Anthony G. Comuzzie

A comprehensive linkage analysis for myocardial infarction and its related risk factors

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Gallstones: Genetics Versus Environment

ObjectiveThe aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. Summary Background DataGallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. MethodsA gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. ResultsIn the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P < .003), obesity (BMI > 30, relative risk 3.7, P < .001), age > 50 (relative risk 2.5, P < .001), and a positive family history of previous cholecystectomy in a first-degree family member (relative risk 2.2, P < .01). In the family study the additive genetic heritability of symptomatic gallstones was 29% (P < .02), age and gender were significant covariates and explained 9.3% of the phenotypic variation in gallbladder disease. ConclusionsThese data suggest that genetic factors are responsible for at least 30% of symptomatic gallstone disease. However, the true role of heredity in gallstone pathogenesis is probably higher because data based on symptomatic gallbladder disease underestimates the true prevalence in the population.

Variation in menstrual cycle length and cessation of menstruation in captive raised baboons

Primatologists have recognized that non-humans undergo the menopause [Biol. Reprod. 68 (2003) 10], which is preceded by years of irregular cycles and decreased fecundity. The similarity of reproductive changes between humans and baboons suggests that the aging female baboon is a particularly promising model to study human menopause and changes that precede it. In an effort to provide an assessment of potential peri-menopausal changes in reproductive function in non-human primates, our goals were to determine if menstrual cycles become more variable with age and to identify the onset of changes consistent with peri-menopause and menopause in baboons. To accomplish these goals, we calculated means and variances for menstrual cycle lengths of females at ages 5, 10, 15, and 20 years and identified onset of menstrual cycle variability (peri-menopause) and cessation of menstruation (menopause). Mean cycle lengths were not significantly different, but significant heterogeneity of variances existed, with younger animals experiencing less variability than older animals. Mean ages of onset for the peri- and menopausal transitions were 18.89 and 26.34 years, respectively. These results provide evidence that captive aging female baboons experience menstrual cycle changes similar to peri- and menopausal women.

Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes project

RATIONALE: Recently, we identified a genotype-by-smoking status interaction with serum leptin levels in a sample of Mexican Americans. However, it is unknown whether this phenomenon occurs in other populations as well.OBJECTIVE: The goal of this study was to examine the genetic architecture of the response to smoking in leptin levels using data from Midwestern Caucasian subjects participating in the Metabolic Risk Complications of Obesity Genes project.METHODS: We employed a variance decomposition analysis using maximum likelihood methods to model genotype-by-smoking interactions for leptin levels and examined the impact of the exclusion of smokers in a subsequent linkage analysis.RESULTS: We found significant evidence (p-value=0.027) for a genotype-by-smoking status interaction for serum leptin levels. In the subsequent linkage analysis with smokers excluded, we obtained a maximum LOD score of 3.4 (P=0.00004) near D8S1128.CONCLUSIONS: These results suggest that a QTL on chromosome 8 may have a differential effect on the expression of leptin in smokers vs nonsmokers, as first identified in Mexican Americans.