George P. Vogler

Heritabilities of Apolipoprotein and Lipid Levels in Three Countries

This study investigated the influence of genes and environment on the variation of apolipoprotein and lipid levels, which are important intermediate phenotypes in the pathways toward cardiovascular disease. Heritability estimates are presented, including those for apolipoprotein E and AII levels which have rarely been reported before. We studied twin samples from the Netherlands (two cohorts; n = 160 pairs, aged 13-22 and n = 204 pairs, aged 34-62), Australia (n = 1362 pairs, aged 28-92) and Sweden (n = 302 pairs, aged 42-88). The variation of apolipoprotein and lipid levels depended largely on the influences of additive genetic factors in each twin sample. There was no significant evidence for the influence of common environment. No sex differences in heritability estimates for any phenotype in any of the samples were observed. Heritabilities ranged from 0.48-0.87, with most heritabilities exceeding 0.60. The heritability estimates in the Dutch samples were significantly higher than in the Australian sample. The heritabilities for the Swedish were intermediate to the Dutch and the Australian samples and not significantly different from the heritabilities in these other two samples. Although sample specific effects are present, we have shown that genes play a major role in determining the variance of apolipoprotein and lipid levels in four independent twin samples from three different countries.

Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United Kingdom, and the United States

OBJECTIVES The purpose was to determine filter ventilation and the nicotine content of tobacco and their contribution to machine-smoked yields of cigarettes from the United States, Canada, and the United Kingdom. METHODS Ninety-two brands of cigarettes (32 American, 23 Canadian, and 37 British brands) were purchased at retail outlets in State College, Pennsylvania, United States, Toronto, Canada, and London, United Kingdom. A FIDUS FDT filter ventilation tester measured the percentage air-dilution from filter vents. High-pressure, liquid chromatography was used to measure the nicotine content of tobacco. Regression techniques were used to examine the contributions of tobacco nicotine content and filter ventilation to machine-smoked yields of tar, nicotine, and carbon monoxide (CO). RESULTS Ninety-four per cent of the American brands, 91% of the Canadian brands, and 79% of British brands were ventilated. The total nicotine content of tobacco and percent nicotine (by weight of tobacco) averaged 10.2 mg (standard error of the mean (SEM) 0.25, range: 7.2 to 13.4) and 1.5% (SEM 0.03, range 1.2 to 2) in the United States, 13.5 mg (SEM 0.49, range: 8.0 to 18.3) and 1.8% (SEM 0.06, range: 1.0 to 2.4) in Canada, 12.5 mg (SEM 0.33, range: 9 to 17.5) and 1.7% (SEM 0.04, range: 1.3 to 2.4) in the United Kingdom. Multiple regression analyses showed that ventilation was by far the largest factor influencing machine-smoked yields of tar, nicotine, and CO. CONCLUSION Filter ventilation appears to be the predominant method for reducing machine-smoked yields of tar, nicotine, and CO in three countries. However, some brands contain about twice as much nicotine (total content or percent nicotine) as do others, indicating that tobacco types or blends and tobacco casings can be used to manipulate nicotine content and nicotine delivery of cigarettes.

Family History as an Indicator of Risk for Reading Disability

Self-reported reading ability of the parents of 174 reading-disabled children and of 182 controls was used to estimate the posterior probability that a child will become reading disabled given that a parent is affected. Using Bayesian inverse probability analysis, it was found that the risk for reading disability is increased substantially (by a factor of from about 4 to over 13) if either parent has had difficulty in learning to read. The absolute risk appears to be sufficiently high to warrant clinical application of family history information as one component of a multifactorial risk assessment battery.

Right ventricular end-diastolic volume as a measure of preload

Right ventricular (RV) end-diastolic volume index (RVEDVI) measured by a modified thermodilution pulmonary artery catheter has been proposed as an improved measure of cardiac preload, compared with pulmonary capillary wedge pressure (PCWP). This study compared the correlation of RVEDVI and PCWP with cardiac index (CI) to determine which parameter better reflected ventricular preload. Modified thermodilution catheters were placed in 38 critically ill patients. Hemodynamic parameters were recorded in these patients at 2- to 4-hour intervals for 1 to 7 days. Complete data sets (1,008) were obtained. Regression analysis was performed comparing PCWP, RVEDVI, RV ejection fraction (RVEF) to CI in the entire group and in individual patients. Because mathematical coupling may exist between RVEDVI and CI, the correlation between these variables was corrected for mathematical coupling using the method described by Stratton. Simple regression analysis of data from all patients, uncorrected for mathematical coupling, yielded a significant correlation between CI and RVEDVI (r = 0.60, p < 0.0001), RVEF (r = 0.37, p < 0.0001), and PCWP (r = 0.01, p < 0.001). Correction for mathematical coupling between RVEDVI and CI resulted in a minor changes of the correlation coefficient to 0.56. In individual patients, a significant, uncorrected correlation (p < 0.05) was found between RVEDVI and CI in 27 of the 38 patients, whereas 11 patients had a significant correlation between PCWP and CI. RVEDVI correlated more closely with CI than did PCWP, even after correlation for mathematical coupling. In both the group as a whole and in individual patients, RVEDVI was a better indicator of cardiac preload.

Quantitative Trait Loci Analysis of Structural and Material Skeletal Phenotypes in C57BL/6J and DBA/2 Second-Generation and Recombinant Inbred Mice

QTL analyses identified several chromosomal regions influencing skeletal phenotypes of the femur and tibia in BXD F2 and BXD RI populations of mice. QTLs for skeletal traits co‐located with each other and with correlated traits such as body weight and length, adipose mass, and serum alkaline phosphatase.

A twin study of non-alcohol substance abuse

Except for alcohol abuse, little is known about the familial aggregation for substance abuse. Here we report twin resemblance for non-alcohol substance use in the Washington University Twin Series, wherein probands were identified by consecutive admission to psychiatric facilities in the St. Louis area. A 5-point substance abuse scale was constructed with values anchored by never used drugs (1) to drug dependence (5). Year of birth was the most powerful predictor of drug use--younger twins scored far higher than older twins. Either heritability or common environment had to be included in the regression model to avoid a significant drop in explained variance, but which was more important could not be resolved. The correlation for identical twins exceeded that for fraternal twins, suggesting the possibility of a heritable factor.

Dopamine receptor genes (DRD2, DRD3 and DRD4) and gene-gene interactions associated with smoking-related behaviors.

Cigarette smoking, like many addictive behaviors, has a genetic component, and the dopamine D2‐like receptor genes (DRD2, DRD3 and DRD4) are candidates for contributing to these behaviors. Phenotypic information concerning smoking‐related behaviors from a nationally representative sample of research volunteers was analyzed for association with polymorphisms in these genes. Genotype status at the DRD2 intron 2 simple tandem repeat was related to cigarettes per day (P = 0.035) and heaviness of smoking index (P = 0.049). The presence of the glycine allele at the S9G polymorphism of the DRD3 gene was associated with frequency/quantity measures of smoking [log‐transformed time to first cigarette (P = 0.031) and heaviness of smoking index (P = 0.035)]. There was a trend for DRD4 long alleles of the variable number of tandem repeats polymorphism to be associated with reduced severity of three withdrawal symptoms [desire/craving (P = 0.054); anger/irritability (P = 0.10); and trouble sleeping (P = 0.068)]. Interactions between genotypes at all three genes were associated with nervousness (P = 0.020) and trouble sleeping (P = 0.015). An interaction between DRD2 and DRD3 was found for trouble concentrating (P = 0.020). These relationships present possible dopamine‐related responses to nicotine that warrant further study.

Familial Aggregation of Lipids and Lipoproteins in Families Ascertained through Random and Nonrandom Probands in the Iowa Lipid Research Clinics Family Study

The aggregation of lipids [total cholesterol (CH) and triglyceride (TG)] and lipoproteins [high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL)] in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study was examined. Nonrandom probands were selected because their lipid levels (at a prior screening visit) exceeded a certain pre-specified threshold. The statistical method conditions the likelihood function on the actual event that the probands value is beyond the threshold. This method allows for estimation of the path model parameters in randomly and nonrandomly ascertained families jointly and separately, thus enabling tests of heterogeneity between the two types of samples. Marked heterogeneity between the random and the hyperlipidemic samples is detected in the multifactorial transmission for TG and HDL, and moderate heterogeneity is detected for CH and LDL, with a pattern of higher genetic heritability estimates in the random than nonrandom samples. The observed pattern of heterogeneity is compatible with a higher prevalence in the random sample of certain dyslipoproteinemias that are associated with nonelevated lipids. For the random samples, genetic heritabilities are higher for CH and HDL (about 60%) than for TG and LDL (about 50%). For the nonrandom samples those estimates are about 45, 40, 35 and 30% for HDL, CH, LDL and TG, respectively. Little to no cultural (familial environmental) heritability is evident for CH and LDL, although 10-20% of the phenotypic variance is due to cultural factors for TG and HDL. These results suggest that the etiologies for lipids and lipoproteins may be quite different in random versus hyperlipidemic samples.

The Washington University Twin Study of alcoholism

Genetic contributions to the liability to develop alcoholism in males of Northern and Western European ancestry are well‐established. However, questions remain concerning the role of genetic variation in the etiology of alcoholism among non‐white populations, among women, and the possibility of etiological heterogeneity in subtypes of alcoholism. The answers to these questions are needed to help define phenotypes for molecular genetic studies searching for QTLs for alcoholism. Twins from 295 pairs were consecutively ascertained at inpatient and outpatient psychiatric and alcohol treatment facilities in St. Louis, MO in 1981–1986. Probands and willing cotwins were evaluated by structured psychiatric interviews, psychometric assessment, and lifetime treatment records. One hundred fifty‐four probands met criteria for alcohol abuse/dependence (AAD), including twins from 45 MZ, 50 same‐sex DZ, and 59 opposite‐sex pairs. Twin‐pair resemblance was evaluated for AAD and alcohol dependence (AD), as well as for subsets defined by gender, patterns of comorbidity, ethnic background, and clinical features. Among males, heritability of AAD and AD was substantial, with little evidence for common environmental contributions to family resemblance. Pair resemblance among females was also substantial, but similar for MZ and DZ pairs, yielding near‐zero heritability estimates. However, based on these sample sizes, the sex differences were not statistically significant. The results confirm prior studies of strong genetic influences on alcoholism in males, but suggest lower genetic influence in females. Power to test other sources of heterogeneity was limited, but the results suggest no evidence for higher heritability for male early onset alcoholism or for alcoholism with comorbid antisocial personality.

Genetic and environmental influences on waist-to-hip ratio and waist circumference in an older Swedish twin population.

OBJECTIVE: To investigate the genetic and environmental influences on waist-to-hip ratio (WHR) and waist circumference (WC) measurements in males and females.DESIGN: Measurements taken from 1989–1991 as part of The Swedish Adoption/Twin Study of Aging (SATSA) were used for analysis. The SATSA sample contains both twins reared together as well as twins reared apart.SUBJECTS: 322 pairs of twins (50 identical, 82 fraternal male pairs and 67 identical, 123 fraternal female pairs); age range: 45–85 y (average age, 65 y).MEASUREMENTS: Waist-to-hip ratio (WHR), waist circumference (WC) and body mass index (BMI).RESULTS: In males, additive genetic effects were found to account for 28% of the variance in WHR and 46% of the variance in WC. In females, additive genetic effects were found to account for 48% of the variance in WHR and 66% of the variance in WC. The remaining variance in males was attributed to unique environmental effects (WHR, 72%; WC, 54%) and in females the remaining variance was attributed to unique environmental effects (WHR, 46%; WC, 34%) and age (WHR, 6%). When BMI was added into these models it accounted for a portion of the genetic and environmental variance in WHR, and over half of the genetic and environmental variance in WC.CONCLUSION: There are both genetic and environmental influences on WHR and WC, independent of BMI in both males and females, and the differences between the sexes are significantly different.