless shared environmental factors are also considered. PP illustrates a phenotype in which sex dependency represents an important component of phenotypic determination that can be revealed by detailed variance components modelling.     

Biological and environmental sources of familial aggregation of blood pressure: the Jerusalem Lipid Research Clinic

Genetic and cultural determinants of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were estimated using a path model on a sample of families examined in the Jerusalem Lipid Research Clinic. This model involves 10 parameters to be estimated from a total of 16 correlations (leaving ample degrees of freedom to test the goodness-of-fit). The general model fitted SBP (X2(6) = 6.95, p = 0.33) and DBP (X2(6) = 5.44, p = 0.49) very well. Both genetic (h2) and cultural (c2) components of inheritance were statistically significant for both blood pressure variables. Under the most parsimonious model, genetic heritabilities (h2) were estimated to be 0.20 and 0.28 for SBP and DBP respectively. Cultural heritability (c2) was 0.12 for SBP and 0.08 for DBP. A significant fraction of the estimate for cultural inheritance was due to a sibling environmental effect not mediated through their parents. Within this population genetic factors, common environmental factors and concomitant variables such as sex, age and origin explained about 40% of blood pressure variability. Most of the variance appears to be due to unmeasured environmental factors and errors of measurement.     

Genetic and environmental influences on level of habitual physical activity and exercise participation

In order to quantify genetic and environmental determinants of physical activity level, 1,610 subjects from 375 families who lived in the greater Québec city area completed a three-day activity record in 1978-1981. Level of habitual physical activity, which includes all the usual activities of life, and exercise participation, which includes activities requiring at least five times the resting oxygen consumption and more, were derived from this record. Familial correlations were computed in several pairs of biologic relatives and relatives by adoption after adjustment for the effects of age, sex, physical fitness, body mass index, and socioeconomic status, and analyzed with a model of path analysis that allows the separation of the transmissible effect between generations (t2) into genetic (h2) and cultural (b2) components of inheritance. The transmission was found to be statistically significant, but was accounted for by genetic factors for level of habitual physical activity (t2 = h2 = 29%), and by cultural factors for exercise participation (t2 = b2 = 12%). Although non-transmissible environmental factors remain the major determinants of these two physical activity indicators in this population, the results suggest that children can acquire from their parents certain customs regarding exercise behavior and that the propensity toward being spontaneously active could be partly influenced by the genotype.     

Mortality in England and Wales attributable to current alcohol consumption

STUDY OBJECTIVE: To estimate the number of deaths attributable to current alcohol consumption levels in England and Wales by age and sex. DESIGN: Epidemiological approach using published relative risks and population data. SETTING: England and Wales. MAIN OUTCOME MEASURES: Numbers of deaths by age and sex and years of life lost for alcohol related conditions. RESULTS: Because of the cardioprotective properties of alcohol, it is estimated that there are approximately 2% fewer deaths annually in England and Wales than would be expected in a non-drinking population. This proportion varies greatly by age and sex and only among men aged over 55 years and women aged over 65 years is there likely to be found a net favourable mortality balance. It is also estimated that there were approximately 75 000 premature years of life lost in England and Wales in 1996 attributable to alcohol consumption. The main causes of alcohol attributable mortality among the young include road traffic fatalities, suicide and alcoholic liver disease. CONCLUSIONS: At a population level, current alcohol consumption in England and Wales may marginally reduce mortality. However, the benefit is disproportionately found among the elderly. Estimating alcohol attributable mortality by age and sex may be a useful indicator for developing alcohol strategies. More research into the possible effect modifications of pattern of consumption, beverage type, age and gender will enable these estimates to be improved.     

The Cincinnati lipid research clinic family study: Analysis of commingling and family resemblance for fasting blood glucose

Our specific aim in this study was to investigate commingling and family resemblance for fasting blood glucose in 160 randomly selected white families from the Princeton School District Lipid Research Clinics Family Study. Adjustment of fasting blood glucose for the influence of age, sex, and the use of oral contraceptives and construction of indices were performed simultaneously using multiple regression methods. Path analysis was carried out, constructing an environmental index based on special diet usage, hematocrit, and obesity, which was also adjusted for the influences of age and sex. Commingling analysis and segregation analysis using the mixed model were also performed. Nearly 16% of the variance of fasting blood glucose was accounted for by age and sex. Obesity itself, which constituted the index, explained an additional 4% of the variance of fasting blood glucose. Significant genetic heritability for fasting blood glucose was documented by both path analysis and segregation analysis. In aggregate, we conclude that though there was a major familial vector accounting for within-family aggregation of blood glucose, it was probably generated by a multifactorial component as compared to a major locus. Under the most parsimonious model, path analysis estimated the genetic and cultural heritabilities as h² = .39 ± .08 and c² = .06 ± .03., respectively.     

Environmental and behavioral determinants of fasting plasma glucose in women. A matched co-twin analysis

Comparing results of an unmatched analysis in a sample of unrelated persons created by randomly selecting one twin from each pair with results of a matched monozygotic co-twin analysis provides a means of distinguishing environmental influences from genetic influences on a dependent variable of interest. Determinants of the fasting plasma glucose level were investigated in a large sample of adult female nondiabetic twins from the Kaiser Permanente Twin Registry. In the subsample of unrelated persons, fasting plasma glucose was significantly and positively associated with age, body mass index, uric acid level, and alcohol intake and was significantly inversely related to leisure time physical activity. When monozygotic twins were treated as matched pairs, only the effects of body mass index and alcohol consumption remained significant, whereas the association with leisure time physical activity was greatly reduced and no longer statistically significant. These results suggest that behavioral and therefore alterable aspects of obesity and alcohol consumption influence the fasting plasma glucose level; alcohol consumption may be a risk factor for non-insulin-dependent diabetes mellitus; and common underlying genetic factor(s) may be responsible for the negative association between physical activity and fasting plasma glucose.     

Clustering of high density lipoprotein cholesterol levels in premenopausal and postmenopausal female twins

Previous family and twin studies indicate that genetic variation makes an important contribution to individual variation in high density lipoprotein cholesterol (HDL) levels, even after adjustment for covariates (such as obesity and alcohol consumption) that also cluster in families. However, most studies assume that genetic mechanisms affecting variation in HDL level are the same in all subgroups of the population (e.g., men versus women, by age). Using data from the Kaiser-Permanente Women Twins Study, we found different patterns of clustering for monozygotic (MZ) and dizygotic (DZ) twins depending on menopausal status. Premenopausal MZ twins were more similar than postmenopausal MZ twins (r_i = 0.79 and r_i = 0.61, respectively, after adjustment for age, alcohol consumption, smoking status, degree of obesity, and leisure-time exercise); premenopausal and postmenopausal DZ twins were alike to the same extent (r_i = 0.31 and r_i = 0.32, respectively, adjusted as above). These data suggest that either postmenopausal MZ twins have a greater degree of shared environment than postmenopausal DZ twins (e.g., postmenopausal female hormone use) or that genetic mechanisms that affect individual variation in HDL level differ in pre- and postmenopausal women. Data were not available on postmenopausal female hormone use. If genetic mechanisms that influence variation in HDL levels differ between pre- and postmenopausal women, genetic epidemiologic methods that assume that genetic and environmental sources of variation are the same for all groups of individuals may lead to false conclusions. © 1993 Wiley-Liss, Inc.     

Alcoholism: epidemiology, diagnosis, and biological aspects

Recent well-designed studies involving standardized diagnostic instruments and random surveys of American households have provided informative data as to the current prevalence of alcohol abuse/dependence in the United States. Data from three epidemiological sites are reviewed, and the breakdown of alcohol abuse/dependence by age, sex, and race is presented. The criteria for the diagnosis of alcoholism are reviewed. Recent emphasis on the use of laboratory studies is addressed, and the need for caution in relying on laboratory results is emphasized. The importance of a careful history and the need to develop a relationship with the patient and family members is noted. Current biological findings in regard to alcoholism include the effect of alcohol on the cell membrane and the evidence, as well as lack of evidence, for genetic contributions to alcoholism. The Tetrahydroisoquinoline (THIQ) theory is briefly reviewed and cautionary remarks concerning premature emphasis on this theory are made.     

Childhood acute lymphoblastic leukemia associated with parental alcohol consumption and polymorphisms of carcinogen-metabolizing genes

BACKGROUND: Limited information is available on the association of parental consumption of alcohol prior to and during pregnancy with the risk of childhood leukemia, as well as for the potentially modifying role of genetic polymorphisms. METHODS: We conducted a population-based, case-control study of 491 incident cases of acute lymphoblastic leukemia age 0-9 years and matched on age and sex to 491 healthy controls. Cases were identified at tertiary care centers in the Province of Québec between 1980 and 1993. Each parent was interviewed separately about alcohol consumption habits. We also used a case-only design with 186 cases to estimate interaction odds ratios between prenatal exposure and child DNA variants in the GSTM1 and CYP2E1 genes. RESULTS: The adjusted odds ratio for any maternal consumption during pregnancy was 0.7 (95% confidence interval = 0.5-0.9). The interaction odds ratios for the GSTM1 null genotype during third pregnancy trimester was 2.4 (95% confidence interval = 1.1-5.4); the interaction odds ratio for CYP2E1 variant G-1295C (or allele *5) during the nursing period was 4.9 (95% confidence interval = 1.5-16.7). CONCLUSIONS: The observed association with maternal alcohol consumption during pregnancy could be due to the potential chemopreventive effects of flavonoids found in wine and beer. These possible effects of alcohol may be at least partially genetically determined, although data are preliminary.     

Severity of alcohol dependence in the Swedish adult population: Association with consumption and social factors

The severity of alcohol dependence can be estimated by the number of DSM-IV criteria that are fulfilled for this disorder. This paper describes the proportions in a general population sample that meet different numbers of diagnostic criteria for alcohol dependence and their association with drinking and social background factors. Data came from a random, cross-sectional, self-report survey of adults from 12 Swedish communities. 28,800 persons, age 19–70, were surveyed through postal questionnaires. 14,706 questionnaires (51%) could be used for analysis. Alcohol dependence was assessed by questions relating to the seven DSM-IV criteria for alcohol dependence. Alcohol consumption and social background factors were examined in relation to alcohol dependence. A total of 73.8% of the general population fulfilled no criteria for alcohol dependence; 4.0% reported 3 or more criteria and qualified for the diagnosis of alcohol dependence. There were trends toward an increasing number of dependence criteria with increasing consumption levels and negative social background factors. The majority of people with alcohol dependence however did not drink at the highest consumption levels, did not live alone, and were not unemployed. Given the current definition of alcohol dependence the majority of people have few criteria fulfilled (3 or 4) and few social problems. This has important implications for treatment as dependence with low severity may require less treatment and less specialist involvement.     

Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.     

Interaction of alcohol and tobacco as risk factors in cancer of the laryngeal region.

The aim of this study is to present risk assessments for the combined effect of alcohol and tobacco in cancer of the larynx. The case control study included all newly diagnosed laryngeal cancer patients under the age of 75 in Denmark during the years 1980-2. Four age and sex matched controls were selected using the municipal person registry in which the case was listed. Ninety six per cent of all cases and 78% of controls participated in the study, which is based on 326 cases and 1134 controls. Information on alcohol consumption and tobacco use was obtained by means of mailed questionnaires. For all laryngeal cancers as well as for the subgroups concerning cancer of the glottis and supraglottis alcohol consumption and tobacco use were found to be important risk factors. The effect of joint exposure was greater than the effect predicted from the sum of effects of each factor acting separately. Thus the combined effect follows a multiplicative rather than additive model.     

Alcohol response and consumption in adolescent rhesus macaques: life history and genetic influences

The use of alcohol by adolescents is a growing problem and has become an important research topic in the etiology of the alcohol use disorders. A key component of this research has been the development of animal models of adolescent alcohol consumption and alcohol response. Because of their extended period of adolescence, rhesus macaques are especially well suited for modeling alcohol-related phenotypes that contribute to the adolescent propensity for alcohol consumption. In this review, we discuss studies from our laboratory that have investigated both the initial response to acute alcohol administration and the consumption of alcohol in voluntary self-administration paradigms in adolescent rhesus macaques. These studies confirm that adolescence is a time of dynamic change both behaviorally and physiologically, and that alcohol response and alcohol consumption are influenced by life history variables, such as age, sex, and adverse early experience in the form of peer-rearing. Furthermore, genetic variants that alter functioning of the serotonin, endogenous opioid, and corticotropin-releasing hormone systems are shown to influence both physiological and behavioral outcomes, in some cases interacting with early experience to indicate gene by environment interactions. These findings highlight several of the pathways involved in alcohol response and consumption, namely reward, behavioral dyscontrol, and vulnerability to stress, and demonstrate a role for these pathways during the early stages of alcohol exposure in adolescence.     

Determinants of transition across the spectrum of alcohol use and misuse in Nigeria

Many studies have examined the risk factors associated with alcohol use disorders. No information is available from developing countries about the factors that may determine the transitions across different levels of use and misuse. Alcohol use and its misuse were assessed in a cohort of 2143 Nigerians using Version 3.0 of the World Health Organization Composite International Diagnostic Interview (WHO-CIDI). This generated six levels of alcohol use and related disorders. Using age of onset variables created for the purpose, analysis was done to determine rates of and risk factor for transition between the levels. Lifetime prevalence estimates were 57.8% for alcohol use, 27.6% for regular use, 2.9% for abuse, and 0.3% for dependence. Whereas 47.8% transited to regular use from lifetime ever use, only 10.5% transited to abuse from regular use and 9.5% from abuse to dependence. Male sex, age 18–49 years and being never married predicted onset of alcohol use. Transition to regular use was predicted only by male sex while transition to abuse was predicted by male sex and age 35–49 years. Factors associated with recovery from abuse were female sex and a student status. Higher rates of transition occurred in the stages preceding the onset of alcohol use disorders. Sex and age were the main determinants of transition, with male gender and middle age being risk factors for transition to problematic use of alcohol.