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

Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide Asian Indians, especially the young and working population (1,2), are reported to have three times higher rates of incidence and prevalence of CAD when compared with western populations (3,4), leading to a greater social and economic impact (3,5,6) Various factors, such as metabolic syndrome, diabetes, diet, unique dyslipidemia (high triglycerides, low high-density lipoprotein cholesterol levels) and possible genetic predisposition are believed to contribute to this rising epidemic in India (3)

Atherosclerosis, the underlying cause of acute coronary syndrome, is a chronic inflammatory disease with multifactorial etiology (7) The contribution of infection to induction and progression of the disease has been surrounded by controversy Although evidence for the role of infection comes from several epidemiological studies demonstrating an association between antibodies to pathogens including cytomegalovirus (CMV), Chlamydia pneumonia, Helicobacter pylori, hepatitis A, herpes simplex virus (HSV) and periodontal bacteria with atherosclerosis (8–11), other studies are less consistent (12) Pathogen burden (ie, the cumulative burden of infection rather than infection by any single pathogen) has been linked to the progression of CAD and its complications (10,13,14)

Chronic infection can cause proatherosclerotic effects by increasing the expression of inflammatory cytokines, chemokines and cellular adhesion molecules, as well as smooth muscle cell proliferation and migration (15) Infection may also trigger vascular damage by molecular mimicry wherein pathogenic antigens trigger an immune response cross-reacting with self-peptides expressed on host tissues (13,15,16)

Pathogen burden is reported to be higher in individuals of Indian origin (17) However, the association between pathogen burden in combination with inflammatory markers and CAD is not well defined in this population It is possible that novel risk factors contribute to the high CAD incidence seen in Indians, which cannot be adequately explained by conventional risk factors alone (3,5) Therefore, the aim of the present study was to examine the association of increasing pathogen burden in combination with novel inflammatory markers with CAD in Indians We also studied the association between antibody levels and individual pathogens with CAD and recurrent cardiac events

Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin

Table 3. Analysis of variance of the plasma lipid biomarkers and rs10757278 SNP. AA AG GG Plasma lipid Mean ± s.e. [mg/dl] Mean ± s.e. [mg/dl] Mean ± s.e. [mg/dl] P value Total cholesterol 5.09 ± 0.05 (164.02) 5.11 ± 0.02 (165.67) 5.13 ± 0.03 (169.02) 0.828 Triglycerides 4.75 ± 0.09 (115.58) 4.89 ± 0.04 (132.95) 4.93 ± 0.06 (138.38) 0.261 HDL cholesterol 3.7 ± 0.04 (40.45) 3.7 ± 0.02 (40.45) 3.78 ± 0.03 (43.82) 0.085 LDL cholesterol 4.55 ± 0.07 (94.63) 4.53 ± 0.03 (92.76) 4.51 ± 0.05 (90.92) 0.888

/pdf/a-common-variant-in-chromosome-9p21-associated-with-coronary-2vf1nwp2x1.pdf

A common variant in chromosome 9p21 associated with coronary artery disease in Asian Indians.

AIMS & OBJECTIVES Cardiovascular disease is highly prevalent among Asian Indians. The objective of the Indian Atherosclerosis Research Study (IARS) is to understand the molecular basis of Coronary Artery Disease (CAD) in this population. METHODS & RESULTS Over 12,500 subjects from 2500 families and 2500 healthy matched controls will be enrolled by year 2010 in the IARS. Selection of participants will be based on stringent inclusion/exclusion criteria. Blood samples will be analyzed for various genes and biomarkers implicated in CAD by employing commercial or in-house developed assays as for indices of early vascular changes. To date, over 6053 individuals from 1644 families with associated demographics, clinical information and bio specimen have been enrolled and comprise of 2131 CAD patients with mean age, 55.02 +/- 0.19 years and 3901 unaffected relatives with mean age, 40.15 +/- 0.22 years. Over 70% of the CAD patients were males. There was significant association of diabetes, hypertension and smoking with CAD status (OR 2.43-4.75; 95% CI 2.01-5.59). Subjects with metabolic syndrome (MS) showed 3 times higher risk of CAD than the non MS group (OR 3.04; 95% CI 2.71-3.41). Preliminary analyses on various atherothrombotic genes relating to lipids, inflammation and growth have identified novel variants as well as unique haplotypes associated with CAD. Proteomic studies revealed strong heritability for plasma TG, IL6, hsCRP and HDL-c levels (h2 46%-86%; p < 0.01). Baseline levels of pro-inflammatory like CRP, sPLA2 and sTWEAK were significantly higher in patients with recurrent or new coronary event. Affected subjects had higher serum antibody titers to CMV, H. pylori and C Pneumoniae infections. Early results from non-invasive assessment of endothelial dysfunction using Periscope suggest that this method is a sensitive tool for delineation of sub clinical atherosclerosis. CONCLUSION The clinical and molecular data will be systematically integrated to develop a refined algorithm for risk prediction in the Asian Indian population.

Rationale, design & preliminary findings of the Indian Atherosclerosis Research Study.

Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 ( 𝑟 = . 3 7 3 ; 𝑃 = . 0 0 0 1 ), sPLA2 ( 𝑟 = . 5 4 4 ; 𝑃 = . 0 0 0 1 ) as also with fibrinogen ( 𝑟 = . 5 7 9 ; 𝑃 = . 0 0 0 1 ). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP ( > 3 . 5 8  mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.

/pdf/usefulness-of-c-reactive-protein-as-a-marker-for-prediction-12u2g0nfly.pdf

Usefulness of C-Reactive Protein as a Marker for Prediction of Future Coronary Events in the Asian Indian Population: Indian Atherosclerosis Research Study

Metabolic syndrome (MetS) is a primary risk factor for cardiovascular disease and is associated with a proinflammatory state. Here, we assessed the contribution of inflammatory and oxidative stress markers towards prediction of MetS. A total of 2316 individuals were recruited in Phase I of the Indian Atherosclerosis Research Study (IARS). Modified ATPIII guidelines were used for classification of subjects with MetS. Among the inflammatory and oxidative stress markers studied, levels of hsCRP (P < .0001), Neopterin (P = .036), and oxLDL (P < .0001) were significantly higher among subjects with MetS. Among the markers we tested, oxLDL stood out as a robust predictor of MetS in the IARS population (OR 4.956 95% CI 2.504-9.810; P < .0001) followed by hsCRP (OR 1.324 95% CI 1.070-1.638; P = .010). In conclusion, oxLDL is a candidate predictor for MetS in the Asian Indian population.

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Veena S. Rao

Papers

Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin

A common variant in chromosome 9p21 associated with coronary artery disease in Asian Indians.

Rationale, design & preliminary findings of the Indian Atherosclerosis Research Study.

Usefulness of C-Reactive Protein as a Marker for Prediction of Future Coronary Events in the Asian Indian Population: Indian Atherosclerosis Research Study

Association of inflammatory and oxidative stress markers with metabolic syndrome in asian indians in India.