2005년 대한 생화학·분자생물학회 하계학술대회를 다녀와서

The investigators, recognizing that coronary artery disease (CAD), including acute myocardial infarction (MI), is the leading cause of death worldwide, carried out a genome-wide associational study on Icelandic patients with MI. Initially more than 300,000 single nucleotide polymorphisms (SNPs) were examined for any association with MI. Ultimately, the study enrolled 4587 cases and 12,769 controls. The strongest association with MI was noted with 3 correlated SNPs, all located within a 190-kb linkage disequilibrium block on chromosome 9p21. The association with MI was replicated in case-control sample sets of persons of European descent from 3 US cities. The identified variant was adjacent to the tumor suppressor genes CDKN2A and CDKN2B. It was associated with MI at a high level of significance (P = 1.2 × 10−20). The proteins encoded by these genes have a key role in regulating cell proliferation, cell senescence, and apoptosis—all important features of atherogenesis.
Approximately 21% of individuals in the study population are homozygous for the variant, and it is estimated that their risk of having MI is 1.64-fold greater than for noncarriers. The risk is 2.02-fold greater for early-onset cases. The population-attributable risk was estimated as 21% for MI in general and 31% for early-onset cases. This is the first common variant found to consistently confer a substantial risk of MI, defined as an odds ratio exceeding 1.20, in multiple case-control groups of European descent. The variant poses a substantial risk from a public health viewpoint, but it explains only a small part of familial clustering of the disease and would not yield high linkage scores. The implication is that other susceptibility variants are as yet unidentified. In addition to MI, there is reason to believe that the present variant might increase the risk of CAD in general. Just how genetic variants influence the pathogenesis of MI remains to be clarified.

A common variant on chromosome 9p21 affects the risk of myocardial infarction

Avian eggshell mineralization: biochemical and functional characterization of matrix proteins

LH/hCG receptors were disrupted by gene targeting in embryonic stem cells. The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testosterone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdominal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round spermatid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in testes. However, it caused a dramatic decrease in StAR and estrogen receptor-alpha (ERalpha) mRNA levels and an increase in ERbeta mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phenotype and biochemical changes were a consequence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained infertile. It is anticipated that the LH receptor knockout animals will increase our current understanding of gonadal and nongonadal actions of LH and hCG.

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Targeted disruption of luteinizing hormone/ human chorionic gonadotropin receptor gene

Molluscan shell proteins

High-density lipoprotein (HDL) is a major carrier of cholesterol in the blood. Unlike other lipoproteins, physiological functions of HDL influence the cardiovascular system in favorable ways except when HDL is modified pathologically. The cardioprotective mechanism of HDL is mainly based on reverse cholesterol transport, but there has been an emerging interest in the anti-inflammatory and antioxidant roles of HDL. These latter activities of HDL are compromised in many pathological states associated with inflammation. Further, abnormal HDL can become proinflammatory contributing to oxidative damage. In this paper, we discuss the functional heterogeneity of HDL, how alterations in these particles in inflammatory states result in loss of both antioxidant activity and reverse cholesterol transport in relation to atherosclerosis, and the need for assays to predict its functionality.

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Friend Turns Foe: Transformation of Anti-Inflammatory HDL to Proinflammatory HDL during Acute-Phase Response

Several procoagulant proteins from snake venoms have been isolated and characterized. They are either serine proteinases or metalloproteinases, which activate specific zymogens of coagulation factors and initiate the coagulation cascade. These procoagulant proteins are useful in treating various thrombotic and hemostatic conditions and contribute to our understanding of molecular details in the activation of specific coagulation factors. Recent studies have shown that the prothrombin activators with serine proteinase activity are structurally and functionally similar to mammalian coagulation factors. Their structural studies should provide us insight into prothrombinase complex formation. Here, we present an overview of snake venom procoagulant factors.

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Procoagulant proteins from snake venoms.

Several snake venoms contain procoagulant proteins that can activate prothrombin. We have purified pseutarin C, a prothrombin activator from the venom of the Australian brown snake (Pseudonaja textilis). It converts prothrombin to thrombin by cleaving both the peptide bonds Arg(274)-Thr(275) and Arg(323)-Ile(324), similar to mammalian factor Xa. It is a protein complex (approximately 250 Kd) consisting of an enzymatic and a non- enzymatic subunit. These subunits were separated by reverse phase HPLC and their interactions with bovine factor Xa and factor Va were studied. The enzymatic subunit of pseutarin C has an approximately 13 fold higher affinity for bovine factor Va (K(d) of 11.4 nM for pseutarin C enzymatic subunit--bovine factor Va interaction as compared to a K(d) of 147.4 nM for the bovine factor Xa-Va interaction). The non-enzymatic component, however, was unable to activate bovine factor Xa. N-terminal sequence analysis of the catalytic subunit of pseutarin C showed approximately 60% homology to mammalian factor Xa and approximately 78% homology to trocarin, a group D prothrombin activator from Tropidechis carinatus venom. Structural information for the non-enzymatic subunit of pseutarin C was obtained by amino terminal sequencing of several internal peptides. The sequence data obtained indicates that the non-enzymatic subunit of pseutarin C has similar domain architecture like the mammalian factor Va and the overall homology is approximately 55%. Thus pseutarin C is the first venom procoagulant protein that is structurally and functionally similar to mammalian factor Xa-Va complex.

Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex.

Asian Indians have a high predisposition to metabolic syndrome (MS) and coronary artery disease (CAD). The present study aimed to estimate MS prevalence in 531 Asian Indian families comprising of 2318 individuals. Anthropometrics and lipid profile were assessed. MS prevalence was estimated using standard Adult Treatment Panel III (ATP-III) and World Health Organisation (WHO) criteria and modified definitions which included lowered cut-offs for waist circumference (WC) (≥90 cm for men and ≥80 cm for women], body mass index (BMI) (≥23 kg/m2) and impaired fasting glucose (IFG) levels. ATP-III criteria identified a significantly higher proportion of people with MS (N = 933; 40.3%) compared with WHO (N = 708; 30.6%; p < 0.0001) while modified ATP-III showed maximum gain in percent prevalence among the revised criteria (17.3%; p = 0.0056). The IDF criteria identified similar proportion of subjects with MS (N = 809; 34.9%) as the revised WHO criteria (N = 792; 34.2%). The number of MS subjects was highest in the 50–59 years age group. MS was diagnosed a decade earlier in unaffected subjects compared with those with CAD/diabetes using the modified MS criteria. WC correlated significantly with BMI and waist–hip ratio (WHR) (p = 0.000). Among MS components, high density lipoprotein cholesterol and BMI contributed significantly in males (71.4% and 85.9%) and females (86.8% and 88.8%), respectively. The higher percentage contribution of WC among males and WHR among females indicates the influence of gynecoid/android pelvis on WHR measures. In conclusion, the revision of definition criteria for MS with lowered cut-offs for WC and BMI is critical for the accurate assessment of MS among Asian Indians.

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Prevalence and component analysis of metabolic syndrome: An Indian atherosclerosis research study perspective

The increasing pressure on health resources has led to the emergence of risk assessment as an essential tool in the management of cardiovascular disease (CVD). Concern exists regarding the validity of their generalization to all populations. Existing risk scoring models do not incorporate emerging ‘novel’ risk factors. In this context, the aim of the study was to examine the relevance of British, European, and Framingham predictive CVD risk scores to the asymptomatic high risk Indian population. Blood samples drawn from the participants were analyzed for various ‘traditional’ and ‘novel’ biomarkers, and their CVD risk factor profiling was also done. The Framingham model defined only 5% of the study cohort to be at high risk, which appears to be an underestimation of CVD risk in this genetically predisposed population. These subjects at high risk had significantly elevated levels of lipid, pro-inflammatory, pro-thrombotic, and serological markers. It is more relevant to develop risk predictive scores for application to the Indian population. This study substantiates the argument that alternative approaches to risk stratification are required in order to make them more adaptable and applicable to different populations with varying risk factor and disease patterns.

/pdf/application-of-cardiovascular-disease-risk-prediction-models-54ejope0wa.pdf

Veena S. Rao

Papers

Friend Turns Foe: Transformation of Anti-Inflammatory HDL to Proinflammatory HDL during Acute-Phase Response

Procoagulant proteins from snake venoms.

Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex.

Prevalence and component analysis of metabolic syndrome: An Indian atherosclerosis research study perspective

Application of cardiovascular disease risk prediction models and the relevance of novel biomarkers to risk stratification in Asian Indians