Patricia P. Moll

The Frequency of Familial Dilated Cardiomyopathy in a Series of Patients with Idiopathic Dilated Cardiomyopathy

BACKGROUND Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

Disparities in Incidence of Diabetic End-Stage Renal Disease According to Race and Type of Diabetes

The incidence of end-stage renal disease in patients with diabetes mellitus is reportedly higher among blacks than among whites. This finding may be explained by the greater prevalence of diabetes among blacks. The relation of the type of diabetes to the risk of diabetic end-stage renal disease is largely unstudied. We addressed these issues in a study of all the black and white diabetic patients with end-stage renal disease (470 blacks and 861 whites) reported to the Michigan Kidney Registry who began treatment during 1974 through 1983. We also reviewed the medical records of a subpopulation of such patients (284 blacks and 310 whites) who were less than 65 years of age at the start of treatment for end-stage renal disease to determine what type of diabetes they had. In this study, we made use of national data on the prevalence of diabetes. We found that the incidence of diabetic end-stage renal disease was 2.6-fold higher (P less than or equal to 0.0001) among blacks after we adjusted for the higher prevalence of diabetes among blacks, with the excess risk occurring predominantly among blacks with non-insulin-dependent diabetes mellitus (NIDDM). Most black patients with diabetic end-stage renal disease had NIDDM (77 percent), whereas most white patients with diabetic end-stage renal disease had insulin-dependent diabetes mellitus (IDDM) (58 percent) (P less than or equal to 0.0005 for the difference between the races). For both races combined, the risk of diabetic end-stage renal disease during the 10-year period we studied was markedly greater for patients with IDDM (5.8 percent) than for those with NIDDM (0.5 percent). Our results indicate an increased risk of diabetic end-stage renal disease among blacks as compared with whites, particularly blacks with NIDDM. Although the risk of diabetic end-stage renal disease is higher in patients with IDDM, the majority of patients with diabetic end-stage renal disease in the population we studied had NIDDM.

Familial Dependence of the Resting Metabolic Rate

Human obesity is known to be a familial disorder. We studied 130 nondiabetic adult southwestern American Indians (74 men and 56 women) from 54 families to determine whether the resting metabolic rate, as measured by indirect calorimetry, is a familial trait that is independent of individual differences in fat-free mass (estimated mass of metabolically active tissue), age, and sex. We found that most of the variance in the resting metabolic rate (83 percent, P less than 0.0001) was accounted for by three covariates--fat-free mass, age, and sex--and that fat-free mass was the most important determinant. Family membership accounted for an additional 11 percent (P less than 0.0001) of the variance in the resting metabolic rate. Thus, resting metabolic rate is a familial trait in this population, and it is independent of differences in fat-free mass, age, and sex. We also found that persons from families with lower resting metabolic rates were no more obese than persons from families with higher metabolic rates. This finding may be partly explained by the close correlation between fat-free mass and percentage of body fat (r = 0.81, P less than 0.0001), which indicates that the resting metabolic rate, as adjusted for fat-free mass, is already partly adjusted for obesity. Only prospective studies will elucidate whether the familial dependence of the resting metabolic rate is a contributing mechanism to the familial predisposition to obesity.

In Vivo Insulin Action Is Familial Characteristic in Nondiabetic Pima Indians

Non-insulin-dependent diabetes mellitus (NIDDM) is a genetic disorder characterized by two major pathogenic processes: reduced insulin action and a relative or absolute decrease in plasma insulin concentrations. We studied 116 nondiabetic siblings from 45 families to determine if in vivo insulin action showed any aggregation among siblings. Subjects were Pima Indians from the Gila River Indian Community in Arizona who, as a group, have the highest reported incidence and prevalence of NIDDM in the world. In vivo insulin action was determined by the euglycemic-clamp technique at two rates of insulin infusion in each subject with resulting mean plasma insulin concentrations of 119 and 1938 μU/ml. After adjustment for age, sex, and degree of obesity, there was significant aggregation among siblings of in vivo insulin action at the high insulin infusion rate (P < .0001). Family membership independently accounted for ∼34% of the variance in this measure of insulin action. Glucose uptake at the lower insulin infusion rate also showed familial aggregation (P < .01), with family membership independently accounting for ∼15% of the variance of this measurement. We conclude that in vivo insulin action is a familial characteristic. The familial component of insulin action occurs in addition to the effects of obesity, age, and sex on insulin action. Therefore it is not sufficient to simply know that an individual is lean or obese to predict his/her in vivo insulin resistance, because it must also be known whether he/she is from an insulin-resistant or insulin-sensitive family. An alteration of insulin action may be an underlying and potentially genetically determined abnormality in Pima Indians that could help explain the familial aggregation of diabetes in this population. Such a genetic mechanism might also operate in populations with Native American admixture (e.g., Mexicans) as well as other populations.

Total cholesterol and lipoproteins in school children: prediction of coronary heart disease in adult relatives.

The distribution of risk factors and the prevalence of coronary heart disease (CHD) were studied in 850 first- and second-degree relatives of 98 healthy index cases selected from 3666 school children surveyed for lipid levels in Rochester, Minnesota. Three groups of families were based on an index childs total plasma cholesterol level: 18 families with a child in less than the fifth percentile (low-cholesterol group), 47 with a child in the fifth to ninety-fifth percentiles (middle-cholesterol group) and 33 with a child in greater than the ninety-fifth percentile (high-cholesterol group). The childrens cholesterol levels clustered with those of their relatives; mortality due to CHD before age 65 was increased by 2.5 times in grandfathers of index cases in the high-cholesterol group compared with those of the middle-cholesterol group (p < 0.016). The prevalence of CHD in all the grandfathers was associated with an index childs total cholesterol, more strongly associated with an index childs low-density lipoprotein cholesterol level and most strongly associated with an index childs high-density lipoprotein cholesterol level as a fraction of total cholesterol. This study establishes that childhood lipid and lipoprotein levels from a single cross-sectional survey identify families at elevated risk for CHD.

Levels of Lipids, Lipoproteins, and Apolipoproteins in a Defined Population

As part of a large cross-sectional investigation--the Rochester Family Heart Study--plasma levels of lipids, lipoproteins, and apolipoproteins were measured in a sample from the general population of male and female subjects who ranged in age from 5 to 90 years. Polyclonal radioimmunoassays developed at the Mayo Clinic were used for measurement of apolipoproteins A-I, A-II, C-II, C-III, and E, whereas a monoclonal enzyme-linked immunosorbent assay was used for apolipoprotein B. On the basis of 984 subjects who reported that they were fasting, were not pregnant, had never smoked, and were taking no medications thought to influence lipid levels, we determined age- and gender-specific percentiles for plasma levels of cholesterol, triglycerides, high-density lipoprotein cholesterol, and six apolipoproteins. These percentiles will facilitate identification of persons who are in the highest and lowest percentiles for their age and gender. The levels of the apolipoproteins varied for both age and gender. This is the first study to provide a reference sample for plasma levels of these apolipoproteins for male and female subjects 5 to 90 years of age selected from the general population.

Insulinemia in Children at Low and High Risk of NIDDM

OBJECTIVE Fasting hyperinsulinemia in the presence of normoglycemia usually indicates insulin resistance and is characteristic of populations at high risk for developing NIDDM. Hyperinsulinemia predicts the development of impaired glucose tolerance and NIDDM in Pima Indians, a population with a high incidence of NIDDM. Insulin concentrations in population-based samples of children who have different risks of developing NIDDM later in life have not been reported previously. RESEARCH DESIGN AND METHODS We compared fasting insulin concentrations in two populations of nondiabetic children, 6–19 yr of age: Pima Indians from southern Arizona and Caucasians from Minnesota. RESULTS Insulin concentration varied with age, sex, glucose concentration, and relative weight. Mean fasting insulin concentration was 140.3 pM in Pima Indian males, 94.4 pM in Caucasian males, 171.5 pM in Pima Indian females, and 107.1 pM in Caucasian females. For each sex, the mean fasting insulin concentration, controlled for age, glucose, and relative weight, was significantly higher in the Pima Indians than in the Caucasians (P < 0.001). CONCLUSIONS From a young age, Pima Indian children have higher fasting insulin concentrations than Caucasian children. As hyperinsulinemia predicts subsequent NIDDM, these data suggest that the susceptibility to NIDDM is manifest at a young age as fasting hyperinsulinemia.

Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. V. Variance components estimated from pedigrees

The human geneticist who wishes to estimate the genetic and environmental components of a quantitative trait has the choice of several sampling designs. Sets of monozygous and dizygous twins, parents and their offspring, and full siblings are often the most convenient samples but invariably yield estimators of genetic variance which are biased by shared environmental factors. More recently, fixed combinations of related and unrelated individuals have been proposed as sampling strategies to improve the separation of genetic and shared environmental correlations between relatives. These fixed designs take the form of family sets (Schull et al. 1970; Chakraborty et al. 1977) or sets of monozygous twins, their spouses and offspring (Nance & Corey, 1976). Unfortunately, human data cannot easily be collected according to a fixed design. A convenient sample usually consists of families which vary in the genetic relatedness of their members. Most human studies have utilized regression coefficients and interclass correlations estimated from pairs of individuals or intraclass correlations from subsets of individuals selected from a random sample of families. These statistics are generally contrasted to estimate the fractions of phenotypic variance due to genetic and environmental factors. The strategies available for combining these estimators do not adequately account for the double counting of individuals and alleles which may occur. For example, the full sib correlations and the parent-offspring correlations are usually estimated from individuals drawn from the same array of nuclear families. Elston (1975) has shown that the correlations between these correlation estimates may not be trivial. Despite the obvious implication, the precise effect of using correlated estimates on inferences about heritability estimates is not clear at this time. In order to minimize the inflation of type I1 error it is not uncommon to discard a large portion of the data. For example, in the Tecumseh Community Health Study, from the 6366 individuals typed for 12 blood markers, less than 100 genetically independent family sets, consisting of an index, a sib and a cousin could be constructed (Orr, personal communication). If the assumption of independence of family sets was rigorously met, only 5 yo of the available data could be utilized and the effect of the nonindependent index-sib and index-cousin correlations would still be unresolved. More importantly, samples of pairs or sets of relatives are usually not randomly sampled and therefore may not represent the same phenotypic variability of a quantitative trait that is determined by t,he frequency distribution of genotypes and environments among and within pedigrees which define the population. Alternatively, we may use the procedure of maximum likelihood estimation (MLE) to combine all of the information available in a sample of randomly selected pedigrees to obtain

Dystrophin analysis in idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (DCM) is characterised by ventricular dilatation and impaired systolic function resulting in congestive heart failure and frequently death. A dilated cardiomyopathy is common in patients with symptomatic Duchenne/Becker muscular dystrophy, a disease caused by dystrophin gene defects. However, cardiomyopathy is rarely the predominant clinical feature of this form of muscular dystrophy. To determine whether dystrophin gene defects might account for a significant number of patients with apparently isolated idiopathic DCM, we performed dystrophin gene analysis in 27 DCM patients, who were ascertained as part of a prospective study on idiopathic DCM. No dystrophin gene defects were found in our patients, whose average age was 50 years. These data suggest that dystrophin defects are not a common cause of idiopathic DCM in this age group in the absence of skeletal muscle cramps or weakness.

Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan-VI. A search for genotype by environment interaction

Abstract We have examined 12 unlinked polymorphic genetic marker systems and found 6 which each identified small but statistically significant differences in normal serum cholesterol levels which did not change significantly with age. The effects associated with 4 of the 6-ABO haptoglobin, Gm and secretor—were consistent in males and females and combined additively to define effects which were also homogeneous over age. There was a marker phenotype by age interaction effect on cholesterol variance in females but not in males. This study supports the hypothesis that a number of polymorphic genes, each with a small additive effect on cholesterol level, play an important role in determining cholesterol variability.