Heritability of hemostasis phenotypes and their correlation with type 2 diabetes status in Mexican Americans

Hypercoagulation often occurs in type 2 diabetes, suggesting pleiotropy of the genes that influence disease liability and hemostasis-related phenotypes. To better understand the relationship between hemostasis and diabetes, we first used maximum-likelihood methods to estimate the relative contribution of additive genetic, measured environmental, and shared household effects to the normal variance of 16 hemostasis-related traits in 813 individuals participating in the San Antonio Family Heart Study. We estimated moderate to high heritabilities (0.20-0.60) for each phenotype. Von Willebrand factor (VWF), thrombin activatable fibrinolysis inhibitor, activated protein C (APC) ratio, factor V, and prothrombin time had heritabilities greater than 0.50. The correlation between type 2 diabetes status and the hemostasis-related traits was then partitioned into genetic and environmental components using bivariate variance-components methods. Significant (p < or = 0.05) positive genetic correlations (0.37-0.51) occurred with factors II and VIII, VWF, total protein S (tPS), and tissue factor pathway inhibitor. Significant negative genetic correlations were estimated for activated partial thromboplastin time (-0.49) and APC ratio (-0.38). By contrast, significant environmental correlations occurred only with factor II (-0.40) and tPS (-0.31). Our results suggest that genes are important contributors to the normal variation in hemostasis-related traits and that genes influencing hemostasis-related traits pleiotropically influence diabetes risk.     

Ionizing radiation and genetic risks: VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease,essential hypertension and diabetes mellitus

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of `genetic susceptibility' and `risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (ϵ4) and decrease (ϵ2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1–C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. Hyperhomocyst(e)inemia is a risk factor for myocardial infarction, stroke and peripheral vascular disease, but the precise nature and intensity of this association, the biochemical mechanisms involved and the role of environmental factors remain to be fully elucidated. Recently, it has been suggested that polymorphisms in genes that code for paraoxonase may need to be added to the list of genetic risk factors for CHD. There are suggestions that high plasma fibrinogen levels (which is exacerbated by smoking which also lowers high density lipoprotein cholesterol levels) may constitute yet another risk factor for CHD. Essential hypertension (EHYT) affects some 10–25% of the people of the industrial world. Its clinical relevance stems from the fact that it is one of the major risk factors for cardiovascular and renal diseases, especially, stroke, coronary heart disease and end-stage renal disease. The role of genetic factors in EHYT is clearly indicated by family studies in which correlations in blood pressure levels have been studied. The variations in the range and magnitude of these correlations however suggest that other, environmental factors must play an important role and which vary from individual to individual and population to population. No major genes controlling blood pressure have been identified. However during the past five years or so, linkage and association studies have shown that there are at least three gene loci, polymorphism at which may contribute to EHYT: these include the AGT, AT1 and ACE genes. Additionally, the molecular basis of three rare mendelian disorders associated with hypertension, namely those involved in glucocorticosteroid-remediable aldosteronism (GRA), Liddle syndrome and apparent mineralocorticosteroid excess (AME) have been delineated. On the basis of clinical phenotypes, four types of diabetes mellitus are distinguished, of which insulin-dependent diabetes melltius (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) have been the subject of extensive studies. IDDM is a group of heterogeneous diseases probably resulting from exposure to some environmental agent(s) in those individuals with a genetically-determined susceptibility. IDDM is the result of the destruction of insulin-producing β-cells of the pancreas, principally by immunologically-mediated (autoimmune) mechanisms. The major defined risk factor is genetic susceptibility: apart from IDDM1 (linked to the HLA complex) and IDDM2 (in the insulin gene region) at least 10 other genes are involved, mutations at which cause susceptibility to IDDM. There is recent evidence for the possible involvement of an endogenous retrovirus in the aetiology of acute onset IDDM. NIDDM is a very common disease and its prevalence varies in different populations. As in the case of IDDM, its major determinant is genetic susceptibility. Compared to IDDM, the concordance rates in monozygotic twins and risks to first-degree relatives are higher. With the exception of MODY subtype with earlier onset, most cases have onset in middle or late life. The known geographical variations in the prevalence and studies of migrant populations suggest that environmental factors might also be important. The number of genes mutations at which cause susceptibility to NIDDM is not yet known and so far, one putative major gene locus has recently been identified in a Mexican–American population. Several candidate genes are currently being investigated. The available data indicate that some of the genes act through inherited susceptibility to insulin resistance and to decreased capacity for insulin secretion. Rare forms are due to dominant mutations i.e., the MODY diabetes and rarer still are forms due to the production of abnormal insulin due to mutations in the insulin gene itself. Finally, a small proportion of diabetes may be due to mutations in the mitochondrial genome. The attributes, risk factors and interrelationships between the three diseases considered in this review clearly show that the task of using this information for reliably predicting the risk of any of these diseases is formidable, even for a scenario of no radiation exposures, not to mention radiation scenarios. Nonetheless, these data provide a useful framework for developing models aimed at quantifying the response of these diseases to an increase in mutation rate due to radiation. One such model is discussed in a later paper of this series.     

Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.     

Molecular genetics of myocardial infarction

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for MI include hypertension, hypercholesterolemia or dyslipidemia, diabetes mellitus, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Disease prevention is an important strategy for reducing the overall burden of MI, with the identification of markers for disease risk being key both for risk prediction and for potential intervention to lower the chance of future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to coronary heart disease (CHD) or MI, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. In this review, we summarize both candidate loci for CHD or MI identified by linkage analyses and candidate genes examined by association studies. We also review in more detail studies that have revealed the association with MI or CHD of polymorphisms in MTHFR, LPL, and APOE by the candidate gene approach and those in LTA and at chromosomal region 9p21.3 by genome-wide scans. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of CHD and MI.     

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models, in which the genetic background is homogeneous and environmental factors can be controlled, are therefore valuable in genetic dissection of multifactorial diseases. We are fortunate to have excellent animal models for both type 1 and type 2 diabetes--the nonobese diabetic (NOD) mouse and the Nagoya-Shibata-Yasuda (NSY) mouse, respectively. Congenic mapping of susceptibility genes for type 1 diabetes in the NOD mouse has revealed that susceptibility initially mapped as a single locus often consists of multiple components on the same chromosome, indicating the importance of congenic mapping in defining genes responsible for polygenic diseases. The NSY mouse is an inbred animal model of type 2 diabetes established from Jcl:ICR, from which the NOD mouse was also derived. We have recently mapped three major loci contributing to type 2 diabetes in the NSY mouse. Interestingly, support intervals where type 2 diabetes susceptibility genes were mapped in the NSY mouse overlapped the regions where type 1 diabetes susceptibility genes have been mapped in the NOD mouse. Although additional evidence is needed, it may be possible that some of the genes predisposing to diabetes are derived from a common ancestor contained in the original closed colony, contributing to type 1 diabetes in the NOD mouse and type 2 diabetes in the NSY mouse. Such genes, if they exist, will provide valuable information on etiological pathways common to both forms of diabetes, for the establishment of effective methods for prediction, prevention, and intervention in both type 1 and type 2 diabetes.     

Shared aetiology of risky sexual behaviour and adolescent misconduct: genetic and environmental influences

Risky sexual behaviour (RSB) is a major risk factor for serious diseases as well as unplanned pregnancy. It is not known if RSB has a genetic basis or if it is only influenced by social and cultural conditions. Adolescent conduct disorder has previously been linked to RSB and has been found to be influenced by both genetic and environmental factors. In this study, we look at normal variation in a broad measure of RSB and in retrospectively reported adolescent misconduct in a large community sample of twins ( n  = 4904) to partition the variance and covariance between the traits into genetic and environmental components. We found that RSB is influenced to the same extent by genes, shared environment and unshared environment. Adolescent misconduct is moderately influenced by genetic factors and only modestly by shared environmental factors. Moreover, RSB is associated with adolescent misconduct ( r  = 0.5), primarily because of genetic correlation between the variables. The implications of our findings as well as possible sex differences are discussed.     

Genetics of thrombophilia: impact on atherogenesis

PURPOSE OF REVIEW: The goal of this review is to present an update on basic and epidemiological findings associating variants in prothrombotic genes with atherogenesis and atherothrombotic disease. RECENT FINDINGS: The relation between atherosclerosis and thrombosis has long been recognized but only recently has it been understood that certain hemostatic factors affect not only thrombus formation, but also have a direct atherogenic role. Atherosclerosis is a complex disorder that results from the interaction of multiple genetic and environmental factors. Numerous polymorphisms and mutations in genes related to the hemostatic system and to vascular redox determinants that modulate nitric oxide bioavailability have been identified in the past decade; their role in atherogenesis and the risk of cardiovascular disease, however, remain uncertain. We will discuss the functional implications and association with disease risk of polymorphisms in coagulation factors (fibrinogen, prothrombin, and factor V); fibrinolytic factors (plasminogen activator inhibitor 1 and lipoprotein(a)); platelet surface receptors; and vascular redox determinants (methylenetetrahydrofolate reductase, endothelial nitric oxide synthase, and the antioxidant enzymes cellular glutathione peroxidase and paraoxonase). SUMMARY: Overall, these genetic variants have a modest effect on risk when considered individually but gain potency when acting synergistically with other genetic or environmental risk factors. We conclude that a better characterization of these interactions, in addition to the identification of potential novel genetic determinants, constitute key issues in the future understanding of the pathogenesis of atherothrombosis.     

Genetic and environmental interrelations between measurements of thyroid function in a healthy Danish twin population

Serum thyrotropin (TSH), free thyroxine (T4), and free triiodothyronine (T3) levels illustrate the thyroid function set point, but the interrelations between these have never been characterized in detail. The aim of this study was to examine the associations between TSH and thyroid hormone levels in healthy euthyroid twins and to determine the extent to which the same genes influence more than one of these biochemical traits; 1,380 healthy euthyroid Danish twins (284 monozygotic, 286 dizygotic, 120 opposite-sex twin pairs) were recruited. Genetic and environmental associations between thyroid function measurements were examined using quantitative genetic modeling. In bivariate genetic models, the phenotypic relation between two measurements was divided into genetic and environmental correlations. Free T4 and free T3 levels were positively correlated (r=0.32, P<0.0001). The genetic correlation between serum free T4 and free T3 levels was rg=0.25 (95% CI 0.14-0.35), suggesting that a set of common genes affect both phenotypes (pleiotropy). The correlation between the environmental effects was re=0.41 (0.32-0.50). From this we calculated that the proportion of the correlation between free T4 and free T3 levels mediated by common genetic factors was 48%. Only 7% of the genetic component of serum free T3 levels is shared with serum free T4. Serum TSH and thyroid hormone levels did not share any genetic influences. In conclusion, thyroid hormone levels are partly genetically correlated genes that affect free T4 levels and exert pleiotropic effects on free T3 levels, although most of the genetic variance for these measurements is trait specific.     

Clustering of insulin resistance, total and central abdominal fat: same genes or same environment?

Obesity, insulin resistance and disturbed glucose metabolism cluster within the Insulin Resistance Syndrome (IRS). Whether this reflects shared genetic or environmental factors detectable in 'normal' populations (not selected for IRS features) is unknown. This study estimated (i) genetic influences on IRS traits and (ii) shared and specific genetic and environmental factors on the relationships between these traits in healthy female twins. Fasting insulin, glucose, total and central fat were measured in 59 monozygotic (MZ) and 51 dizygotic (DZ) female twin pairs aged (+/- SD) 52 +/- 13 years. Body fat was measured by dual-energy X-ray absorptiometry, insulin resistance and secretion by a modified homeostasis model assessment. Using intraclass correlation coefficients and univariate model-fitting analyses, genetic influences were found in total fat, central fat, insulin resistance, fasting glucose and insulin secretion, with genetic factors explaining 64, 57, 59, 75 and 68% of their variance, respectively, using the latter technique. In matched analysis intra-pair differences in total and central fat related to intra-pair differences in insulin resistance (r2 = 0.19, P < 0.001). Multivariate model-fitting showed a close genetic relationship between total and central fat (r = 0.88). The genetic correlation between IR and central fat (0.41) was significantly greater than that for total fat (0.24), suggesting that central fat is not only a predictor of, but shares considerable genetic influence with, insulin resistance. In Cholesky analysis, these genetic influences were separate from those shared between central and total fat. In conclusion, both shared and specific genetic factors regulate components of the IRS in healthy females. However, there were discrete genetic influences on beta-cell insulin secretion, not shared with other IRS components, suggesting that a separate genetic propensity exists for Type 2 diabetes. These findings suggest we may understand the genetic and environmental influences on IRS from the study of the normal population.     

Heritability of Longitudinal Changes in Coronary-Heart-Disease Risk Factors in Women Twins

Numerous studies have demonstrated genetic influences on levels of coronary heart disease (CHD) risk factors, but there also may be genetic effects on the intraindividual variation in these risk factors over time. Changes in risk factors are likely to reflect genetic-environmental interactions and may have important implications for understanding CHD risk. The present study examines the heritability of changes in CHD risk factors, using data from the two examinations by the Kaiser Permanente Women Twins Study, performed a decade apart. The sample consisted of 348 pairs of women twins who participated in both examinations, including 203 MZ pairs and 145 DZ pairs. Average ages at the two examinations were 41 and 51 years, respectively. By means of three different statistical analytic approaches, moderate heritability estimates were demonstrated for changes in LDL cholesterol (h2 = .25-.36) and in HDL cholesterol (h2 = .23-.58), some of which were statistically significant. Although small to moderate heritability estimates were found for systolic blood pressure (.18-.37; P < .05 for some estimates), no genetic influence on changes in diastolic blood pressure was detected. Based on longitudinal twin data in women, this study demonstrates a genetic influence on changes in both lipoprotein risk factors and systolic blood pressure over a decade. In addition to environmental factors, which clearly are operating, the effect of various "variability genes" may be acting independently of the genetic influences on the absolute levels of these risk factors. Both mapping the gene(s) underlying intraindividual variations in these CHD risk factors and understanding their function(s) could lead to targeted intervention strategies to reduce CHD risk among genetically susceptible individuals.     

Type 2 diabetes as an inflammatory cardiovascular disorder

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors ("common soil" hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting anti-inflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.     

Genetic and environmental components of family history in type 2 diabetes

Family history of diabetes is a major risk factor for type 2 diabetes (T2D), but whether this association derives from shared genetic or environmental factors is unclear. To address this question, we developed a statistical framework that models four components of variance, including known and unknown genetic and environmental factors, using a liability threshold model. Focusing on parental history, we simulated case–control studies with two first-degree relatives for each individual, assuming 50 % genetic similarity and a range of values of environmental similarity. By comparing the association of parental history with T2D in our simulations to case–control studies of T2D nested in the Nurses’ Health Study and Health Professionals Follow-up Study, we estimate that first-degree relatives have a correlation of 23 % (95 % CI 15–27 %) in their environmental contribution to T2D liability and that this shared environment is responsible for 32 % (95 % CI 24–36 %) of the association between parental history and T2D, with the remainder due to shared genetics. Estimates are robust to varying model parameter values and our framework can be extended to different definitions of family history. In conclusion, we find that the association between parental history and T2D derives from predominately genetic but also environmental effects.     

Genetic and environmental influences on body fat distribution, fasting insulin levels and CVD: are the influences shared?

Central body fat distribution has been shown to be related to hyperinsulinemia, insulin resistance, hypertriglyceridemia, and atherosclerosis to a greater degree than general obesity. There are known to be both genetic and environmental effects on all components of this clustering. Whether these genetic effects are due to one set of genes in common to the components or whether genetic influences on insulin resistance and/or general/abdominal fatness 'turn on' other genes that affect other components of the syndrome is not clear. We analyzed data from the Swedish Adoption/Twin Study of Aging (60% female; monozygotic = 116, dizygotic = 202; average age 65 years) to determine whether there were genetic and/or environmental factors shared among general body fat distribution, abdominal body fat distribution, fasting insulin levels and cardiovascular disease. We found additive genetic effects in males to be significantly different from those in females with genetic effects accounting for variance in waist-hip ratio (males = 28%; females = 49%), body mass index (males = 58%; females = 73%), fasting insulin levels (FI) (males = 27%; females = 49%), and cardiovascular disease (CVD) (males = 18%; females = 37%). There were also shared genetic and environmental effects among all the variables except CVD, but a majority of the genetic variance for these measures was trait specific.     

整合冠心病风险SNPs功能及分子网络特征筛选疾病易感基因

目的:冠心病(Coronary Heart Disease,CHD)是一种由多因素(遗传因素、环境因素以及它们之间的相互作用)引起的复杂疾病。本文从遗传因素和分子互作模式识别新的冠心病易感基因。方法:结合冠心病群体遗传SNPs数据和PPI数据,通过群体遗传数据的风险评估、功能SNPs的判定和PPI网络基因的分类,以功能SNPs属性、网络拓扑属性和基因功能属性为特征,利用两步分类的方法筛选新的冠心病易感基因。结果:获得了69个新的冠心病易感基因,其中43个被文献证实与冠心病的发生发展密切相关,且识别的新的易感基因注释的KEGG通路中有很多是已知的易感基因所没有注释到的,如MAPK signaling pathway,Calcium signaling pathway,Focal adhesion和Chemokine signaling pathway等,其中Chemokine signaling pathway被证实是CHD发展的关键通路。结论:应用本文提出的整合筛选策略,能识别与冠心病相关的新的易感基因,可为冠心病的预防、诊断和治疗提供新的研究方向。     

A twin study of the etiology of prolonged fatigue and immune activation.

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors. Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation. By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation. PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.     

Contribution of the familial and genetic factors on monocyte chemoattractant protein-1 variation in healthy human pedigrees

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine whose circulating levels have been detected in the lesions of several diseases such as pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. However, the factors involved in the regulation of its production remain largely unknown. The main aim of the present paper was to ascertain the contribution of the familial/genetic factors on the production of MCP-1 in apparently healthy individuals. We also tested the possible relationships between the plasma levels of MCP-1 and other cytokines involved in bone metabolism (receptor activator NF-kB ligand (RANKL), osteoprotegerin (OPG), interleukin-6, macrophage-colony stimulating factor, tumor necrosis factor-alpha). Using ELISA assays the cytokine levels were measured in 570 apparently healthy individuals belonging to ethnically homogeneous Caucasian families. We found that MCP-1 levels were significantly (P<0.01) correlated with RANKL (in both sexes) and with OPG only in women. The study showed that adjusted for potential covariates, 72% of the MCP-1 variance, was attributable to familial effects. About 49% was due to potential genetic factors and the rest was explained by common environmental sources shared by spouses within each family. In conclusion, our data provide reliable evidence for the substantial role of genetic factors in the determination of the phenotypic variability of MCP-1 plasma levels. The association between the osteoclastogenic cytokines and MCP-1 levels in healthy pedigrees is of special interest and might shed light on MCP-1 involvement in bone remodeling.     

Prevalence of myocardial infarction polymorphisms in Afyonkarahisar, Western Turkey

The aim of the study was to investigate relationship between polymorphisms in genes that are clinical and environmental features and the risk of myocardial infarction (MI) in Afyonkarahisar subjects living in Turkey. Prevalence of the several genes polymorphisms, ≤45 (42.04 ± 3.3) and ≥46 (57.19 ± 7.5) years were studied in individuals with MI and without MI (40.30 ± 9.01) individuals were studied. We tested 140 with MI individuals for factor V (FV) Leiden, FV H1299R, Prothrombin G20210A, factor XIII (FXIII) V34L, β-fibrinogen b-455G/A, plasminogen activator inhibitor-1 (PAI-1)-675 4G/5G, human platelet antigens 1 (HPA-1) a/b, apolipoprotein B (ApoB) R3500Q, apolipoprotein E (ApoE), E2, E3, and E4, angiotensin-converting enzyme (ACE) D/I, 5,10 methylenetetrahydrofolate reductase (MTHFR) 677C/T, and MTHFR 1298A/C polymorphisms using a ViennaLab CVD strip assay. This study results were compared without MI control groups. According to the our results, prothrombin, factor XIII and MTHFRC677T deletions were the most frequent genetic variants in risk groups of hyperlipidemic patients (value of odds ratio sequentially [OR] = 4.5, p = 0.05, [OR] = 2.16, p = 0.04 and [OR] = 2.8, p = 0.09). MTHFRA1298C and PAI-1 deletions were most frequent genetic variants in risk groups for MI in patients with diabetes mellitus (value of odds ratio sequentially [OR] = 3.79, p = 0.06 and [OR] = 5 × 10(8), p = 0.000). ACE deletions were positively associated with family history of cardiovascular events (OR = 3.62, p = 0.03). We found a strong relationship between genetic variants and risk factors. Significant associations between genetic variants predicting cardiovascular events and common risk factors (hyperlipidemia, smoking, diabetes mellitus and family history) patients were found.     

冠心病易感基因的筛选

作为一种多基因疾病 ,冠心病是由遗传和环境因素共同作用的结果 ,在许多国家是主要的死因之一。由于目前冠心病的发病机制尚不十分清楚 ,阻碍了其易感基因的定位分离研究。冠心病遗传因素的确定 ,显然将有助于其易感基因定位分离研究。迄今除发现了个别的相关基因外 ,绝大部分的遗传易感性相关基因尚未被发现 ,其研究仍然存在许多问题。为此 ,本文就其易感基因可能的研究策略和方法作一综述。这些方法同样也适用于诸如中风、外周血管阻塞、高血压、心力衰竭等心血管疾病以及其它多基因疾病     

Genetic Pleiotropy Explains Associations between Musical Auditory Discrimination and Intelligence

Musical aptitude is commonly measured using tasks that involve discrimination of different types of musical auditory stimuli. Performance on such different discrimination tasks correlates positively with each other and with intelligence. However, no study to date has explored these associations using a genetically informative sample to estimate underlying genetic and environmental influences. In the present study, a large sample of Swedish twins (N = 10,500) was used to investigate the genetic architecture of the associations between intelligence and performance on three musical auditory discrimination tasks (rhythm, melody and pitch). Phenotypic correlations between the tasks ranged between 0.23 and 0.42 (Pearson r values). Genetic modelling showed that the covariation between the variables could be explained by shared genetic influences. Neither shared, nor non-shared environment had a significant effect on the associations. Good fit was obtained with a two-factor model where one underlying shared genetic factor explained all the covariation between the musical discrimination tasks and IQ, and a second genetic factor explained variance exclusively shared among the discrimination tasks. The results suggest that positive correlations among musical aptitudes result from both genes with broad effects on cognition, and genes with potentially more specific influences on auditory functions.