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 proband's 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.     

Biological and environmental sources of variation in plasma lipids and lipoproteins: the Jerusalem Lipid Research Clinic

We have previously described a general pattern of homogeneity in genetic and cultural determinants of blood lipids and lipoproteins among the major origin groups in the Israeli population. This paper reports on these determinants of total plasma cholesterol (TC), triglyceride (TG), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), and of the HDL-C/TC ratio, estimated from the total sample of 4,000 families whose members were examined in the Jerusalem Lipid Research Clinic. Both genetic (h2) and cultural (c2) components of inheritance were significant for all lipid variables. Under the most parsimonious model genetic heritability (h2) ranges from 0.45 for LDL-C, 0.47 for HDL-C to 0.64 for HDL-C/TC ratio. Cultural heritability (c2) was 0.03 for LDL-C, 0.04 for TC, 0.05 for TG and 0.07 for HDL-C and HDL-C/TC ratio. Within this population, as in others, genetic factors appear to be the major determinants of lipid variation, suggesting relative homogeneity of environmental correlates of plasma lipids.     

Approaches to familial aggregation: hypothesis testing and estimation when families are selected through parent probands under a variant of single ascertainment

Epidemiologic approaches to testing and estimating familial aggregation of a disease consist of comparing rates of disease in relatives of individuals with the disease (known as case probands) with rates of disease in relatives of individuals without the disease (known as control probands). Gold et al. (J Am Stat Ass 1967;62: 409-420) derived an explicit mathematical model and sampling methods, under which this approach is equivalent to testing the null hypotheses that the disease risk in families is homogenous. A basic assumption of this model is that every family member has the same risk of disease and that disease status is independent among family members, although the disease risk may vary between families. When the disease is suspected of having a genetic component, rather than being purely environmental, this model has been shown to be appropriate for detecting disease aggregation in siblings, when relatives are siblings of probands. This model however is unrealistic for use in nuclear families when the affected status of offspring is not independent of the affected status of parents, and these families are selected through an affected or an unaffected parent, so that a parent is the proband and relatives are offspring of probands. We extend the Gold et al. model to allow for the disease risk in offspring to vary with the affected status of the parent. We assume that families are selected through affected and unaffected parents, under a variation of single ascertainment. Under this study design, we show that the usual test of association between affected status of probands and relatives, performed by comparing sample proportions of affected relatives of affected and unaffected probands, respectively, is no longer equivalent to a test of homogeneity of disease risk in offspring. Instead, it is equivalent to testing that the disease risk in offspring is independent of the number of affected parents. This test reduces to a test of homogeneity if and only if one assumes that the variation in disease risk in offspring, between families, is solely due to the variation in the number of affected parents. As a result, we show that under this study design, the standard chi2 test must be modified in order to obtain a valid test of familial aggregation. In addition the sample proportions of affected relatives of case and control probands, respectively, are shown to provide unbiased estimates of the expected risk of disease in an offspring given an affected/unaffected parent. We apply these results to methods of sample selection and discuss the practical implications of these findings.     

The Cincinnati Lipid Research Clinic family study: cultural and biological determinants of lipids and lipoprotein concentrations.

A general linear model is described here for cultural and biological inheritance of lipids and lipoproteins. This model involves 10 parameters to be estimated from a total of 17 correlations, leaving ample degrees of freedom to test the goodness of fit. The model fits very well to each of the five lipid and lipoprotein variables analyzed here from a Lipid Research Clinic family data set. Both genetic and cultural inheritance are significant for each trait with the single exception that triglyceride levels fail to support genetic inheritance. Under the most parsimonious hypothesis, the genetic heritability (h2) ranges from .194 +/- .092 for triglyceride to .624 +/- .093 for low-density lipoprotein-cholesterol. Cultural heritability ranges from .070 +/- .030 for total cholesterol to .149 +/- .034 for triglyceride.     

Familial aggregation of VO(2max) response to exercise training: results from the HERITAGE Family Study.

The aim of this study was to test the hypothesis that individual differences in the response of maximal O(2) uptake (VO(2max)) to a standardized training program are characterized by familial aggregation. A total of 481 sedentary adult Caucasians from 98 two-generation families was exercise trained for 20 wk and was tested for VO(2max) on a cycle ergometer twice before and twice after the training program. The mean increase in VO(2max) reached approximately 400 ml/min, but there was considerable heterogeneity in responsiveness, with some individuals experiencing little or no gain, whereas others gained >1.0 l/min. An ANOVA revealed that there was 2.5 times more variance between families than within families in the VO(2max) response variance. With the use of a model-fitting procedure, the most parsimonious models yielded a maximal heritability estimate of 47% for the VO(2max) response, which was adjusted for age and sex with a maternal transmission of 28% in one of the models. We conclude that the trainability of VO(2max) is highly familial and includes a significant genetic component.     

Pleiotropy and heterogeneity in the expression of atherogenic lipoproteins: the IRAS Family Study

OBJECTIVE: Dyslipidemia is an important determinant of coronary disease. Phenotypic correlations between atherogenic lipids are well established, but the contribution of common genetic influences is less clear. METHODS: This study investigates the pair-wise genetic (rhog) and environmental (rhoe) correlations between apoB, LDL-C, HDL-C, and triglyceride (Tg) from Hispanic and African American families of the IRAS Family Study. RESULTS: Heritability estimates (?2) indicate significant genetic effects on apoB (?2=0.46+/-0.05), LDL-C (?2=0.40+/-0.05), HDL-C (?2=0.47+/-0.05), and Tg (?2=0.35+/-0.05) (all p<0.001). Genetic and environmental correlations were strong for apoB-LDL-C (rhog=0.87, rhoe=0.84), apoB-Tg (rhog=0.38, rhoe=0.65), and HDL-C-Tg (rhog=-0.42, rhoe=-0.46). Environmental correlations were strong for apoB-HDL-C (rhoe=-0.40), LDL-C-HDL-C (rhoe=-0.24), and Tg-LDL-C (rhoe=0.33) with weak genetic correlations for these pairs (rhog=-0.09, 0.10, 0.09 respectively). CONCLUSIONS: These results suggest multiple pathways leading to atherogenic dyslipidemia. There are common genetic and environmental influences contributing to variations in apoB and LDL-C as well as apoB and Tg. In addition, the inverse relation between Tg and HDL-C appears to have both genetic and environmental basis. Identifying genes involved in atherogenic dyslipidemia will require careful dissection of the genetic architecture of these pathways.     

Circadian variations in hemolymph lipids and lipoproteins and in hepatopancreatic lipids of the shrimp Penaeus japonicus

Lipids content of the haemolymph and the hepatopancreas in the decapod Crustacean P. japonicus exhibits a bicircadian rhythm characterized by one maximum in the night and another one during the day. The maximal values in the haemolymph are approximately two and a half times greater (8 mg/ml) than minimal ones (3 mg/ml). Variations are less important in the hepatopancreas. A bicircadian rhythm of lipid classes in the haemolymph is observed very significantly in concentration of polar lipids and free sterols with maximal values (6.87 mg/ml and 0.59 mg/ml) and minimal values (2.63 mg/ml and 0.23 mg/ml) respectively. Polar lipids are the major lipid fractions in the haemolymph (87%). The electrophoretic behaviour of haemolymph lipoproteins is determined.     

Lipid polymorphism and the roles of lipids in membranes

The reasons for lipid diversity in membranes are not understood. Here we review evidence supporting the proposal that factors related to the polymorphic capabilities of lipids provide a rationale for lipid diversity. In particular, the ability of lipids to adopt different polymorphic phases appears to be related to a generalized shape property, where lipids with a cylindrical geometry preferentially adopt the bilayer phase whereas ‘cone’ shaped lipids adopt the hexagonal H_II phase. Lipid diversity may then be considered to satisfy three demands. The first is obviously a need for bilayer forming lipids to provide the basic permeability barrier, whereas the second concerns a need for non-bilayer lipids and associated structures for fusion and related membrane contact phenomena to proceed. A third, and less obvious demand satisfied by non-bilayer lipids concerns the ability of lipids of different shapes to modulate the order in the hydrocarbon region when constrained to a bilayer organization. These possibilities are summarized in a metamorphic mosaic model of membranes.     

Familial Resemblance in Eating Behaviors in Men and Women from the Quebec Family Study

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Research Methods and Procedures: Eating behavioral traits were assessed with the Three‐Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent‐offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non‐familial environmental factors and gene‐gene and gene‐environmental interactions seem to be the major determinants of the eating/behavioral traits.     

Estimation of transmission probabilities in families ascertained through a proband with variable age-at-onset disease: application to the HLA A, B and DR loci in Finnish families with type 1 diabetes. The DiMe Study Group

An open problem of some interest in the study of HLA has been the possible existence of transmission distortion in the human HLA complex. In this paper, transmission probabilities are estimated and tested using data on HLA A, B and DR loci genotypes of parents and offspring ascertained from the entire population of Finland (Childhood Diabetes in Finland Study) through one or more offspring diagnosed with insulin-dependent diabetes mellitus (IDDM) during the recruitment period from September 1986 to July 1989. First, we show how to get unbiased estimates of transmission probabilities from the family data collected in the disease registry of incident cases. This is accomplished by assuming that transmission of HLA genes to children in the general population is conditionally independent given the parents' genotypes, and the birth dates of all offspring. Based on the sampling (ascertainment) process in the study on Childhood Diabetes in Finland, younger siblings of the index child (the oldest proband) are independent of the ascertainment and therefore give rise to unbiased inference regarding allele transmission. The hypothesis of Mendelian transmission of alleles at each locus was tested using the standard chi(2) test. Goodness-of-fit of the Mendelian inheritance model to the individual locus data is calculated by maximizing the likelihood function over allele transmission intensities at each locus. The existence of a strong transmission distortion is not supported by this study at the loci considered.     

Effect of cod liver oil supplementation on plasma lipids, lipoproteins, lipase activity and platelet aggregation in normotensive and hypertensive volunteers

No significant change in plasma levels of total cholesterol (TC), triglycerides, phospholipids, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), lipase activity and TC/HDL-C ratio could be observed in both normotensive and hypertensive individuals after cod liver oil supplementation. Measure of platelet aggregation rates did not also show any significant change after cod liver oil ingestion in both normotensive and hypertensive individuals. The results suggest that supplementation of normal diets with 600 mg cod liver oil per day for 50 days neither affects plasma lipids, lipoproteins and lipase activity nor affects platelet aggregation in both normotensive and hypertensive individuals.     

Clinical genealogy and genetic-mathematical study of families of probands with uterine cancer in the Chernovitsy Region

Complex clinic-genealogical and genetic-mathematical investigation of 482 patients with uterus cancer from Chernovtsy region was carried out. It was proved that primary in the population is multifactoral origin of uterus cancer. Percentage of genetic component in general susceptibility to disease was 11.40 9.40. Recurrent risk of the malignant tumor in progeny has been estimated. Results of the investigation are the base for development and execution of uterus cancer precaution and segregated with it oncopathology in proband relatives.     

Genetic analysis of adiponectin and obesity in Hispanic families: the IRAS Family Study

Adiponectin, coded for by the APM1 gene, is a novel adipocyte-derived hormone implicated in energy homeostasis and obesity. Several genetic studies have observed evidence of association between APM1 gene polymorphisms and features of the metabolic syndrome, such as insulin resistance and obesity. As part of a comprehensive genetic analysis of the APM1 gene, we have screened 96 unrelated individuals for polymorphisms in the promoter, coding regions, and 3untranslated region (UTR). Three promoter single-nucleotide polymorphisms (SNPs), two rare coding SNPs (G113A and T1233C), and 13 SNPs in the 3UTR were identified. Eighteen SNPs were genotyped in 811 Hispanic individuals from 45 families in the IRAS Family Study (IRASFS). SNPs were tested for association with six obesity quantitative traits (body mass index, waist, waist:hip ratio, subcutaneous adipose tissue, visceral adipose tissue, and visceral:subcutaneous ratio). Significant evidence of association to at least one of the obesity traits was identified in seven of the 18 SNPs (<0.001–0.05). The promoter SNP INS CA-11156 was the most consistently associated SNP and was associated significantly with all measures of obesity, except the visceral:subcutaneous ratio (P-values 0.009–0.03). Haplotype analysis supported this evidence of association, with haplotypes containing an insertion of one CA repeat at position –11156 consistently being associated with lower obesity values (P-value <0.001–0.05). The adiponectin polymorphisms, in particular those in the promoter region, thus show significant association with obesity measures in the Hispanic population. Additional studies are needed to confirm our findings and determine which polymorphism causes the functional effect.     

Segregation analysis of low levels of high-density lipoprotein cholesterol in the collaborative Lipid Research Clinics Program Family Study.

Complex segregation analysis with the unified mixed model in white families from nine lipid research clinics was carried out to delineate the mode of familial transmission of plasma high-density-lipoprotein cholesterol (HDL-C). Three groups of families from the collaborative Lipid Research Clinics Program Family Study were assessed: 1,146 selected at random, 483 obtained through hypercholesterolemic probands, and 177 selected from the random sample because a number had low HDL-C, the sample sizes being 4,279, 1,807 and 735, respectively. The data were first transformed and adjusted for effects of covariates. Analyses were performed within clinic and selection strata and also pooled across clinics within strata. The results were consistent across strata and identified two major HDL-C clusters with means separated by approximately 3 SD. There was significant evidence of transmission of a major factor for low HDL-C, but transmission did not conform to Mendelian segregation expectations. There was also evidence of significant multifactorial transmission. Since low HDL-C levels are a major independent risk factor for coronary heart disease, the association of a major factor with familial aggregation of low HDL-C emphasizes the importance of detailed within-family sampling for low HDL-C after identifying a proband whose predominant dyslipoproteinemia is low HDL-C.     

Polar lipids in phototrophic bacteria of the Rhodospirillaceae and Chromatiaceae families.

The polar lipids of photosynthetic purple bacteria of the genera Chromatium, Thiocapsa, Thiocystis, Ectothiorhodospira, Rhodopseudomonas, Rhodospirillum, and Rhodomicrobium were analyzed. Characteristic compositions of the polar lipids were found for most of the Rhodospirillaceae and Chromatiaceae species. Phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin were the major phospholipids in most species. Phosphatidylcholine was present as a major component in all species of the genus Ectothiorhodospira, but was not detected in the remaining Chromatiaceae. It was also present in most of the Rhodospirillaceae species. No glycolipids were found in any of the Ectothiorhodospira species. In the Rhodospirillaceae, the glycolipids mono- and digalactosyl diglycerides were generally absent. Sulfoquinovosyl diglyceride was present in significant amounts in at least three species of the Rhodospirillaceae and may have been present in most of them, but only in traces. All of the Chromatiaceae species contained several glycolipids, one of which was similar to monogalactosyl diglyceride. Ornithine lipids were found in large amounts in most Rhodospirillaceae, but were absent in Ectothiorhodospira and in the other Chromatiaceae. The species examined could be divided into three groups on the basis of their lipid composition: (i) the genus Ectothiorhodospira; (ii) the remaining Chromatiaceae; and (iii) the Rhodospirillaceae. The data presented are compared with those available in the literature, and differences from other phototrophic organisms are discussed.     

The aggregation of isolated human platelets in the presence of lipoproteins and prostacyclin.

Addition of prostacyclin (PGI2) temporarily inhibits platelet aggregation and permits the isolation of platelets free from plasma proteins, which have the same sensitivity as those in plasma [Moncada, Radomski & Vargas (1982) Br. J. Pharmacol. 75, 165P]. By using a modification of this technique we have established that platelets isolated from normal subjects aggregate more readily in response to ADP and adrenaline when physiological concentrations of low-density lipoproteins (LDL) are present. At high LDL concentrations spontaneous aggregation occurs. High-density lipoproteins (HDL) and very-low-density lipoproteins (VLDL) had no effect on agonist-induced platelet aggregation at normal concentrations, but HDL sensitized at higher concentrations. These effects by lipoproteins are not accompanied by changes in platelet lipid content. Cyclohexanedione treatment of LDL to modify apolipoproteins appeared to abolish the sensitization effect, indicating that binding to receptors was essential for the effects of LDL. LDL, but not HDL, overcame the inhibitory effect of PGI2 on platelet aggregation, except at very high concentrations of PGI2. PGI2 raised the cyclic AMP content of isolated platelets, but LDL only partially prevented this rise. These results suggest that LDL may have a greater role in platelet aggregation than previously recognized and may also regulate effects of PGI2. These findings may be of relevance to an understanding of cardiovascular diseases.     

Heterogeneity in the biological and cultural determinants of high-density lipoprotein cholesterol in five North American populations: the Lipid Research Clinics Family Study

Heterogeneity in the source of familial resemblance for high-density lipoprotein (HDL) cholesterol in 5 different Lipid Research Clinics (Cincinnati, Iowa, Minnesota, Oklahoma and Stanford) was assessed using a general linear model for cultural and biological inheritance. No evidence of heterogeneity was found in any of the parameters of the model. Under the most parsimonious hypothesis, using data pooled over all clinics, genetic and cultural heritability were both significant and were estimated to be 0.52 +/- 0.04 and 0.09 +/- 0.02, respectively; there was cultural transmission but no maternal effects; marital and nontransmitted sibship environmental resemblance were significant.