Martha B. Haviland

The Relationship Between Risk Factor Levels and Presence of Coronary Artery Calcification is Dependent on Apolipoprotein E Genotype

An important research question in the study of the genetics of coronary artery disease (CAD) is whether information about genetic variation will improve our ability to predict CAD beyond established risk factors. This question is especially relevant to the goal of identifying young, asymptomatic adults with coronary atherosclerosis who would benefit most from interventions to reduce risk. Coronary artery calcification (CAC) detected by electron-beam computed tomography is a relatively new method for detecting coronary atherosclerosis in asymptomatic individuals that has been shown to be a more accurate indicator of coronary atherosclerosis in asymptomatic individuals than other noninvasive techniques. In a study of asymptomatic women (n=169) and men (n=160) between the ages of 20 and 59 representative of the Rochester, Minnesota population, we used logistic regression to ask whether the most common Apolipoprotein (Apo) E genotypes (epsilon3/2, epsilon3/3, and epsilon4/3) predict the presence of CAC. The addition of information about ApoE genotypes to logistic models containing each separate risk factor did not improve prediction of CAC (P>0.10 in both women and men). However, there was significant evidence (P<0.10) that associations between variation in the probability of having CAC and variation in body mass index, plasma total cholesterol, and plasma ApoB in men and body mass index, plasma triglycerides, plasma ApoA1, and plasma ApoE in women were dependent on ApoE genotype. Thus, variation in the gene coding for ApoE may play a role in determining the contribution of established risk factors to risk of CAC.

A measure of adaptation to problematic academic and interpersonal tasks of middle school

This study examined the development and validation of a measure of adaptation to problematic academic and interpersonal tasks that arise during the transition to middle school (Survey of Adaptational Tasks of Middle School-SAT-MS). In terms of Bronfenbrenner’s framework of “ecological transitions,” a set of psychosocial tasks was reliably identified, and the perceived impact of these tasks was found to be related to self-concept and perceived school environment. Sex differences consistent with differential developmental expectations emerged. The results suggested that for girls, peer relationship tasks were most salient with regard to criterion measures, whereas for boys, peer relationship, conflict with authority, and academic pressure tasks all related to criterion measures. The major findings were replicated for both a predominantly white, suburban sample and a predominantly urban, nonwhite sample. The results are discussed in terms of the needs of children during periods of adaptational challenge. Inquiry into those aspects of the school environment that provide barriers to children’s successful academic and interpersonal functioning is clearly increasing. There is a growing realization that numerous “hassles” (i.e., microstressors, or brief, frequently occurring life situations that require immediate adaptation or coping) faced by students during the school day can have a deleterious impact on adjustment (Lazarus & Folkman, 1984). During transitions from one school to another there is a confluence of factors that heighten the adaptational demands on students: unfamiliar physical environment, largely new set of peers and adults with whom to interact, uncertainty about

Biological Complexity and Strategies for Finding DNA Variations Responsible for Inter-individual Variation in Risk of a Common Chronic Disease, Coronary Artery Disease

Most common chronic diseases of humans aggregate, but do not segregate, in families. The segregation-linkage research paradigm has not provided great insights into their genetic etiology. In this paper, using coronary artery disease as an example, we discuss hierarchical organization, coherence, emergent properties and dynamism as features that characterize the complexity of genotype-phenotype relationships. We summarize a research strategy for evaluating the contribution of genetic and environmental factors to the prediction of inter-individual variation in risk of disease. We then review a statistical strategy that employs cladistic theory to identify individuals carrying mutant DNA sequences responsible for an observed association between marker variation in a gene and inter-individual variation in biological traits that determine risk of a common multifactorial disease. Finding these DNA sequences is a necessary step in our search for an understanding of the nature of the mapping of genetic variation into variation in risk of a disease like coronary artery disease.

Application of cladistics to the analysis of genotype-phenotype relationships

We seek to understand the relative contribution of allelic variations of a particular gene to the determination of an individuals risk of atherosclerosis or hypertension. Work in progress is focusing on the identification and characterization of mutations in candidate genes that are known to be involved in determining the phenotypic expression of intermediate biochemical and physiological traits that are in the pathway of causation between genetic variation and variation in risk of disease. The statistical strategy described in this paper is designed to aid geneticists and molecular biologists in their search to find the DNA sequences responsible for the genetic component of variation in these traits. With this information we will have a more complete understanding of the nature of the organization of the genetic variation responsible for quantitative variation in risk of disease. It will then be possible to fully evaluate the utility of measured genetic information in predicting the risk of common diseases having a complex multifactorial etiology, such as atherosclerosis and hypertension.

Syndrome X: Is it for real?

The term syndrome X has been applied to the association of hypertension, non-insulin-dependent diabetes mellitus (NIDDM), android obesity, insulin resistance, and dyslipidemia. In this paper, based on population samples from Tecumseh, Michigan, and Hiroshima, Japan, characterized by persons > or = 40 years of age, we examine the validity of regarding this constellation of traits as a true syndrome, i.e., an array of traits with a single, unifying pathophysiology underlying its components. Data were not available on insulin resistance and dyslipidemia, and obesity was expressed as body mass index (BMI) without the division into android and non-android types. The four ethnic-gender data sets were analyzed on the basis of two age classes, age > or = 40 years and age > or = 50 years, and two obesity classes, BMI > or = 27 and > or = 30. A simple chi 2 test of goodness-of-fit under a model of independence revealed non-random associations between hypertension, NIDDM, and BMI which were in part attributable to an excess of persons with all three traits. However, when the four data sets were subjected to separate log-linear analyses of the three-way association tables, none of the three-factor interaction terms (i.e., syndrome X) was significant. High significance was, however, observed in the two-factor interaction term for BMI*hypertension. It is concluded that the significant association between these three traits is driven by the BMI*hypertension interaction, and there is no evidence in these data sets of a significant role for a syndrome X. Genet.

Correlates of family history of coronary artery disease in children

The atherosclerotic process begins in childhood but, in general, does not reach the clinical horizon until after the fifth decade of life, at which point the best opportunities for prevention and intervention have been lost. In order to identify children with a high risk of developing coronary artery disease (CAD), risk factors measured in children that are the most informative indicators of future risk must be identified. Using a novel analytical strategy that incorporates a continuum of information about context dependency, we investigated whether there were significant differences in intermediate biochemical and physiological traits between children (189 females and 188 males, ages 5-20.5 years) with and without a strong family history of clinically-defined CAD at three levels of context dependency (coarse grain, medium grain, and fine grain). In the coarse-grained analysis we tested for differences in mean levels of nine intermediate traits (lipids, apolipoproteins, blood pressure traits) and indices of external and internal environmental context (age, body mass index, smoking status). Female children with a strong family history had higher average levels for total cholesterol, triglyceride, Apo B, and systolic blood pressure and were on average older and weighed more than female children with a weak family history of CAD. Male children with a strong family history of CAD had higher average levels of triglycerides and were on average older than male children with a weak family history. In the medium-grained analysis we investigated whether the regression relationships between each intermediate trait and each measure of environmental context was significantly different between children with and without a strong family history of CAD. Our results indicate that children with a strong family history of CAD have a significantly different relationship between their intermediate traits and environmental contexts than children with a weak family history. In the fine-grained analysis, we stratified the sample into age, BMI, and smoking subgroups and tested for mean differences in the intermediate traits between children with and without a strong family history. For seven of the nine intermediate traits we found evidence of significant mean differences between children with and without a strong family history of CAD in particular age and BMI subgroups in nonsmokers that were not expected given the results from separate age-dependent or BMI-dependent marginal analyses. From these analyses, we conclude that the inferences about intermediate biochemical and physiological trait associations with family history of CAD depend on where on the coarse-grain to fine-grain continuum of context dependency the analysis is performed. In many cases, inferences at one level of investigation are different than the inferences made at a coarser or finer level. This study documents the complexity of the associations between intermediate traits and risk of CAD and raises the question of how many models are needed to maximize disease prediction and where these models should fall on the coarse- to fine-grain continuum.

Cladistic analysis of the apolipoprotein AI‐CIH‐AIV gene cluster using a healthy French Canadian sample. I. Haploid analysis

A cladistic analysis was carried out to identify haplotypes hypothesized to differ for functional DNA sequence variations within the apolipoprotein (apo) AI‐CIII‐AIV gene cluster that affect plasma lipid, lipoprotein and apolipoprotein levels. A sample of unrelated healthy French Canadians was studied. First, a cladogram of the observed apo AI‐CIII‐AIV haplotypes was estimated. Then this cladogram was used to define a statistical analysis of the association between haplotype variation and variation in plasma lipid, lipoprotein and apolipoprotein levels. Three haplotypes were identified which were associated with small (5–12% of the total sum of squares) pleiotropic effects on plasma lipid, lipoprotein and apolipoprotein traits and these effects were context, i.e. gender, dependent.