Familial clustering of insulin and abdominal visceral fat: the HERITAGE Family Study

Abdominal visceral fat (AVF) is an obesity-related phenotype thought to be associated with insulin resistance, diabetes mellitus, and atherosclerosis. Significant genetic influences on both AVF and insulin levels have been reported. However, information is lacking as to whether common genetic influences on AVF and insulin levels exist. AVF was assessed by computed tomography scan, and fasting insulin was measured by RIA in 512 members of 98 sedentary Caucasian families participating in the HERITAGE Family Study. Baseline data, collected before exercise training, were used in the present investigation. A bivariate familial correlation model was applied to evaluate whether there are familial influences that are common to insulin and AVF before and after adjustment for total fat mass (FM), and to assess the overall heritability of insulin and AVF. The maximal heritability for AVF, before and after adjustment for total FM, was 42% and 50%, respectively; and for insulin, it was 21%. Interestingly, 29% of the familial influences on insulin were also common to AVF, whereas 14% of the familial influences on AVF were shared by insulin. Furthermore, after AVF was adjusted for total FM, these common familial influences were increased to 48% and 20%. Genes and/or familial nongenetic factors with pleiotropic effects seem to influence both AVF and plasma insulin levels to a certain degree. Genes involved in the regulation of lipid storage and mobilization in the abdominal fat depot are potential candidates for these genetic pleiotropic effects.     

Elastin mutation and cardiac disease

Characterization of the molecular basis of structural cardiac disease includes elucidating the pathogenesis of certain vascular disease by demonstrating mutations of the Elastin gene as the cause of familial supravalvular aortic stenosis (SVAS) and Williams' syndrome (WS). Defining the etiology of SVAS has clinical implications in terms of prenatal and presymptomatic diagnosis and possible earlier intervention with medical therapy. This review considers the evidence relating Elastin mutations to SVAS and WS and outlines the possible mechanisms by which these mutations give rise to cardiac disease. Finally, the implications which Elastin mutation identification has on current clinical practice and future research directions are considered.     

Introduction to the special issue: Developmental perspectives on addictive behaviors.

A developmental perspective on drug abuse includes an understanding of the "natural history" of drug-using patterns and the context of such behavior in the lives of individuals. This context includes the developmental precursors of addictive behavior at an earlier stage of life, as well as an understanding of how certain stages of life, such as adolescence, may predispose such behavior. The articles in this special issue include studies of familial influences, behavioral and psychosocial correlates that are specific to a developmental period, and gender-related developmental sequelae. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

End-of-life decisions in the home care setting

Recent advances in the identification of genetic abnormalities associated with certain types of cancer have stimulated the development of screening and counseling programs for hereditary and familial forms of cancer. In 1995, such a program was established in a collaboration between three familial cancer clinics in Amsterdam. Given the potential impact of genetic screening and counseling on the psychosocial health of participants, it was considered essential that the program be evaluated from its inception to determine the participants' satisfaction with the services provided. A pilot study was initiated in which individuals who received genetic counseling for cancer were asked to provide feedback on the perceived quality of the services provided, and to identify areas in which additional services may be required. Preliminary results based on 36 counseled individuals indicated generally high levels of satisfaction with the care provided by the clinical geneticist and with the procedures at the familial cancer clinics. Several areas were identified that deserve additional attention: (1) the role of the family doctor in the genetic counseling; (2) communication of information regarding the possible impact of genetic counseling and testing on daily life; (3) communication between the clinical geneticist and other health care workers, and (4) psychosocial support during and after the process of genetic counseling.     

Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy

Lewy bodies in Parkinson' s disease (PD) are strongly immunoreactive with antibodies against alpha-synuclein, which is mutated in some familial cases of the disease. We carried out immunohistochemical examinations of the brains of multiple system atrophy (MSA) patients using anti-alpha-synuclein antibodies. Strong alpha-synuclein immunoreactivity was found in glial cytoplasmic inclusions (GCIs), which are of oligodendroglial origin and occur exclusively in MSA. Alpha-synuclein-immunoreactive neuronal cytoplasmic inclusions (NCIs) were also found occasionally in the substantia nigra, pontine and inferior olivary nuclei, and dentate fascia. These findings indicate that alpha-synuclein is also a major component of GCIs and NCIs in MSA and strongly suggest that alpha-synuclein aggregation is a common process in certain neurodegenerative diseases, including PD and MSA.     

Future developments in genetic research. I. Technological possibilities

The attention in genetic research is shifting from the determination' of (rare) monogenic disorders to identification of genetic risk factors for important diseases at adult age. Mapping of all man's 80,000-100,000 genes will also provide more insight into the gene polymorphisms and mutations that are associated with various types of cancer, certain cardiovascular diseases, diabetes and neurodegenerative disorders, including Alzheimer dementia. Apart from new diagnostic possibilities, the DNA techniques create new prospects for the study of the pathogenesis of diseases and the devising of new strategies for treatment. Examples are familial hypercholesterolaemia, diabetes, breast cancer and colorectal carcinoma.     

Genes, environment and individual differences in alcohol expectancies among female adolescents and young adults.

Alcohol expectancies are an important proximal causal risk factor in several models of the familial transmission of alcohol use, abuse, and dependence, yet the familial transmission of alcohol expectancies is not well understood. The purpose of this study was to examine the familial transmission of positive alcohol expectancies. Participants were 2,627 14- to 22-year-old female twins. Experiences shared by twins, rather than genetic factors, explained most of the familial similarity for positive alcohol expectancies, but an even larger proportion of the variation in positive alcohol expectancies was explained by nonfamilial factors. The extent to which the familial similarity for positive alcohol expectancies was moderated by age, race, drinking status, and the sharing of peer groups was also examined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Structure and possible function of an alpha-tocopherol-binding protein

A protein has been isolated from rat liver cytosol that specifically binds alpha-tocopherol. It does not occur in other tissues. Its amino acid sequence has been determined and it was found to have great homology with 11-cis-retinaldehyde-binding protein of the retina. This tocopherol-binding protein may be defective in a certain type of familial vitamin E deficiency syndrome.     

Head position preference in the human newborn: a new look

Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation.     

Parents and families as contexts for the development of substance use and substance use disorders.

Parenting and familial influences on substance use and substance use disorders (SUDs) are important areas of study both for theories of etiology and for the development of preventive and treatment interventions. The articles in this special section illustrate both the value and the challenges of studying parenting and familial influences. Noteworthy issues include the need for mediational and moderational models examining the processes by which familial influences operate in a longitudinal framework to consider outcomes in a developmental context. Future directions include a multidisciplinary expansion of these studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Familial clustering of obesity and breast cancer

One of the most striking characteristics of breast cancer (BC) is a tendency to familial aggregation. In order to evaluate whether familial clustering of obesity could account, at least in part, for the familial aggregation of BC, we compared the adult body size of entire sets of first-degree relatives belonging to 60 families with two or more cases of BC (case families) and 120 BC-free families (control families). Case families included an index case recently admitted for primary BC who had a confirmed first-degree family history for the disease. Control families included one population-based healthy index control with no family history and age-matched (2:1) to index cases. Index cases and controls, recruited from a pool of participants in a large case-control study, completed a questionnaire covering their own body size history as well as that of each of their first-degree relatives (598 case and 1,128 control relatives) using a validated system of body silhouette drawings. The odds ratio (OR) for premenopausal familial BC associated with having one parent markedly obese compared to none was 0.17 (95% confidence interval [CI] 0.04-0.65), while having both parents obese resulted in an OR of 0.25 (95% CI 0.04-1.56). Obesity among siblings was not related to premenopausal familial BC risk nor was familial obesity a significant predictor of familial BC after menopause. Index cases from both menopausal groups tended to be thinner than their unaffected relatives at age 40 years and thereafter. The inverse relationship between parental obesity and premenopausal BC risk is concordant with the protective effect of obesity on early-onset BC previously reported at the individual level.     

MHC-disassortative mating preferences reversed by cross-fostering

House mice (Mus musculus domesticus) avoid mating with individuals that are genetically similar at the major histocompatibility complex (MHC). Mice are able recognize MHC-similar individuals through specific odour cues. However, to mate disassortatively for MHC genes, individuals must have a referent, either themselves (self-inspection) or close kin (familial imprinting), with which to compare the MHC identity of potential mates. Although studies on MHC-dependent mating preferences often assume that individuals use self-inspection, laboratory experiments with male mice indicate that they use familial imprinting, i.e. males learn the MHC identity of their family and then avoid mating with females carrying 'familial' MHC alleles. To determine if female mice use familial imprinting, we cross-fostered wild-derived female mouse pups into MHC-dissimilar families, and then tested if this procedure reversed their mating preferences compared with in-fostered controls. Our observations of the female's mating behaviour in seminatural social conditions and the genetic typing of their progeny both indicated that females avoided mating with males carrying MHC genes of their foster family, supporting the familial imprinting hypothesis. We show that MHC-dependent familial imprinting potentially provides a more effective mechanism for avoiding kin matings and reducing inbreeding than self-inspection.     

Parent and Peer Predictors of Physical Aggression and Conflict Management in Romantic Relationships in Early Adulthood.

Violence between romantic partners is widespread, but developmental precursors of perpetration and victimization are little understood. Among participants followed from birth to 23 years of age, familial and extrafamilial childhood and adolescent relationships were examined in connection with couple violence in early adulthood. Predictors included early childhood physical abuse and witnessing of parental partner violence, features of parent-child interactions at the age of 13 years, and close friendship quality at the age of 16 years. Controlling for early familial violence, intrusive or overly familiar behavior in videotaped parent-child collaborations at 13 years of age consistently predicted violence perpetration and victimization in early adulthood. Friendship quality at the age of 16 years contributed over and above familial predictors. Understanding the role of both familial and extrafamilial close relationship precursors may lead to effective strategies for ameliorating the problem of romantic partner violence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Twenty-four-hour respiratory quotient: the role of diet and familial resemblance

Body weight and obesity show familial resemblance that could be the result of familial correlation of fat oxidation, low levels of which have been implicated in the etiology of weight gain and obesity. We studied the familial correlation of both 24-h respiratory quotient (RQ), an index of the ratio of fat to carbohydrate oxidation, and the possible influence of dietary macronutrient composition expressed by the food quotient (FQ), i.e. the theoretical RQ produced by the diet. We measured the habitual FQ of the 7 days diet by weighed food records, followed by measurement of 24-h RQ in respiration chambers in 71 healthy Caucasian siblings from 31 families. After adjustment for age, gender, and 24-h energy balance, 24-h RQ correlated in families as indicated by an intraclass correlation coefficient (r(i)) of 0.31 (P = 0.03). FQ, adjusted for age and gender, was also a familial trait for the two days immediately preceding diet (r(i) = 0.32, P < 0.01). The familial effect on 24-h RQ, adjusted for age, gender, and 24-h energy balance, remained after adjustment for the FQ of the two days preceding diet (r(i) = 0.27, P < 0.05) and was reduced but not abolished after further adjustment for fasting plasma insulin plus free fatty acids (r(i) = 0.24, P < 0.09). By a correlation analysis aimed at separating familial and individual nonfamilial factors influencing both 24-h RQ and FQ, we found a great but insignificant familial (etaF = 0.49, P < 0.18) and a somewhat lower, but significant individual nonfamilial correlation (etaNF = 0.35, P < 0.03). We conclude that substrate oxidation rates measured by RQ exhibit familial correlation after proper adjustment for confounders such as energy balance, gender, and age, and that this effect could not be fully explained by preceding diet composition, fasting plasma insulin, and free fatty acids. Further RQ and the habitual dietary composition shared familial and nonfamilial factors.     

Apolipoprotein E in the brain and its role in Alzheimer's disease

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the brain response to injury. The coordinated expression of apoE and its main receptor, the apoE/apoB (LDL) receptor, appears to regulate the transport of cholesterol and phospholipids during the different phases of the reinnervation process. The recent discovery that a peculiar form of apoE, the apoE4, is strongly linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the central nervous system (CNS) is particularly important in relation to the function of the cholinergic system which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence suggests that apoE4 allele has a direct impact on cholinergic function in AD.     

Olfactory recognition of conspecifics by domestic Norway rats

In order to learn more about their ability to recognize one another via olfaction, domestic male rats were given a series of preference tests in which pairs of odors from male conspecifics were presented. Both immature and mature males prefer (p less than .05) the odor from immature strangers over that from immature cage mates but are indifferent to the ordors from mature strangers versus cage mates. Both immature and mature males prefer (p less than .05) the odor from mature novel cage mates over that from mature cage mates to which they are temporarily habituated but are indifferent to the odors from immature novel versus familial cage mates. Mature males prefer (p less than .08) the odor from a cage mate over the subject's own odor, and they prefer (p less than .01) their own odor over no odor. Under certain conditions, male rats can discriminate between the odors from (a) strangers versus cage mates, (b) two cage mates, and (c) their own body versus a cage mate.     

The effects of familial risk, personality, and expectancies on alcohol use and abuse.

This study tested a structural model of the association between familial risk, personality risk, alcohol expectancies, and alcohol abuse in a sample of 224 young adult offspring of alcoholics and 209 offspring of nonalcoholics. The results provided support for 2 personality-risk pathways, a social deviance proneness and an excitement/pleasure seeking path, that accounted for a significant portion of the association between a familial alcoholism and alcohol abuse. The path from familial alcoholism to social deviance proneness lead directly to alcohol problems. The path from familial alcoholism to excitement/ pleasure seeking was associated with increased drinking, which, in turn, was associated with alcohol problems. Positive alcohol expectancies accounted for part of the association between excitement seeking and alcohol use. The results suggest 2 different biopsychosocial mechanisms that elevate risk for abuse in the offspring of alcoholics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Screening and treatment of children and adolescents with hypercholesterolemias and dyslipidemias

Evidence was provided that atherogenesis develops for several decades before pathological changes are manifested. It may thus be stated, that the "incubation period" of atherosclerotic pathological consequences is very long but it is reduced markedly already from childhood and adolescence in subjects with an atherogenic lipoprotein phenotype. Atherogenic lipoprotein phenotype comprises subjects suffering from one or more, frequently from a combination of several of the following metabolic indicators: hypercholesterolaemia, elevated levels of LDL-cholesterol, apolipoprotein B, lipoprotein (a), reduced levels of HDL-cholesterol and apolipoprotein A-1. The atherogenic lipoprotein phenotype is in 95% conditioned by inborn metabolic errors, i.e. familial hyperlipoproteinaemia and dyslipoproteinaemia. In the population the following are encountered most frequently: combined familial hyperlipidaemia, familial hypertriacylglycerolaemia and familial hypercholesterolaemia. Active screening and treatment of children and adolescents from these affected families is of great importance in primary prevention of atherosclerotic complications in adult age.     

Biochemical composition of human peripheral arteries examined with near-infrared Raman spectroscopy

OBJECTIVE: To describe the clinical, serologic, and immunogenetic features of familial idiopathic inflammatory myopathy (IIM) and to compare these with the features of sporadic IIM. METHODS: Clinical signs and symptoms, autoantibodies, HLA-DRB1 and DQA1 alleles, and GM/KM phenotypes were compared among 36 affected and 28 unaffected members of 16 unrelated families in which 2 or more blood relatives developed an IIM. In addition, findings in patients with familial IIM were compared with those in 181 patients with sporadic IIM. The families included 3 pairs of monozygotic twins with juvenile dermatomyositis, 11 families with other siblings or relatives with polymyositis or dermatomyositis, and 2 families with inclusion body myositis. RESULTS: The clinical features of familial IIM were similar to those of sporadic IIM, although the frequency of myositis-specific autoantibodies was lower in familial than in sporadic IIM. DRB1*0301 was a common genetic risk factor for familial and sporadic IIM, but contributed less to the genetic risk of familial IIM (etiologic fraction 0.35 versus 0.51 in sporadic IIM). Homozygosity at the HLA-DQA1 locus was found to be a genetic risk factor unique to familial IIM (57% versus 24% of controls; odds ratio 4.2, corrected P = 0.002). CONCLUSION: These findings emphasize that 1) familial muscle weakness is not always due to inherited metabolic defects or dystrophies, but may be the result of the development of IIM in several members of the same family, and 2) multiple genetic factors are likely important in the etiology and disease expression of familial IIM, as is also the case for sporadic myositis, but DQA1 homozygosity is a distinct risk factor for familial IIM.     

Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study

Elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen concentrations are risk factors for coronary heart disease. We investigated environmental, familial, and genetic influences on PAI-1 antigen and fibrinogen concentrations in 2029 adults from 512 randomly ascertained families in 4 US communities. We used maximum-likelihood segregation analysis to fit several genetic and nongenetic modes of inheritance to the data to determine whether mendelian inheritance of a major gene could best explain the familial distributions of these 2 hemostatic factors. Age- and gender-adjusted familial correlations for PAI-1 antigen level averaged 0.16 in first-degree relatives (95% CI=0.11 to 0.21); the spouse correlation was positive but not statistically significant (r=0.10, 95% CI=-0.02 to 0.23). Complex segregation analysis indicated a major gene associated with higher PAI-1 concentrations in 65% of individuals from these families. Demographic, anthropometric, lifestyle, and metabolic characteristics together explained 37% to 47% of the variation in PAI-1 antigen levels, and the inferred major gene explained an additional 17% of the variance. Positive and statistically significant age- and gender-adjusted familial correlations in first-degree relatives indicated a possible heritable component influencing plasma fibrinogen concentration (r=0. 17, 95% CI=0.13 to 0.22); however, segregation analysis did not provide statistical evidence of a major gene controlling fibrinogen level. These family data suggest that there are modest familial and genetic effects on the concentration of PAI-1.