Varun Sharma

Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects independent of HO-1 pathway.

mtDNA G10398A variation provides risk to type 2 diabetes in population group from the Jammu region of India.

Mitochondrion plays an integral role in glucose metabolism and insulin secretion. Mitochondrial electron-transport chain (ETC) is involved in adenosine triphosphate (ATP) generation and ATP mediated insulin secretion in pancreatic β-cells. β-cell dysfunction is a critical component in the pathogenesis of type 2 diabetes (T2D). The mtDNA G10398A variation (amino acid change: Alanine → Threonine) within the NADH dehydrogenase (ND3) subunit of complex I of mtDNA ETC, has emerged as a variation of clinical significance in various disorders including T2D. This variation is supposed to result in altered complex I function, leading to an increased rate of electron leakage and reactive oxygen species (ROS) production, which might cause β-cell damage and impaired insulin secretion. The aim of the study was to explore the association of mtDNA G10398A variation with T2D in a total of 439 samples (196 T2D cases and 243 healthy controls) belonging to the Jammu region of Jammu and Kashmir (J&K). The candidate gene association analyses showed significant association of mtDNA G10398A variant with T2D and the estimated odds ratio (OR) was 2.83 (1.64–4.90 at 95% CI) in the studied population group. The extent of genetic heterogeneity in T2D and diversity of the Indian population groups, make such replication studies pertinent to understand the etiology of T2D in these population groups.

Replication of newly identified type 2 diabetes susceptible loci in Northwest Indian population

OBJECTIVE To replicate the association of newly identified variants of TMEM163 (transmembrane protein 163) and COBLL1 (cordon-bleu protein-like 1) with type 2 diabetes (T2D) in Northwest Indian population. METHODS We performed a replication study of variants rs998451 and rs6723108 of gene TMEM163 and rs7607980 of gene COBLL1. The variations were genotyped using Taqman allele discrimination assay in 1209 Northwest Indians (651 T2D cases and 558 controls). The association of each SNP with the disease was evaluated using logistic regression. RESULTS All the three SNPs examined in this study did not show any significant association with T2D. For rs998451 and rs6723108 of TMEM163 the observed odds ratios were 0.71 with a 95% CI of 0.28-1.84 (p=0.484) and 1.80 with a 95% CI of 0.74-4.40 (p=0.196), respectively. For rs7607980 the estimated odds ratio was 1.01 with 95% CI of 0.70-1.44 (p=0.946). CONCLUSION We conclude that lack of association could be because of population structure of Indian Population that is conglomeration of various ethnic groups. For a conclusive association study of T2D in India, it is critical that such studies are carried out among endogamous ethnic groups rather than conventional practice of pooling samples based on Geographical/regional or linguist affiliations like Asian Indian, North or South Indian etc.

Ancient Human Migrations to and through Jammu Kashmir- India were not of Males Exclusively

Jammu and Kashmir (J&K), the Northern most State of India, has been under-represented or altogether absent in most of the phylogenetic studies carried out in literature, despite its strategic location in the Himalayan region. Nonetheless, this region may have acted as a corridor to various migrations to and from mainland India, Eurasia or northeast Asia. The belief goes that most of the migrations post-late-Pleistocene were mainly male dominated, primarily associated with population invasions, where female migration may thus have been limited. To evaluate female-centered migration patterns in the region, we sequenced 83 complete mitochondrial genomes of unrelated individuals belonging to different ethnic groups from the state. We observed a high diversity in the studied maternal lineages, identifying 19 new maternal sub-haplogroups (HGs). High maternal diversity and our phylogenetic analyses suggest that the migrations post-Pleistocene were not strictly paternal, as described in the literature. These preliminary observations highlight the need to carry out an extensive study of the endogamous populations of the region to unravel many facts and find links in the peopling of India.

A case report on a novel MT-ATP6 gene variation in atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

Replication of MACF1 gene variant rs2296172 with type 2 diabetes susceptibility in the Bania population group of Punjab, India

Microtubule actin cross-linking factor 1 (MACF1) gene variant rs2296172 has recently been associated with type 2 diabetes (T2D). However, this variant has never been evaluated as such in Indian populations. In the present replication study, we genotyped variant rs2296172 by Taqman allele discrimination assay in 432 individuals belonging to the Bania caste group from Punjab, India. The single-nucleotide polymorphism (SNP) was evaluated for association with T2D, in a population based candidate gene case-control association study design, by estimating odds ratio with 95% confidence interval. The SNP rs2296172 of MACF1 was found to be significantly associated with T2D (p = 0.02) and odds ratio (OR) = 1.59 (1.06–2.38) at 95% CI . We further emphasize that the Indian population as such is a conglomeration of various endogamous population groups. It is critical that such replication studies be carried out in various populations to find association of variants to T2D susceptibility and understand genetic heterogeneity. However, it is important to avoid pooling of samples to address the concern of population stratification.