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Geneticists and epidemiologists often observe that certain hereditary disorders co-occur in individual patients significantly more (or significantly less) frequently than expected, suggesting there is a genetic variation that predisposes its bearer to multiple disorders, or that protects against some disorders while predisposing to others.
Dudley investigate systematically the pleiotopy by doing the first genome-wide study of genetic pleiotropy. Single gene deletion strains, representing all 4700 nonessential genes, were analyzed for growth under 21 different conditions, ranging from induction of DNA damage to iron limitation. Of these mutant strains, 551 exhibited growth defect in only one or two conditions. Strikingly, 216 strains show growth defects in 3-14 conditions, a much higher degree of pleiotropy than may be expected based on a random distribution of phenotypes which provides empirical evidence supporting the importance of pleiotropy in biological systems.
Rzhetzky et al. reviewed 1.5 million medical records involving 161 diseases and computed pairwise correlations of disease co-occurrences and they find striking tendencies for certain diseases to co-occur in individuals and also point that most complex phenotypes are probably rooted in genetic variation that is significantly shared (in either a competitive or cooperative manner) by multiple disease phenotypes.
André Rzhetsky and colleagues arrived at a similar conclusion without even looking at genotypes. They scoured the medical records of 1.5 million patients of the Columbia University Medical System and considered the overlap in disease diagnoses for 124 relatively common diseases. After adjusting for correlations due to age and sex, they find striking tendencies for certain diseases to co-occur in individuals (for example, autism, bipolar depression and schizophrenia). They even estimate that some of these diseases are likely to share as many as 20% or more of their susceptibility alleles.
Using the data from OMIM database that represents and up-to-date repository of all known disease genes and the disorders they constructed a network of human diseases in which two disorders are connected to each other if they share at least one gene in which mutations are associated with both disorders. Although they found clustering among the disease of the same class but the resulted HDN didn't fall into many single nodes corresponding to specific disorders or grouped into small clusters of a few closely related disorders; instead it form a large network of human disease. Of 1,284 disorders in OMIM database, 867 had at least one link to other disorders, and 516 disorders form a giant component, suggesting that the genetic origins of most diseases, to some extent, are shared with other diseases.
Using the data from GWAS Catalog From the 54 studied complex disorders they found 26 of genes are sharing interaction
there are many examples of different mutations in the same gene (allelic heterogeneity) giving rise to phenotypes currently classified as different disorders. For example, mutations in TP53 have been linked to 11 clinically distinguishable cancer-related disorders
Pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. The underlying mechanism is that the gene codes for a product that is for example used by various cells, or has a signalling function on various targets. The cause is a mutation in a single gene that codes for an enzyme (phenylalanine hydroxylase) that converts the amino acid phenylalanine to tyrosine, another amino acid.
In "simple" disorders with proven Mendelian inheritance, a single-nucleotide aberration in the genome can cause one disease while protecting against another; one nucleotide substitution can also manifest in multiple physiological systems. For example, a single-nucleotide substitution in a human Î²-globin gene (HBB) triggers in its bearer a drastic change of erythrocyte shape (sickle-cell anemia) but protects against invasion of the protozoan parasite (Plasmodium falciparum) that causes malaria. When designing a mathematical model that describes pairs of disease phenotypes, we can think of sickle-cell anemia and malaria as competing for the same nucleotide site in the human genome. In another example, a single-nucleotide polymorphism in the CFTR gene profoundly affects the bearer's digestive, reproductive, and respiratory systems and causes excessive loss of salt through sweating (a group of symptoms collectively known as cystic fibrosis). By analogy with our metaphor of phenotype competition for genes, we will say that these disparate phenotypic manifestations in cystic fibrosis cooperatively share the same nucleotide substitution (i.e., the substitution has a pleiotropic effect).
With the development of systems biology, studies have shown that phenotypically similar diseases are often caused by functionally related genes, being referred to as the modular nature of human genetic disease. This modularity, as recently supported by various reports, suggests that causative genes for the same or phenotypically similar diseases may generally reside in the same biological module, either a protein complex (Lage et al, 2007), a pathway (Wood et al, 2007), or a subnetwork of protein interactions (Lim et al, 2006). Aside from human disease, recent large-scale studies in yeast (Fraser and Plotkin, 2007; McGary et al, 2007) and worm (Lee et al, 2008) also support the idea that genes sharing mutant phenotype are tightly linked in the network.
Pleiotropic effects are a common phenomenon in reported studies of complex disease.
One clear finding to emerge from the published genetic studies of autoimmunity is that different autoimmune diseases share susceptibility loci (Fig. 1). This may not be surprising given the observations that certain diseases can co-occur both in single individuals and in families more often than predicted by chance , , ,  K.F. Tait, T. Marshall, J. Berman, J. Carr-Smith, B. Rowe and J.A. Todd et al., Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository, Diabet Med 21 (2004), pp. 358-362. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (34) and  and that loci identified by linkage studies in different human autoimmune diseases and in mouse models of autoimmunity cluster together  and .
There are two main strategies for mapping the genomic factors behind the complex traits which are linkage analysis and association mapping. Both methods allows a comprehensive scan of the entire genome for disease genes in a hypothesis-independent manner
Family-based vs. case and control studies
Association studies compare allele frequencies in cases and controls to assess the contribution of genetic variants to phenotypes in specific populations
Different types of association-based designs are used for mapping the genomic determinates of complex diseases.
Population-based case-control association studies have been a popular alternative in gene finding strategies. case-control study compares two groups that are expected to differ in their prevalence of disease-susceptibility alleles. Sufficiently large study populations can be readily assembled without the need to enroll also family members of the recruited participants However, population stratification and admixture may lead to spurious association, and hence biased finnding on the gene-disease association. Population stratification happens when there is a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry. In this case, false positive association can occur because of the confounding effects of population stratification. Furthermore, there can always be cryptic
relatedness in the sample, especially among the cases.
All methods proposed in the literature have the common feature of comparing alleles transmitted from the parents to alleles not transmitted to the affected offspring or alleles transmitted to the unaffected offspring.
Family-based association methods evaluate whether particular alleles are transmitted from parents down to affected offspring in a proportion that is different than expectation under the null hypothesis, , the null hypothesis being "no linkage and no association" or "no association, in the presence of linkage". Hence it avoids false positives that arise when association is present but linkage is not, as might happen in the presence of admixture and/or population stratification.
The transmission disequilibrium test was originally proposed for a parent-parent-affected offspring design (31) but has been extended to include siblings discordant for the disease under study and general family designs.
Collecting a sample of unrelated cases and controls is easier compared to collecting family-based samples; moreover, to get the same power as a case-control study design, a larger number of family-based samples will have to be ascertained and genotyped. However, family-based designs are still more appropriate mainly because unlike population-based studies, family-based designs are robust against population substructure, and significant findings always imply both linkage and association.
Linkage and association
In many ways linkage and association provide complementary data.
It evaluates whether there is excess sharing in for alleles or chromosomal segments transmitted to
affected siblings over genrations.
It is based on the recombination rate between the marker and the disease locus hence unlike the association studies it requires a genetic map; in fact, in a linkage analysis we seek to estimate the recombination fraction between a disease locus of unknown location and genetic markers of known location and to test whether this recombination fraction is signi¬cantly different from 0.5 (the disease locus is unlinked to the genetic markers).
In many ways linkage and association provide complementary data and using a joint approach allows combining the merits of both methods.
A founder population is descended from limited number of individuals (founders) as a consequence of some type of bottleneck.
Samples of individuals from founder populations have already proved immensely useful in mapping genes that underlie Mendelian disorders mainly rare recessive disease genes. It is becoming increasingly apparent that studies locating genes underlying complex phenotypes also benefit from the study of samples from founder population in several ways.
Fewer numbers of haplotypes being segregated through the generations in founder population compared to outbred population reduce the number of markers for Genome wide scans; moreover, in a more outbred population with considerably higher numbers of haplotypes, the causative allele is more likely to be located on several haplotypic backgrounds, thereby diluting its signal to an extent that precludes its identification by genetic means then the value of population isolates and their genomic LD patterns may thus be even greater when lower-frequency variants are considered.
Founder populations display higher degree of genetic homogeneity because of the limited
number of founders (and thus a limited gene pool) and absence of migration, this diminish the risk of unidentified population stratification; in addition, extensive allelic and locus heterogeneity, a key feature of common complex diseases that can obscure the association signal within disease-associated genomic regions is lower in isolate population compared to outbred populations.
In contrast to monogenic diseases, where the genetic composition of an individual often solely determines the disease phenotype, environmental factors are critical risk factors for complex diseases.
Environmental risk factors are generally more uniform in founder populations than in large outbred populations and thus the genetic effects may be easier to identify in the former.
Furthermore, the availability of extensive genealogical records can provide large genealogies, potentially very informative for genetic studies.
Alcohol, tobacco and coffee are the most commonly consumed psychoactive substances in the world 1. Due to the large public health burden attributable to alcohol and tobacco use, deeper understanding of the etiology of their use is crucial. In addition, some researchers postulate that there is a relationship between the use of these substances and that of illicit drugs Therefore, understanding the overlap of consumption of these legal psychoactive substances may provide a foundation for elucidating factors contributing to the use, abuse, and dependence of licit and illicit drugs.
Their concurrent use has been consistently shown across a wide variety of populations with moderately strong correlations between tobacco and alcohol use and between coffee and tobacco use 2. Coffee and alcohol consumption are also associated, especially when either substance is used heavily 2. Several models have been proposed to explain the clustering in the use of these substances. These include biobehavioral models in which the effects of one substance serve as cues for the use of others (Istvan & Matarazzo, 1984), personality models in which an underlying psychological trait or set of traits (e.g., antisocial behavior, depression, or neuroticism) predispose an individual to polysubstance use (Mangan & Golding, 1984); moreover, genetic studies utilizing twins and family approaches have clearly shown a considerable role for a for genetics in use of these substances. Studies in adult twins examining caffeine use, alcohol use, and cigarette smoking concluded that a common pathway underlies the use of these three substances. In a more recent study, Li et al. 61 conducted a meta-analysis on the basis of manually integrating 2343 items of cross-platform data linking genes and chromosome regions to addiction from peer-reviewed publications spanning 30 years fromn 1976 to 2006, Focusing on alcohol, nicotine, cocaine and opiod they identified five common patway behind these substances. Three of these pathways- namely, long-term potentiation, the MAPK (mitogen-activated protein kinase) signalling pathway and neuroactive ligand-receptor interaction - have been linked to addiction in previous studies. More importantly, the significance of the other two pathways in drug addiction - namely the GnRH signalling pathway and gap junctions - was not previously recognized.
Moreover, our most significant OF QTL on mouse Chr 1 was synthenic to a cluster of metabolic phenotypes of hypertension in our studies of French-Canadian families (53) and hypertensive dyslipidemic rats
Substance and stress: A growing body of evidence from fundamental science and translational studies also points to a number of biological connections between substance use and stress 4, such as abnormalities in corticotropin-releasing hormone and nor-adrenergic systems 5, dysregulation of reward systems 6 and abnormalities in glutamatergic and gamma aminobutyric acid (GABA)-ergic pathways 7. Stress has been also found both in experimental and clinical research to relate to initiation, intensification, and relapse to substance use 5; 8-10
drug-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis allows glucocorticoids to sensitize the reward pathway. Therefore, it is possible that individual differences in HPA axis activity-with high and low cortisol states-underlie some of the individual mechanistic differences in vulnerability to addiction.
Accumulating literature indicates the close interactions between HPA axis activity and the mesocorticolimbic dopaminergic system. Preclinical studies have shown that glucocorticoids alter mesolimbic dopamine signaling, thus amplifying the positive reinforcing effects of alcohol and other drugs of abuse. This sensitization of the reward system would render the subject more responsive to drugs of abuse and, consequently, more vulnerable to the development of addiction
The modern concept of stress and its importance for many human diseases was developed by the pioneering neuroendocrinologist Hans Selye, who discovered that various noxious stimuli caused what he called a 'general adaptation syndrome,' mediated in part by the pituitary and adrenal glands.
An important component of the stress-responsive system is the hypothalamic-pituitary-adrenal (HPA) axis. Exposure to stress activates the HPA axis (Fig. 2). HPA axis activation or suppression influences addiction24, 25, 26, 27. The question can therefore be posed: is there a genetic link between HPA axis function and addiction?
Previous studies using opioid antagonists demonstrate that the endogenous opioid system, via opioid receptors demonstrate inhibitory control over the HPA axis. Other studies showed that patient with heroin dependence are having a hypo-responsive HPA system and those with dependence on cocaine show a hyper-responsive HPA axis
In animal models stressors can influence the rewarding properties of drugs at each of the stages in laboratory animal self-administration studies, including initiation, maintenance, extinction and reinstatement, which are thought to model human states of initiation and maintenance of addictions, withdrawal and relapse. Thus, in general, stress can enhance acquisition, increase resistance to extinction, and induce reinstatement of self-administration. Animal studies also document physiological and corresponding molecular alterations in components of the HPA axis caused by acute or chronic administration of drugs of abuse.
In a series of clinical studies, recently abstinent cocaine-dependent subjects were read individually tailored scripts designed to provoke stressful, drug-cue related or neutral, relaxing experiences. Stressful and drug-cue related, but not neutral, scripts evoked increased craving, anxiety and cardiovascular measures, as well as increased plasma levels of ACTH, cortisol, prolactin and norepinephrine, not only indicating involvement of the HPA axis, but also suggesting that the sympatho-adreno-medullary system is involved in cocaine craving during abstinence29.
Mice lacking the mu opiate receptor gene (OPRM1) show dramatically reduced or absent analgesia, reward, physical dependence and respiratory depression in response to opiates. the most common coding region polymorphism in this gene is mutation that change asparagine (Asn) to an aspartic acid (Asp) substitution at amino acid position 40. In vitro studies demonstrate that beta-endrophine binds to the mutated form (Asp40) with threefold greater affinity than the prototype 118A (Asn40) receptor. -Clinical studies showed that subjects heterozygous for this mutation showed a greater HPA response to opioid antagonist than subjects with the only prototype receptor. Additionally, people with the mutated genotype had a more favorable clinical response to treatment for alcoholism with the opioid antagonists. This difference in response to treatment may be mediated by impact of the receptor on HPA axis activation.
Another evidenc of genic link among HPA axis, stress response and addiction was identified through the studies on COMT gene, which encodes an enzyme that catalyzes the degradative metabolism of the catecholamine neurotransmitters dopamine, norepinephrine and epinephrine, as well as hydroxylated estrogens. A common mutation in exon 4 change valine to methionine at amino acid 158. The mutated form has greater thermolability and a three- to fourfold lower enzymatic activity than the valine form. Genetic linkage and association studies pointed that this polymorphism may be involved in several different psychiatric disorders. The low-activity methionine form is associated with increased risk for alcoholism in several studies. This mutation also influence HPA axis function. After administration of naloxone, subjects with homozygous mutation had higher increases in plasma ACTH and cortisol than heterozygous or homozygous non-mutated.
Overall, the activity of the HPA axis seems to undergo extensive plasticity as a result of exposure to drugs of abuse. Furthermore, HPA responsivity is affected by genetic variants. Along with the finding that stress is a precipitating factor in relapse, these results point to the importance of more extensive studies of genetic variants in the HPA axis and drug addiction.
Incidentally, genes such as OPRM1 and COMT were suggested to connect substance use and stress response through the hypothalamic-pituitary-adrenal (HPA) axis, an important component of response to stress11; 12
interact with individual genetic susceptibility to alter synthesis, expression, and signaling in stress-related pathways (e.g., corticotrophin releasing factor [CRF], glucocorticoids, norepinephrine, gamma-aminobutyric acid [GABA], neuropeptide Y [NPY], brain-derived neurotrophic factor [BDNF], serotonin, glutamate, and dopamine.
Drugs of abuse such as alcohol and nicotine profoundly affect the stress pathways. Acute and regular binge use of these drugs results in alterations in gene expression, with signaling effects on both reward and stress-related molecules
There is a substantial literature on the significant association between acute and chronic stress and the motivation to abuse addictive substances (see30 for review). Many of the major theories of addiction also identify an important role of stress in addiction processes. These range from psychological models of addiction that view drug use and abuse as a coping strategy to deal with stress, to reduce tension, to self medicate, and to decrease withdrawal-related distress,31-37 to neurobiological models that propose incentive sensitization and stress allostasis concepts to explain how neuroadaptations in reward, learning, and stress pathways may enhance craving, loss of control, and compulsion, the key components in the transition from casual use of substances to the inability to stop chronic use despite adverse consequences, a key feature of addiction.38-40 In this section, we review the converging lines of evidence that point to the critical role that stress plays in increasing addiction vulnerability.
Notably, sex plays an important role in stress-related sensitivity to the reinforcing effects of drugs and in stress enhancement o f drug self-administration.
Findings indicate that HPA-activated corticosterone release is important for acquisition of drug self-administration.131,153-155 Corticosterone administration also facilitates psychomotor stimulant effects of cocaine and morphine.156 Furthermore, GC receptor antagonists injected into the VTA decrease morphine-induced locomotor activity,157 suggesting that activity of GC receptors in the VTA could mediate dopamine-dependent behavioral effects. Mice with deletion of the GR gene show a dose-dependent decrease in motivation to self-administer cocaine.158 These data suggest that HPA-related corticosterone release could at least partially mediate the dopamine increases seen after drug administration
A growing body of evidence from fundamental science and translational studies also points to a number of biological connections between substance use and stress 4, such as abnormalities in corticotropin-releasing hormone and nor-adrenergic systems 5, dysregulation of reward systems 6 and abnormalities in glutamatergic and gamma aminobutyric acid (GABA)-ergic pathways 7. Stress has been also found both in experimental and clinical research to relate to initiation, intensification, and relapse to substance use 5; 8-10
Substance use and obesity
The biological mechanisms of feeding and addiction have overlapped throughout our evolutionary history. The opiate antagonist naloxone inhibits feeding in mammals29, in slugs and snails30 and even in amoebae31. The most clearly established commonality of the mechanisms of food and drug intake is their ability to activate the dopamine- containing link in brain reward circuitry
Pharmacological blockade of, or experimental damage to, forebrain dopamine systems attenuates free feeding and lever-pressing for food reward, as well as the rewarding effects of cocaine, amphetamine, nicotine and alcohol33. Although the mesolimbic dopamine projection from the ventral tegmental area to the nucleus accumbens is most frequently implicated in reward function, other forebrain dopamine projections are almost certainly involved
The researchers performed genetic analyses on more than 30,000 subjects participating in 8 large cohort studies, including the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES- Reykjavik Study), the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the European Special Population Network consortium (EUROSPAN), the Family Heart Study, the Framingham Heart Study, Old Order Amish (OOA), and the Rotterdam Study (RS).
Genetic loci studied included those identified in previous studies as well as new candidate loci for abdominal fat deposition.
After analysing more than 2 million regions of the human genome, the researchers found that the gene variant, NRXN3, which has previously been associated with alcohol dependence, cocaine addiction and illegal substance abuse, also predicts the tendency to become obese among these genes NRXN3, which has previously been associated with alcohol dependence, cocaine addiction and illegal substance abuse too and MC4R gene is associated to binge eating behavior
NRXN3 is part of a family of central nervous adhesion molecules and is highly expressed in the central nervous system. Prior studies of NRNX3 point towards an important role in alcohol dependence, cocaine addiction, and illegal substance abuse -. In addition, opioid dependence has been linked to the chromosome 14q region . One study found that short-term cocaine exposure in mice is sufficient to increase the expression of NRXN3 beta in the globus pallidus. Since interactions among NRXNs and NLGNs link postsynaptic and presynaptic function. Authors conclude this changes expression of NRXN3 may induce changes in both the presynaptic neurons and in the postsynaptic STN neurons in globus pallidus. Many of the neuronal pathways in these sub-cortical regions of the brain in which NRXN3 is expressed are involved with learning and reward training .
The variant was present in 20 per cent of the individuals studied. The analysis showed that people with the gene variant have a 10 to 15 per cent increased risk of being obese compared with those have not.
These studies suggest that obesity is a centrally mediated trait and sharing common neurobiological basis with substance use
Neuroimaging scans suggest reduced brain activity of dopamine, a naturally occurring substance that modulates feelings of pleasure, may contribute to obesity as well as drug addiction. Previous research has shown that drugs that increase dopamine concentrations in this area decrease appetite. Conversely, drugs that block dopamine receptors increase appetite and lead to significant weight gain.
Pharmacological blockade of, or experimental damage to, forebrain dopamine systems attenuates free feeding and lever-pressing for food reward, as well as the rewarding effects of cocaine, amphetamine, nicotine and alcohol
The findings on the two other well-replicated obesity genes, MC4R and FT also suggest that obesity and addiction may share common neurologic underpinnings. MC4R, have also been shown to be associated with centrally-mediated phenomena including binge eating behavior. Studies in mice indicate that FTO expression is particularly pronounced in regions of the brain known to regulate energy balance , and recent data suggest that variants in the FTO gene may regulate food intake and selection .
Most notable genes identified through genome-wide association studies (GWAS) are FTO, MC4R and NRXN3 all three are highly active in encoding brain proteins
NRXN3 is the third obesity-associated gene to be identified; notably, all three are highly active in encoding brain proteins. Since NRXN3 is active in the brain and also implicated in addiction, these traits may share some neurologic underpinnings. Although the investigators do not have data to suggest a direct connection between drug abuse and obesity, they believe that it is possible to indirectly infer a link because both traits have this gene in common. The hope is that one day, researchers may be able to find drugs that target the molecular pathways through which obesity genes exert their influence, plus incorporate several obesity genes into a genetic test to identify people at risk of becoming obese.
Consumption of food, other than eating from hunger, and some drug use are initially driven by their rewarding properties, which in both instances involves activation of mesolimbic dopamine (DA) pathways. Food and drugs of abuse activate DA pathways differently (table 1). Food activates brain reward circuitry both through palatability (involves endogenous opioids and cannabinoids) and through increases in glucose and insulin concentrations (involves DA increases), whereas drugs activate this same circuitry via their pharmacological effects (via direct effects on DA cells or indirectly through neurotransmitters that modulate DA cells such as opiates, nicotine, Î³-aminobutyric acid or cannabinoids
Substance use & cardiovascular:
Excessive alcohol intake is associated with elevated risk of liver disease, heart failure, cancer, and accidental injury, and is a leading cause of death in industrialized countries. However, considerable research suggests that moderate alcohol intake is associated with health benefits, among them a decreased risk of cardiovascular disease
The American Heart Association has also reported moderate consumption of alcohol to be associated with dramatically decreased risk of stroke among both men and women, regardless of age or ethnicity
A study of alcohol consumption and subsequent high blood pressure for eight years among over 7,000 women found that those who consumed an average of about half a drink a day had a 15% lower chance of developing high blood pressure than did women who abstained from alcohol. This is very important because it's one of the few risk factors over which a person has control.
Tobacco and cardiovascular
Smoking is an important risk factor for cardiovascular disease, in particular for myocardial infarction, stroke and sudden death (1,2,3). The relationship between chronic smoking and development of hypertension is still unclear and controversial. Despite the acute pressor effect of cigarette smoking, several epidemiological studies failed to confirm an independent link between smoking and hypertension. Therefore, smoking is traditionally not considered a risk factor for hypertension development.
The cardiovascular responses to smoking represent a complex interplay between hemodynamic factors, autonomic nervous system and multiple vasoactive mediators (4). Conventional office blood pressure in smokers is consistently lower than the ambulatory blood pressure to which these subjects are exposed to when they are smoking. Indeed, ambulatory daytime blood pressure is higher in hypertensive smokers than in non-smokers with similar office blood pressure. The increase in ambulatory blood pressure seen after smoking is evident in both young and elderly hypertensives (5,6). There is growing evidence that arterial stiffening plays a major role in the pathogenesis of cardiovascular disease. Aortic stiffness is an independent predictor of both stroke and coronary events (7,8). Furthermore, normotensive subjects with lower arterial elasticity are more prone to develop hypertension (9). Therefore, the concept that smoking increases arterial stiffness, leading to chronic elevated blood pressure and target organ damage is attractive and logical.
There are several genic links among alcohol and blood pressure modification. One example is APOE gene. APOE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. It apperars that this gene is playing a role in hypertension, moreover, it is also reported that variation in APOE gene in only alcohol users influence the level of LDL. Carriers of APOE2 allele have lower LDL cholesterol compared to those with APOE4 allel.
Finally, both the impact of alcohol and the development of alcohol dependence and consumption are related to its pharmacokinetics. Main alcohol-metabolizing enzymes, including cyp2e1, adh2, adh3 and aldh2 genes, have a highly variable prevalence of their polymorphisms in different populations complicated by admixture , such as in Mexican Americans. Several studies from Japan have demonstrated genetic differences in ethanol-metabolizing enzymes and their impact on blood pressure , as well as coronary heart disease risk factors .
these studies clearly point in the direction that the kinetics of environmental factors, such as alcohol, must also be considered in addition to its dynamic characteristics. Clearly, we are at the beginning of a complex, yet relevant understanding of gene-environment interaction in the pathogenesis, complications and treatment of cardiovascular disease.
ALDH2 is the enzyme that breakdown alcohol, an inactive variant of aldehyde dehydrogenase 2 has been identified. People who inherit the inactive form of this gene from both parents ( ALDH2 *2*2 genotype) drink less than people with ALDH2 *1*2 and much less than people with ALDH2 *1*1 genotypes. Because inheritance of these genetic variants does not affect lifestyle factors other than alcohol intake, an association between ALDH2 genotypes and blood pressure would indicate that alcohol intake has an effect on blood pressure without any confounding.
There is a substantial literature on the significant association between acute and chronic stress and the motivation to abuse addictive substances (see for review). Many of the major theories of addiction also identify an important role of stress in addiction processes. These range from psychological models of addiction that view drug use and abuse as a coping strategy to deal with stress, to reduce tension, to self medicate, and to decrease withdrawal-related distress to neurobiological models that propose incentive sensitization and stress allostasis concepts to explain how neuroadaptations in reward, learning, and stress pathways may enhance craving, loss of control, and compulsion, the key components in the transition from casual use of substances to the inability to stop chronic use despite adverse consequences, a key feature of addiction In this section, we review the converging lines of evidence that point to the critical role that stress plays in increasing addiction vulnerability.
This reduced heart rate response in alcohol users is in agreement with the alcohol stress-response dampening theory 31 that proposes alcohol reduces the adverse effects of various psychosocial stressors 31; 32. For example, alcohol's dampening effect on HR has been shown in response to various psychosocial stimuli 33-36. however, this pattern of results is not always consistently reported 37. In an attempt to integrate many divergent findings, one theory proposes that alcohol disrupts the initial appraisal of stressful information by constraining the spread of activation of associated information previously established in long-term memory 37.
HR and BP
The evidences among substance use and cardiovascular disease is controversial, Cigarette smoking is the most important preventable cause of premature death in the United States. It accounts for more than 440,000 of the more than 2.4 million annual deaths. Cigarette smokers have a higher risk of developing several chronic disorders. These include fatty buildups in arteries, several types of cancer and chronic obstructive pulmonary disease (lung problems). Atherosclerosis (buildup of fatty substances in the arteries) is a chief contributor to the high number of deaths from smoking. Many studies detail the evidence that cigarette smoking is a major cause of coronary heart disease, which leads to heart attack.
Similar to habitual alcohol users, habitual tobacco users also showed a significant decrease in their cardiovascular response to psychological stress compared to non tobacco users; besides, former tobacco users had higher cardiovascular response to the stress than current tobacco users consistent with the previous findings for lower HR response in smokers compared to non smokers 50; 51, in contrast, other studies have found greater HR responses to mental challenges in smokers than in nonsmokers 52; 53. These inconsistencies may be due to differences in methodologies and study designs for instance, the determination of substance use status may be different across studies.
Although the relief from stress and negative affections is considered to be a main reason for smoking, 54; 55population studies have shown conflicting results on the effect of smoking on stress and negative affections. , Findings from animal studies have shown that concurrent chronic nicotine treatment and stress prevents stress-induced impairment of LTP 56; 57 and the impairment of LTP during chronic stress can be reversed by chronic nicotine treatment 58.
Caffeine has previously been implicated in increasing the risk of high blood pressure; however, recent studies have not confirmed any association. In a 12-year study of 155,000 female nurses, large amounts of coffee did not induce a "risky rise in blood pressure". Previous studies had already shown statistically insignificant associations between coffee drinking and clinical hypertension.
Obesity is characterized by the accumulation of an excessive amount of fatty or adipose tissue. Obesity results from unbalanced energy budgets and it has been linked to a long list of adverse health problems specially high blood pressure and cardiovascular diseases.
Obesity and BP:
Obesity is a leading risk factor for the disorder, and as such, may be a key element in one of these subsets. Prospective cohort investigations have demonstrated positive correlations between weight gain and blood pressure (BP) elevation.1 For example, in the Framingham Study, it was estimated that for each 4.5 kg of weight gain, there is an associated increase in systolic BP of 4 mm Hg in both men and women.2 Pathophysiological mechanisms linking the increases in adiposity to the elevations in BP are not very well understood. They may include alterations in renal handling of sodium and water, sympathetic nervous system activity, insulin sensitivity, and fatty acid metabolism,3 with some of these alterations being induced by hormones, growth factors, and cytokines expressed by adipose tissue in response to its expansion.
Based on population studies, risk estimates indicate that at least two-thirds of the prevalence of hypertension can be directly attributed to obesity . Apart from hypertension, abdominal adiposity has also been implicated in the pathogenesis of coronary artery disease, sleep apnoea, stroke and congestive heart failure
The precise mechanisms linking obesity to hypertension and increased cardiovascular risk are not fully understood. However, neuroendocrine mechanisms and, most recently, factors derived from adipose are thought to play a major role [15,16]. Obesity might lead to hypertension and cardiovascular disease by activating the renin-angiotensin-aldosterone system, by increasing sympathetic activity, by promoting insulin resistance and leptin resistance, by increased procoagulatory activity and by endothelial dysfunction. Further mechanisms include increased renal sodium reabsorption, causing a shift to the right of the pressure-natriuresis relationship and resulting in volume expansion . Obstructive sleep apnoea may importantly contribute to sympathetic activation in obesity. Finally, obesity may increase cardiovascular risk through subclinical inflammation.
We have suggested above that the genetic-neurobiological mechanisms of obesity may critically influence the effect of obesity on blood pressure. In addition, there are clues that genetic factors may modify the influence of the blood pressure response to obesity.
There is a strong rationale for the concept that modifying genes could importantly influence the blood pressure effects of obesity. We have recently obtained evidence that supports this concept. We measured arterial pressure directly and continuously using radiotelemetry in 2 strains of obese rats with mutations in the leptin receptor gene-the Zucker obese rat with the fa/fa mutation and the Koletsky obese spontaneously hypertensive rat with the fak/fak mutation.23 Both mutations result in a loss of function of the leptin receptor and in leptin-resistant obesity. The effects of leptin-resistant obesity on blood pressure were quite different in these 2 strains. During low salt diet, obese Zucker rats had slightly higher pressures than their lean controls, whereas obese Koletsky rats (like ob mice) had slightly lower pressures than their lean controls. During high salt diet, the Koletsky obese rats developed striking salt-sensitive increases in arterial pressure. The obese Zucker rats did not. These findings suggested that the effects of leptin-resistant obesity on blood pressure in the 2 strains are influenced by differences in genetic background in the 2 strains. This concept merits further study.
First, in addition to its effects on appetite and metabolism, leptin has sympathetic, vascular, and renal actions that can influence blood pressure. Second, the effect of obesity on blood pressure may depend critically on the genetic-neurobiological mechanisms underlying the obesity. Third, obesity is not always associated with increased blood pressure, at least in rodent models. Fourth, modifying alleles in the genetic background may critically influence the blood pressure response to obesity.
Multivariate genetic modeling of the correlation in liabilities to develop these conditions suggested the presence of a common latent factor mediating the clustering of hypertension, diabetes, and obesity in this twin sample. This common factor was influenced by both genetic and environmental effects (59% 8 genetic, 41% environmental). The genetic influences on the common latent factor were due to dominant rather than additive sources; the environmental influences appeared to be specific rather than shared by co-twins.
The striking contrast in results for each category of hypertension lends strong support to the idea that hypertension of obesity has a different genetic basis than other categories of hypertension.
Several mechanisms have been implicated in the association between obesity and hypertension, including activation of sympathetic nervous system, abnormal renal sodium handling, insulin resistance, and physical compression of the kidney.
Leptin is a 167 amino acid hormone that is almost exclusively produced by adipose tissue and possibly secreted by a constitutive mechanism. The effects of this peptide are mediated by receptors (Ob-R), most of them located in the hypothalamus, belonging to the class l cytokine receptor family. As of yet, 6 leptin receptor isoforms are known (Ahima and Flier 2000).
Leptin is considered a homeostatic hormone regulating food intake and body weight. Acting on the hypothalamic nuclei, leptin decreases appetite, and increases energy expenditure through sympathetic activation, which consequently decreases adipose tissue mass and body weight. The hormone levels are decreased during fasting and increased after several days of overfeeding as an effort to help regulate energy balance in humans. In addition to regulating food intake and adipose tissue mass, leptin has been found to be involved in cardiovascular physiological processes like sympathetic nerve system activation, In the kidney, leptin may affect blood pressure mainly by two opposing ways: the first is through renal sympathetic activation (Haynes, Sivitz, et al 1997), and the second is related to nitric oxide (NO) synthesis (Vecchione et al 2002). The renal effect of leptin also depends on the exposure time to the hormone. As it has been observed, acutely administered leptin usually does not increase blood pressure in animal or human studies, but when given for longer periods of time, leptin does elevate blood pressure in animal models.
Obesity might lead to hypertension and cardiovascular disease by activating the renin-angiotensin-aldosterone system, by increasing sympathetic activity, by promoting insulin resistance and leptin resistance, by increased procoagulatory activity and by endothelial dysfunction. Further mechanisms include increased renal sodium reabsorption, causing a shift to the right of the pressure-natriuresis relationship and resulting in volume expansion. Obstructive sleep apnoea may importantly contribute to sympathetic activation in obesity. Finally, obesity may increase cardiovascular risk through subclinical inflammation.
Obesity and stress:
Stress is known to be linked to body weight, but the precise nature and molecular mechanisms of this connection remain poorly defined. Some people lose weight and other people gain weight in response to stress. Some centrally acting mechanisms such as the influence of stress and obesity on the hypothalamic control of food intake and metabolism have been described. Reporting in Nature Medicine, Kuo and colleagues now show that the stress-triggered release of neuropeptide Y (NPY) can also directly stimulate fat angiogenesis in the periphery, as well as the proliferation and differentiation of new fat cells. These effects are mediated by the neuropeptide Y2 receptor (NPY2R), which might therefore be an attractive target for anti-obesity drugs.
how that the stress-triggered release of neuropeptide Y (NPY) can also directly stimulate fat angiogenesis in the periphery, as well as the proliferation and differentiation of new fat cells. These effects are mediated by the neuropeptide Y2 receptor (NPY2R), which might therefore be an attractive target for anti-obesity drugs.
Stress has been linked to the pathogenesis of many diseases, but its mechanisms of action and role as a risk factor remain unclear. Its rise has paralleled the incidence of obesity1, leading to serious health consequences. One type of obesity in particular, abdominal/visceral obesity, has been linked to the development of metabolic syndrome, and is a serious risk factor for cardiovascular diseases and diabetes.
In spite of this perceived association between stress and obesity, the nature of the relationship remains uncertain-some people lose weight when stressed, whereas others gain weight. Although there is much evidence that stress and obesity are related to the hypothalamic control of food intake and metabolism, little is known about the peripheral processes by which stress affects adiposity.
Stress stimulates sympatho-adrenomedullary activity, which is responsible for fight-or-flight responses. It is also the body's main mechanism of weight loss, acting through beta-adrenoceptor-mediated lipolysis and inhibition of adipocyte proliferation2 in white adipose tissue (WAT), and stimulation of thermogenesis in brown adipose tissue (BAT)3. Paradoxically, sympathetic activity seems to be increased in obese humans4, indicating that beta-adrenergic activity might compensate for other factor(s) that promote weight gain.
This region was founded by about 600 people, and has already grown to the current population of almost 300 thousands.
So it is a founder population and provides two important advantages for gene finding first of all it is a relatively homogenous population from the genetic point of view and second, is the large size of LD blocks that reduces the number of markers for whole genome scan studies.
Neuropeptide Y (NPY) is a 36 amino acid protein which acts as a transmitter in the nervous system. NPY is involved in regulation of circadian rhythms, sexual functioning, anxiety and stress response, peripheral vascular resistance and contractility of the heart. Certain data indicate that neuropeptide Y is also involved in the regulation of feeding behavior including food intake and carbohydrate preference as well as metabolic and lipogenic rates. Therefore, NPY may be involved in regulation of body fat and development of obesity. For example, chronic intracerebroventricular administration of neuropeptide-Y to normal rats mimiced hormonal and metabolic changes of obesity.
NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy.The main effect is increased food intake and decreased physical activity. NPY is secreted by the hypothalamus, and, in addition to increasing food intake, it increases the proportion of energy stored as fat and blocks nociceptive signals to the brain.
One study found that over expression of endogenous NPY in the transgenic rats was associated with lower blood pressure in baseline and during stress. Another study found that mutation in NPY T1128C polymorphism is associated with hypertension in Indian population.