Genetic determinants of phenotypic diversity in humans

New technologies for rapidly assaying DNA sequences have revealed that the degree and nature of human genetic variation is far more complex then previously realized. These same technologies have also resulted in the identification of common genetic variants associated with more than 30 human diseases and traits.     

Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis

A metabolite of homocysteine (Hcy), the thioester Hcy thiolactone, damages proteins by modifying their lysine residues which may underlie Hcy-associated cardiovascular disease in humans. A protein component of high density lipoprotein, Hcy thiolactonase (HTase) hydrolyzes thiolactone to Hcy. Thiolactonase is a product of the polymorphic PON1 gene, also involved in detoxification of organophospates and implicated in cardiovascular disease. Polymorphism in PON1 affects the detoxifying activity of PON1 in a substrate-dependent manner. However, how PON1 polymorphism affects HTase activity is unknown. Here we report a strong association between the thiolactonase activity and PON1 genotype in human populations. High thiolactonase activity was associated with L55 and R192 alleles, more frequent in blacks than in whites. Low thiolactonase activity was associated with M55 and Q192 alleles, more frequent in whites than in blacks. High thiolactonase activity afforded better protection against protein homocysteinylation than low thiolactonase activity. These results suggest that variations in HTase may play a role in Hcy-associated cardiovascular disease.     

Genetic and social factors in the development of aggression

The effect of the variants of the serotonin transporter gene (5-HTT) on aggressiveness was studied in male and female control subjects and athletes. Sports were found to generally decrease aggressiveness; this was true both for women doing nonaggressive sports and for men doing combat sports. The control group of men was characterized by higher indices of aggressiveness (physical and verbal aggression, negativism, and suspiciousness) than women were. Women, irrespective of age and whether they participated in sports, exhibited a relationship between 5-HTT gene variants and the displaced aggressiveness and negativism scales: the SS genotype was associated with a higher displaced aggressiveness and a low negativism. Men exhibited a different relationship. The general aggressiveness index was significantly higher in carriers of the LL genotype than in carriers of the SS genotype, whereas these subjects did not differ significantly in the parameters measured by individual scales. In men, the cerebral processes that are presumed to underlie aggressiveness were found to be related to 5-HTT gene variants. The HP component of the cerebral potential responsible for automatic detection of differences was increased and the P3a component responsible for involuntary attention and cognitive control. This suggests that carriers of the SS genotype use more cognitive resources to process information. This may be because the stimulus itself seems to be more “complex,” which results in the involvement of additional resources of the frontal cortex. It may also be assumed that carriers of the SS genotype tend to analyze the incoming information more deeply. This, more “serious” analysis of external information may underlie their refraining from impulsive behavior, which is often aggressive.     

Genetical genomic determinants of alcohol consumption in rats and humans

Background

We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations.

Results

In the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption.

Conclusion

Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.     

Genetic determinants of cancer metastasis

Metastasis can be viewed as an evolutionary process, culminating in the prevalence of rare tumour cells that overcame stringent physiological barriers as they separated from their original environment and developmental fate. This phenomenon brings into focus long-standing questions about the stage at which cancer cells acquire metastatic abilities, the relationship of metastatic cells to their tumour of origin, the basis for metastatic tissue tropism, the nature of metastasis predisposition factors and, importantly, the identity of genes that mediate these processes. With knowledge cemented in decades of research into tumour-initiating events, current experimental and conceptual models are beginning to address the genetic basis for cancer colonization of distant organs.     

Genetic and environmental determinants of skin color

Skin reflectance measurements on a sample of 154 Black and 191 White same-sex twin pairs, attending Philadelphia area schools, are analyzed to determine the effects of genetic and environmental factors. The measurements obtained in July and August, on the forehead, inner upper arm, and flexor surface of the forearm with red, green, and blue filters, were reduced to one index which we call skin color. Analysis of this index using the path analysis of Rao et al. ('74) estimates the major variance components due to racial, residual genetic, and common environmental factors as 67%, 5%, and 22%, respectively.     

Genetic determinants of antibiotic resistance in enterobacteria

Antibiotic resistance of enterobacterial strains from population isolated in Krasnodar region is rather often controlled by the "plasmid" genes. The conclusion is based on using the colony hybridization with [32P]-DNA fragments of plasmids, carrying the genetic determinants of antibiotic resistance, as a method for antibiotic resistance, genes screening. Kanamycin resistance in the majority of strains is coded by APH (3') II gene, streptomycin resistance by APH (3") gene, chloramphenicol resistance by CATI, sulphonilamide resistance by DHPS type II gene. Tetracycline resistance of the studied enterobacterial strains is not connected with the widespread genetic determinants of a new class tetracycline resistance.     

Genetic and environmental determinants of menstrual characteristics

BACKGROUND:

The impact of women''s menstrual cycle on her quality of life, health, work, and community is substantial. Menstrual disturbance is linked with general ill conditions such as migraine, asthma, and endocrinopathies. The clinical significance of medical interventions to prevent these conditions becomes clear if the role of genetic or environment is clarified.

AIMS:

To identify the genetic and environmental contribution on menstrual characteristics.

SETTING AND DESIGN:

This was a cross-sectional study in 2 Asian countries.

MATERIALS AND METHODS:

2 cohorts of monozygotic and dizygotic twins born between (1945-1988, n = 122) and (1951-1993, n = 71) were taken. A standard questionnaire was designed inclusive of socio- demographic characteristics of subjects as well as menstrual history (duration, interval, amount, irregularity). Subjects were interviewed by phone.

STATISTICAL ANALYSIS:

Quantitative variables were analyzed using Falconars’ formula as well as maximum likelihood analysis. Structural modeling was then applied to twin correlations to provide estimates of the relative genetic and/or environmental factors contribution in determining the measured trait.

RESULTS:

Menstrual characteristics were found to be under environmental influence where the best fitting model for menstrual interval and duration was common environment. CDF plotting confirmed the results for both variables. Proband-wise concordance analysis for amount of menstruation, amenorrhea, and irregular menstruation revealed no genetic influence. The best fitting model for menstrual irregularity was CE (C73%, E27%). The same model was defined for amenorrhea (C48%, E52%).

CONCLUSIONS:

Environmental factors are most likely responsible to determine the menstrual flow, its integrity, and regularity. These factors need to be studied further.     

Genetic determinants of hepatic steatosis in man

Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD.     

Genetic determinants of hyaloid and retinal vasculature in zebrafish

Background

The retinal vasculature is a capillary network of blood vessels that nourishes the inner retina of most mammals. Developmental abnormalities or microvascular complications in the retinal vasculature result in severe human eye diseases that lead to blindness. To exploit the advantages of zebrafish for genetic, developmental and pharmacological studies of retinal vasculature, we characterised the intraocular vasculature in zebrafish.

Results

We show a detailed morphological and developmental analysis of the retinal blood supply in zebrafish. Similar to the transient hyaloid vasculature in mammalian embryos, vessels are first found attached to the zebrafish lens at 2.5 days post fertilisation. These vessels progressively lose contact with the lens and by 30 days post fertilisation adhere to the inner limiting membrane of the juvenile retina. Ultrastructure analysis shows these vessels to exhibit distinctive hallmarks of mammalian retinal vasculature. For example, smooth muscle actin-expressing pericytes are ensheathed by the basal lamina of the blood vessel, and vesicle vacuolar organelles (VVO), subcellular mediators of vessel-retinal nourishment, are present. Finally, we identify 9 genes with cell membrane, extracellular matrix and unknown identity that are necessary for zebrafish hyaloid and retinal vasculature development.

Conclusion

Zebrafish have a retinal blood supply with a characteristic developmental and adult morphology. Abnormalities of these intraocular vessels are easily observed, enabling application of genetic and chemical approaches in zebrafish to identify molecular regulators of hyaloid and retinal vasculature in development and disease.     

Genetic determinants of ethanol-induced liver damage

BACKGROUND: Although a clear correlation exists between cumulative alcohol intake and liver disease, only some of the alcohol abusers develop signs of ethanol-induced liver damage. To identify some of the genetic variations predisposing persons to alcoholic liver disease (ALD), a genetic study was performed in heavy drinkers from the cohort of the Dionysis study, a survey aimed at evaluating liver disease in the open population of two towns in Northern Italy (6917 individuals). MATERIALS AND METHODS: 158 heavy drinkers (approximately 85% of all heavy drinkers in the population; daily alcohol intake > 120 g in males and >60 g in females) were investigated by the analysis of nine polymorphic regions, mapping in exons III and IX of the alcohol-dehydrogenase (ADH)-2 gene, in exon VIII of the ADH3 gene, in intron VI, in the promoter region of the cytochrome P4502E1 (CYP2E1) gene, and in the promoter region of the tumor necrosis factor-alpha gene. RESULTS: Heavy drinkers with or without ALD significantly differed for the distribution of alleles of the cytochrome P4502E1 (CYP2E1) and alcohol-dehydrogenase-3 (ADH-3) genes. In one town, allele C2 in the promoter region of the CYP2E1 gene had a frequency of 0.06 in healthy heavy drinkers, of 0.19 in heavy drinkers with ALD (p = 0.012), and of 0.33 in heavy drinkers with cirrhosis (p = 0.033). In the other town, whose inhabitants have different genetic derivation, a prominent association between ALD and homozygosity for allele ADH3*2 of ADH3 was found, with a prevalence of 0.31 in heavy drinkers with ALD and of 0.07 in healthy heavy drinkers controls (p = 0.004). CONCLUSIONS. Both heterozygosity for allele C2 of CYP2E1 and homozygosity for allele ADH3*2 of ADH3 are independent risk factors for ALD in alcohol abusers. The relative contribution of these genotypes to ALD is dependent on their frequency in the population. Overall, heavy drinkers lacking either of these two genotypes are 3.2 and 4.3 times more protected from developing ALD and cirrhosis respectively.     

Genetic determinants of bone mass.

A genetic contribution to bone mass determination was first described in the early 70s. Elucidation of gene contribution to this has since been attempted through studies analyzing associations between bone mass acquisition and/or maintenance and polymorphic variations of several genes. The first to be described was the vitamin D receptor gene (VDR), initially claimed to contribute to almost 75% of the genetic variation in bone mineral density (BMD) in twin and general population studies. Not all of the studies published to date conclude that a clear relationship exists between polymorphic VDR alleles and BMD, and the molecular basis for the VDR gene polymorphisms influence on bone mineralization has not yet been clarified. Since then, other genes with a significant role in bone metabolism such as estradiol receptor, collagen type 1alpha1, TGF-beta1, interleukin-6, calcitonin receptor, alpha2-HS-glycoprotein, osteocalcin, calcium-sensing receptor, interleukin-1 receptor antagonist, beta3-adrenergic receptor, apolipoprotein E, PTH, IGF-I and glucocorticoid receptor have been analyzed. Some polymorphic variations in these genes have been associated in some works with significant differences in BMD, with even more significant contributions when associations of different gene polymorphisms were analyzed. Again, the molecular basis for the contribution of these alleles to bone mass determination has not yet been described. A different approach has been attempted by linkage analysis of loci involved in bone density in pedigrees with low BMD using BMD as a quantitative trait. Recent results do not confirm, in these families, any association with any of the previously reported genes, but rather with other as yet unidentified genes. The genetic contribution to mild variations in the general population, as a result of environmental and endogenous individual influences, probably differs completely from that providing a pathologic BMD.     

Genetic determinants of neurovirulence and attenuation of poliovirus

The results of mapping of genetic determinants for poliovirus attenuation are reviewed. Possible mechanisms of the phenotypic expression of attenuating mutations located in different regions of the viral genome are discussed.     

Genetic determinants of obesity-related lipid traits

In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol. These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.