Structure, function, and genetics of lipoprotein (a)

South Asia is home to one of the largest population of people with metabolic syndrome (MetS). The prevalence of MetS in South Asians varies according to region, extent of urbanization, lifestyle patterns, and socioeconomic/cultural factors. Recent data show that about one-third of the urban population in large cities in India has the MetS. All classical risk factors comprising the MetS are prevalent in Asian Indians residing in India. The higher risk in this ethnic population necessitated a lowering of the cut-off values of the risk factors to identify and intervene for the MetS to prevent diabetes and cardiovascular disease. Some pharmacological and nonpharmacological interventions are underway in MetS to assess the efficacy in preventing the diabetes and cardiovascular disease in this ethnic population.

Metabolic syndrome in South Asians.

Objectives
1. To determine the prevalence of Metabolic Syndrome in adults aged 18 years and above in Chandigarh, India. 2. To determine the socio-demographic factors associated with MS. 3. To determine the agreement between IDF (International Diabetes federation definition) and ATP-III (National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults criteria).

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Metabolic syndrome: a challenging health issue in highly urbanized Union Territory of north India.

Network analysis is a novel method to understand the complex pathogenesis of inflammation-driven atherosclerosis. Using this approach, we attempted to identify key inflammatory genes and their core transcriptional regulators in coronary artery disease (CAD). Initially, we obtained 124 candidate genes associated with inflammation and CAD using Polysearch and CADgene database for which protein-protein interaction network was generated using STRING 9.0 (Search Tool for the Retrieval of Interacting Genes) and visualized using Cytoscape v 2.8.3. Based on betweenness centrality (BC) and node degree as key topological parameters, we identified interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), interleukin-1 beta (IL-1B), tumor necrosis factor (TNF) and prostaglandin-endoperoxide synthase 2 (PTGS2) as hub nodes. The backbone network constructed with these five hub genes showed 111 nodes connected via 348 edges, with IL-6 having the largest degree and highest BC. Nuclear factor kappa B1 (NFKB1), signal transducer and activator of transcription 3 (STAT3) and JUN were identified as the three core transcription factors from the regulatory network derived using MatInspector. For the purpose of validation of the hub genes, 97 test networks were constructed, which revealed the accuracy of the backbone network to be 0.7763 while the frequency of the hub nodes remained largely unaltered. Pathway enrichment analysis with ClueGO, KEGG and REACTOME showed significant enrichment of six validated CAD pathways - smooth muscle cell proliferation, acute-phase response, calcidiol 1-monooxygenase activity, toll-like receptor signaling, NOD-like receptor signaling and adipocytokine signaling pathways. Experimental verification of the above findings in 64 cases and 64 controls showed increased expression of the five candidate genes and the three transcription factors in the cases relative to the controls (p<0.05). Thus, analysis of complex networks aid in the prioritization of genes and their transcriptional regulators in complex diseases.

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Network analysis of inflammatory genes and their transcriptional regulators in coronary artery disease.

CELSR2–PSRC1–SORT1 gene expression and association with coronary artery disease and plasma lipid levels in an Asian Indian cohort

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

Coronary artery disease (CAD) is a multifactorial disease, and family history is the best available tool to assess gene-environment interaction. This study addressed the heritability of quantitative traits, namely lipid, coagulation/fibrinolysis and pro-inflammatory markers in the ongoing family-based Indian Atherosclerosis Research Study and assessed the effect of the type/lineage of CAD family history on inheritance patterns in the high-risk Indian population. A total of 518 families comprising 2,305 individuals were recruited in phase I of the IARS; of these, 1,195 individuals from 220 families were included in the heritability analysis. With the exception of leptin, all phenotypes exhibited significant age- and sex-adjusted heritability (p < 0.0001). Amongst all the phenotypes analysed after adjustment for confounding factors, the significantly higher heritability estimates of triglycerides (0.53, p < 0.0001), lipoprotein (a) (0.83, p < 0.0001) and interleukin-6 (0.46, p < 0.0001) with low spouse pair correlations identifies them as possible CAD risk factors. Families with parental history of CAD had onset of CAD symptoms at much younger ages with significantly higher heritability of proinflammatory markers, whereas in families with sibling history of CAD, more risk factors were present at significantly higher levels. Triglycerides, lipoprotein (a) and interleukin-6 appear to be promising atherothrombotic candidate phenotypes in this population. Genes controlling these phenotypes are possible candidate genes linked with CAD. An informed understanding and incorporation of 'family history' as a screening tool may help in the prevention and pre-emption of CAD.

Natesha B Khadrinarasimhaih

Papers

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

Genetic contribution to variation in atherothrombotic phenotypes in the Asian Indian population - the Indian atherosclerosis research study.