Insecurity in a New Silk Road

Withdrawal of US-NATO troops from Afghanistan, remains an issue for military operations of new-old participants in the process of further destabilization of the political situation in Central Asia. The process of political destabilization of the region raises many a questions about new relationship between interests of USA, China, Russia and India in this region. Pronounced influence of radical Islamic movements in the broader area of Asia makes this region tremendously important for the further development of global political relations in this part of the world. The crisis in relations between Russia and the West makes reconfiguration of global strategic interests in the region more complex.

Assessment of Genetic Risk Factors for Cardiovascular Diseases in Pakistani Population

Cardiovascular diseases (CVDs) are the prime cause of death accounting for 17.7 million deaths every year globally. In Pakistan, prevalence of CVDs is also considerably high. CVDs are multifactorial with many risk factors involved in the pathophysiology of the disease including the genetic predisposition. Genetically, CVDs may be monogenic or polygenic. Also, there is heterogeneity among genetic predisposition of cardiac disorders in different populations of the world. This study aims to investigate the genetic risk factors related to CVDs in Pakistani population. In this study, the whole genome sequencing data of Pakistani individuals (PJL) from 1000 Genomes Project (n=96), whole exome sequencing data from Exome Aggregation Consortium (predominantly containing individuals from Pakistan) (n=8256), and whole exome sequencing data of British Pakistanis (n=3222) were analyzed using different bioinformatics tools against a manually curated list of 1187 genes associated with major CVDs. The analysis of genetic variants with ANNOVAR and CADD tools highlighted 561 deleterious variants from 1000 Genomes PJL, 7374 deleterious variants from ExAC (SAS), and 6028 deleterious variants from British Pakistanis datasets in protein coding regions. The analysis with VEP showed 03 Loss of Function variants from 1000 Genomes PJL, 30 Loss of Function variants from ExAC (SAS), and 29 Loss of Function variants from British Pakistanis datasets. Further, the filtration from ClinVar database revealed 03 pathogenic and 02 likely pathogenic variants from 1000 Genomes Project PJL, 112 pathogenic, and 42 likely pathogenic variants from ExAC (SAS), and 42 pathogenic and 16 likely pathogenic variants from British Pakistanis datasets. The comparative analysis of prioritized deleterious variants showed many variants having two fold or higher allele frequency in Pakistani population than in other populations of the world. Likewise, the population differentiation analysis highlighted 10 deleterious SNVs greatly differentiated from world populations and 02 deleterious SNVs moderately differentiated from other South Asian populations. The principal components analysis showed the grouping of Pakistani and other South Asian populations with Europeans and Americans for deleterious mutations of CVDs. XIV To further analyze the filtered data for CVDs, whole genome sequencing of an individual with hyperlipidemia, obesity, and coronary artery disease was carried out using SOLiD 5500xl NGS system, and whole exome sequencing of 05 patients with dilated cardiomyopathy was carried out using Illumina NGS system. After variants calling and applying the same analysis pipeline, 27 deleterious SNVs were observed in 25 genes associated with hyperlipidemia and risk of coronary artery disease. Two genes, MTRR (methionine synthase reductase), and PLB1 (Phospholipase B1) contained two deleterious variants each, and are associated with low levels of low density lipoprotein-cholesterol (LDL-C) and risk of coronary artery disease. Furthermore, 11 deleterious variants, also filtered from the healthy dataset, were observed having significantly higher allele frequency in SAS Populations than in other populations of the world. In addition, two genes, KCNJ12 (potassium voltage-gated channel subfamily J member 12) and CDC27 (cell division cycle 27 protein), were identified having highest number of deleterious nonsynonymous and non-coding variants. From whole exome analysis of 05 dilated cardiomyopathy patients, 54 variants were identified in genes associated with dilated cardiomyopathy, which were prioritized in mutational load analysis as well. Here, the highest number of deleterious variants was observed in TTN (titin) and MUC19 (Mucin 19) genes. Also, there were 19 deleterious SNVs in homozygous state with global minor allele frequency < 1.0%. Overall, 278 deleterious SNVs were having higher allele frequency in SAS than in other populations of the world. Further, three rare allele frequency (AF < 1%) loss of function SNVs in C2orf40, MYOM3, and TMED4 genes, a homozygous frameshift insertion in RTKN2., and a splice site homozygous deletion in SLC6A6 were found in at least one of the patients. To conclude, this study comprehensively presents a picture of deleterious mutations for cardiac disorders in Pakistani population. The mutational load for major CVDs in a descending order was for hypertension, atherosclerosis, coronary aneurysm, heart failure, coronary artery disease, cardiomyopathies, cardiac arrhythmias, and congenital heart defects. The effect of this genetic predisposition (which is a non- modifiable risk factor) can be suppressed by minimizing the modifiable risk factors such as healthy lifestyle.