Multi-faceted dysregulated immune response for COVID-19 infection explaining clinical heterogeneity.

Clinical heterogeneity and varied prognosis are well noted for SARS-CoV-2 infection. Altered immune response is a major feature for the adverse prognosis however focus on altered immune response has been primarily limited to hyper-inflammatory responses like Cytokine storm. A deeper understanding of viral pathobiology and the interplay of innate and adaptive immune cells against SARS-CoV-2 infection is essential to optimize intervention strategy and future preparedness for SARS-CoV-2 or its related viral diseases. To uncover the immunological signatures driving the progression of SARS-CoV-2 infection, we performed an extensive immunophenotype on blood samples from 79 hospitalized patients with mild/moderate to severe infections as well as from healthy controls and recovered donors to understand the interplay between innate and adaptive responses impacting severity and prognosis. We observed multifarious immune dysregulation, varied across patients of the clinical spectrum. We observed 4 major dysregulations of immune phenotypes 1) depletion of M1φ (impaired antiviral response as APC), 2) immune suppression/exhaustion via activation of repressor like CD4+/CD8+PD1, TIM3, LAG3 3) inappropriate differentiation of lymphocyte (extreme elevated proportion of CD4 naive, memory B and T cells along with reduction of inflammatory activator like TLR2/4/TIGIT) and 4) cytokine storm. Our results show the identification of biomarkers to differentiate the different trajectories for SARS-CoV-2 infection.

Upper respiratory tract microbiome profiles in SARS-CoV-2 Delta and Omicron infected patients exhibit variant specific patterns and robust prediction of disease groups.

IMPORTANCE: The role of the upper respiratory tract (URT) microbiome in predicting lung health has been documented in several studies. The dysbiosis in COVID patients has been associated with disease outcomes by modulating the host immune system. However, although it has been known that different SARS-CoV-2 variants manifest distinct transmissibility and mortality rates in human populations, their effect on the composition and diversity of the URT microbiome has not been studied to date. Unlike the older variant (Delta), the newer variant (Omicron) have become more transmissible with lesser mortality and the symptoms have also changed significantly. Hence, in the present study, we have investigated the change in the URT microbiome associated with Delta and Omicron variants and identified variant-specific signatures that will be useful in the assessment of lung health and can be utilized for nasal probiotic therapy in the future.

Identification of a shared, common haplotype segregating with an SGCB c.544 T > G mutation in Indian patients affected with sarcoglycanopathy.

Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy.

Mapinsights: deep exploration of quality issues and error profiles in high-throughput sequence data.

High-throughput sequencing (HTS) has revolutionized science by enabling super-fast detection of genomic variants at base-pair resolution. Consequently, it poses the challenging problem of identification of technical artifacts, i.e. hidden non-random error patterns. Understanding the properties of sequencing artifacts holds the key in separating true variants from false positives. Here, we develop Mapinsights, a toolkit that performs quality control (QC) analysis of sequence alignment files, capable of detecting outliers based on sequencing artifacts of HTS data at a deeper resolution compared with existing methods. Mapinsights performs a cluster analysis based on novel and existing QC features derived from the sequence alignment for outlier detection. We applied Mapinsights on community standard open-source datasets and identified various quality issues including technical errors related to sequencing cycles, sequencing chemistry, sequencing libraries and across various orthogonal sequencing platforms. Mapinsights also enables identification of anomalies related to sequencing depth. A logistic regression-based model built on the features of Mapinsights shows high accuracy in detecting 'low-confidence' variant sites. Quantitative estimates and probabilistic arguments provided by Mapinsights can be utilized in identifying errors, bias and outlier samples, and also aid in improving the authenticity of variant calls.

Influence of Maternal Breast Milk and Vaginal Microbiome on Neonatal Gut Microbiome: a Longitudinal Study during the First Year.

It is believed that establishment of the gut microbiome starts very early in life and is crucial for growth, immunity, and long-term metabolic health. In this longitudinal study, we recruited 25 mothers in their third trimester, of whom 15 had vaginal delivery while 10 had an unplanned cesarean section (C-section). The mother-neonate pairs were followed for 1 year, and we generated 16S metagenomic data to study the neonatal gut microbiome along with mother's breast milk and vaginal microbiomes through 12 months after delivery, at 1, 3, 6, and 12 months. We inferred (i) mode of delivery is an important factor influencing both composition and entropy of the neonatal gut microbiome, and the genus Streptococcus plays an important role in the temporal differentiation. (ii) Microbial diversity monotonically increases with age, irrespective of the mode of delivery, and it is significantly altered once exclusive breastfeeding is stopped. (iii) We found little evidence in favor of the microflora of mother's breast milk and a vaginal swab being directly reflected in the offspring's gut microbiome; however, some distinction could be made in the gut microbiome of neonates whose mothers were classified as community state type III (CSTIII) and CSTIV, based on their vaginal microbiomes. (iv) A lot of the mature gut microbiome is possibly acquired from the environment, as the genera Prevotella and Faecalibacterium, two of the most abundant flora in the neonatal gut microbiome, are introduced after initiation of solidified food. The distinction between the gut microbiome of babies born by vaginal delivery and babies born by C-section becomes blurred after introduction of solid food, although the diversity in the gut microbiota drastically increases in both cases. IMPORTANCE Gut microbiome architecture seems to have a potential impact on host metabolism, health, and nutrition. Early life gut microbiome development is considered a crucial phenomenon for neonatal health as well as adulthood metabolic complications. In this longitudinal study, we examined the association of neonatal gut microbiome entropy and its temporal variation. The study revealed that adult-like gut microbiome architecture starts taking shape after initiation of solidified food. Further, we also observed that the difference of microbial diversity was reduced between vaginally delivered and C-section babies compared to exclusive breastfeeding tenure. We found evidence in favor of the inheritance of the microflora of mother's posterior vaginal wall to the offspring's gut microbiome.

Multiple migrations from East Asia led to linguistic transformation in NorthEast India and mainland Southeast Asia.

NorthEast India, with its unique geographic location in the midst of the Himalayas and Bay of Bengal, has served as a passage for the movement of modern humans across the Indian subcontinent and East/Southeast Asia. In this study we look into the population genetics of a unique population called the Khasi, speaking a language (also known as the Khasi language) belonging to the Austroasiatic language family and residing amidst the Tibeto-Burman speakers as an isolated population. The Khasi language belongs to one of the three major broad classifications or phyla of the Austroasiatic language and the speakers of the three sub-groups are separated from each other by large geographical distances. The Khasi speakers are separated from their nearest Austroasiatic language-speaking sub-groups: the "Mundari" sub-family from East and peninsular India and the "Mon-Khmers" in Mainland Southeast Asia. We found the Khasi population to be genetically distinct from other Austroasiatic speakers, i.e. Mundaris and Mon-Khmers, but relatively similar to the geographically proximal Tibeto Burmans. The possible reasons for this genetic-linguistic discordance lie in the admixture history of different migration events that originated from East Asia and proceeded possibly towards Southeast Asia. We found at least two distinct migration events from East Asia. While the ancestors of today's Tibeto-Burman speakers were affected by both, the ancestors of Khasis were insulated from the second migration event. Correlating the linguistic similarity of Tibeto-Burman and Sino-Tibetan languages of today's East Asians, we infer that the second wave of migration resulted in a linguistic transition while the Khasis could preserve their linguistic identity.

Autosomal recessive inheritance of a novel missense mutation of ITGB4 for Epidermolysis-Bullosa pyloric-atresia: a case report.

Epidermolysis-Bullosa (EB), a rare Mendelian disorder, exhibits complex phenotypic and locus-heterogeneity. We identified a nuclear family of clinically unaffected parents with two offsprings manifesting EB-Pyloric-Atresia (EB-PA), with a variable clinical severity. We generated whole exome sequence data on all four individuals to (1) identify the causal mutation behind EB-PA (2) understand the background genetic variation for phenotype variability of the siblings. We assumed an autosomal recessive mode of inheritance and used suites of bioinformatic and computational tools to collate information through global databases to identify the causal genetic variant for the disease. We also investigated variations in key genes that are likely to impact phenotype severity. We identified a novel missense mutation in the ITGB4 gene (p.Ala1227Asp), for which the parents were heterozygous and the children homozygous. The mutation in ITGB4 gene, predicted to reduce the stability of the primary alpha6beta4-plectin complex compared to all previously studied mutations on ITGB4 reported to cause EB.

Temporal dynamics of oropharyngeal microbiome among SARS-CoV-2 patients reveals continued dysbiosis even after Viral Clearance.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has posed multiple challenges to global public health. Clinical features and sequela of SARS-CoV-2 infection include long-term and short-term complications often clinically indistinguishable from bacterial sepsis and acute lung infection. Post-hoc studies of previous SARS outbreaks postulate secondary bacterial infections with microbial dysbiosis. Oral microbial dysbiosis, particularly the altered proportion of Firmicutes and Proteobacteria, observed in other respiratory virus infection, like influenza, has shown to be associated with increased morbidity and mortality. Oropharynx and lung share similar kinds of bacterial species. We hypothesized that alteration in the Human Oropharyngeal Microbiome in SARS-CoV-2 patients can be a clinical indicator of bacterial infection related complications. We made a longitudinal comparison of oropharyngeal microbiome of 20 SARS-CoV-2 patients over a period of 30 days; at three time points, with a 15 days interval; contrasting them with a matched group of 10 healthy controls. Present observation indicates that posterior segment of the oropharyngeal microbiome is a key reservoir for bacteria causing pneumonia and chronic lung infection on SARS-CoV-2 infection. Oropharyngeal microbiome is indeed altered and its α-diversity decreases, indicating reduced stability, in all SARS-CoV-2 positive individuals right at Day-1; i.e. within ~24 h of post clinical diagnosis. The dysbiosis persists long-term (30 days) irrespective of viral clearance and/or administration of antibiotics. There is a severe depletion of commensal bacteria phyla like Firmicutes among the patients and that depletion is compensated by higher proportion of bacteria associated with sepsis and severe lung infection from phyla Proteobacteria. We also found elevated proportions of certain genus that have previously been shown to be causal for lung pneumonia in studies of model organisms and human autopsies' including Stenotrophomonas, Acenetobactor, Enterobactor, Klebsiella and Chryseobacterium that were to be elevated among the cases. We also show that responses to the antibiotics (Azithromycin and Doxycycline) are not uniform for all individuals.

Diagnosis of Indigenous Non-Malarial Vector-Borne Infections from Malaria Negative Samples from Community and Rural Hospital Surveillance in Dhalai District, Tripura, North-East India.

The aetiology of non-malaria vector-borne diseases in malaria-endemic, forested, rural, and tribal-dominated areas of Dhalai, Tripura, in north-east India, was studied for the first time in the samples collected from malaria Rapid Diagnostic Kit negative febrile patients by door-to-door visits in the villages and primary health centres. Two hundred and sixty serum samples were tested for the Dengue NS1 antigen and the IgM antibodies of Dengue, Chikungunya, Scrub Typhus (ST), and Japanese Encephalitis (JE) during April 2019-March 2020. Fifteen Dengue, six JE, twelve Chikungunya, nine ST and three Leptospirosis, and mixed infections of three JE + Chikungunya, four Dengue + Chikungunya, three Dengue + JE + Chikungunya, one Dengue + Chikungunya + ST, and one Dengue + ST were found positive by IgM ELISA tests, and four for the Dengue NS1 antigen, all without any travel history. True prevalence values estimated for infections detected by Dengue IgM were 0.134 (95% CI: 0.08-0.2), Chikungunya were 0.084 (95% CI: 0.05-0.13), Scrub were 0.043 (95% CI: 0.01-0.09), and Japanese Encephalitis were 0.045 (95% CI: 0.02-0.09). Dengue and Chikungunya were associated significantly more with a younger age. There was a lack of a defined set of symptoms for any of the Dengue, Chikungunya, JE or ST infections, as indicated by the k-modes cluster analysis. Interestingly, most of these symptoms have an overlapping set with malaria; thereby, it becomes imperative that malaria and these non-malaria vector-borne disease diagnoses are made in a coordinated manner. Findings from this study call for advances in routine diagnostic procedures and the development of a protocol that can accommodate, currently, in practicing the rapid diagnosis of malaria and other vector-borne diseases, which is doable even in the resource-poor settings of rural hospitals and during community fever surveillance.

Gut microbiome architecture of wild greater one-horned rhinoceros:a vulnerable species from Kaziranga National Park, India.

Rhinoceros unicornis, also known as the greater one-horned rhinoceros (GoHR), is a vulnerable wildlife species found in the Indian subcontinent with an estimated global population of 3582, of which an estimated 2995 resides in India. The Kaziranga National Park of Assam is the home to ~80.56% of the GoH population in India. Recent advances in genetics and microbial studies underscored the importance of gut microbial symbiosis as a crucial factor for host metabolic health and environmental interaction, particularly for higher mammals. Alteration of the normal microbiome can also be an indicator of chronic disease and infection. Freshly voided dung samples from nine dung heaps of free ranging or wild GoH rhinoceros were collected from Kaziranga National Park for mapping the gut microbial architecture through 16S-metagenomic approach. In our sample, the GoH gut harbours 168.8±12.55 (SE) bacteria-specific OTUs belonging to 21 phyla of which the gram-negative Proteobacteria is the most abundant phyla. Other abundant phylas found in the GoH gut are Firmicutes and Bacteroidetes. Although the GoH rhinoceros gut can utilize fibrous plant by microbial fermentation, the aerobic, nonfermenting Acinetobacter (20.7%), Stenotrophomonas (17.8%) and Brevundimonas (9.1%) constitute about 50% of all identified genus. Functional prediction of the GoH microbiome reveals that>50% of the bacteria present are involved in metabolism followed by cellular processes and information processing. A significant proportion (>1%) are associated with different diseases. In summary, our study characterized bacterial communities of nine wild GoH to identify some unique features and its implication in disease and survival of GoH.

dbGENVOC: database of GENomic Variants of Oral Cancer, with special reference to India.

Oral cancer is highly prevalent in India and is the most frequent cancer type among Indian males. It is also very common in southeast Asia. India has participated in the International Cancer Genome Consortium (ICGC) and some national initiatives to generate large-scale genomic data on oral cancer patients and analyze to identify associations and systematically catalog the associated variants. We have now created an open, web-accessible database of these variants found significantly associated with Indian oral cancer patients, with a user-friendly interface to enable easy mining. We have value added to this database by including relevant data collated from various sources on other global populations, thereby providing opportunities of comparative geographical and/or ethnic analyses. Currently, no other database of similar nature is available on oral cancer. We have developed Database of GENomic Variants of Oral Cancer, a browsable online database framework for storage, retrieval and analysis of large-scale data on genomic variants and make it freely accessible to the scientific community. Presently, the web-accessible database allows potential users to mine data on ∼24 million clinically relevant somatic and germline variants derived from exomes (n = 100) and whole genomes (n = 5) of Indian oral cancer patients; all generated by us. Variant data from The Cancer Genome Atlas and data manually curated from peer-reviewed publications were also incorporated into the database for comparative analyses. It allows users to query the database by a single gene, multiple genes, multiple variant sites, genomic region, patient ID and pathway identities. Database URL: http://research.nibmg.ac.in/dbcares/dbgenvoc/.

Insights into the demographic history of Asia from common ancestry and admixture in the genomic landscape of present-day Austroasiatic speakers.

BACKGROUND: The demographic history of South and Southeast Asia (S&SEA) is complex and contentious, with multiple waves of human migration. Some of the earliest footfalls were of the ancestors of modern Austroasiatic (AA) language speakers. Understanding the history of the AA language family, comprising of over 150 languages and their speakers distributed across broad geographical region in isolated small populations of various sizes, can help shed light on the peopling of S&SEA. Here we investigated the genetic relatedness of two AA groups, their relationship with other ethno-linguistically distinct populations, and the relationship of these groups with ancient genomes of individuals living in S&SEA at different time periods, to infer about the demographic history of this region. RESULTS: We analyzed 1451 extant genomes, 189 AAs from India and Malaysia, and 43 ancient genomes from S&SEA. Population structure analysis reveals neither language nor geography appropriately correlates with genetic diversity. The inconsistency between "language and genetics" or "geography and genetics" can largely be attributed to ancient admixture with East Asian populations. We estimated a pre-Neolithic origin of AA language speakers, with shared ancestry between Indian and Malaysian populations until about 470 generations ago, contesting the existing model of Neolithic expansion of the AA culture. We observed a spatio-temporal transition in the genetic ancestry of SEA with genetic contribution from East Asia significantly increasing in the post-Neolithic period. CONCLUSION: Our study shows that contrary to assumptions in many previous studies and despite having linguistic commonality, Indian AAs have a distinct genomic structure compared to Malaysian AAs. This linguistic-genetic discordance is reflective of the complex history of population migration and admixture shaping the genomic landscape of S&SEA. We postulate that pre-Neolithic ancestors of today's AAs were widespread in S&SEA, and the fragmentation and dissipation of the population have largely been a resultant of multiple migrations of East Asian farmers during the Neolithic period. It also highlights the resilience of AAs in continuing to speak their language in spite of checkered population distribution and possible dominance from other linguistic groups.

SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions.

SARS-CoV-2 was first reported from China. Within three months, it evolved to 10 additional subtypes. Two evolved subtypes (A2 and A2a) carry a non-synonymous Spike protein mutation (D614G). We conducted phylodynamic analysis of over 70,000 SARS-CoV-2 coronaviruses worldwide, sequenced until July2020, and found that the mutant subtype (614G) outcompeted the pre-existing type (614D), significantly faster in Europe and North-America than in East Asia. Bioinformatically and computationally, we identified a novel neutrophil elastase (ELANE) cleavage site introduced in the G-mutant, near the S1-S2 junction of the Spike protein. We hypothesised that elevation of neutrophil elastase level at the site of infection will enhance the activation of Spike protein thus facilitating host cell entry for 614G, but not the 614D, subtype. The level of neutrophil elastase in the lung is modulated by its inhibitor α1-antitrypsin (AAT). AAT prevents lung tissue damage by elastase. However, many individuals exhibit genotype-dependent deficiency of AAT. AAT deficiency eases host-cell entry of the 614G virus, by retarding inhibition of neutrophil elastase and consequently enhancing activation of the Spike protein. AAT deficiency is highly prevalent in European and North-American populations, but much less so in East Asia. Therefore, the 614G subtype is able to infect and spread more easily in populations of the former regions than in the latter region. Our analyses provide a molecular biological and evolutionary model for the higher observed virulence of the 614G subtype, in terms of causing higher morbidity in the host (higher infectivity and higher viral load), than the non-mutant 614D subtype.

Exome-wide scan identifies significant association of rs4788084 in IL27 promoter with increase in hepatic fat content among Indians.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic that often progresses to liver cirrhosis and hepatocellular carcinoma. In contrast to most world populations where NAFLD is mostly prevalent among obese, NAFLD among Indians and generally among South and South-East Asians is unique and highly prevalent among individuals who are lean. Genetics of NAFLD in Indian populations is understudied. In this study, we have used an exome-wide approach to identify genetic determinants of hepatic fat content (HFC) in India. METHODS: HFC was measured in 244 participants using Proton magnetic resonance spectroscopy (H1-MRS). Quantitative trait loci (QTL) mapping was done exome-wide, to identify SNPs associated with HFC. The effects of the interaction between adiposity and QTLs on HFC were studied using a regression model. Association of the significant loci with disease severity was studied in 146 NAFLD patients among 244 participants, who underwent liver biopsy. RESULTS: Our study identified 4 significantly associated SNPs (rs738409 and rs2281135 (PNPLA3), rs3761472 (SAMM50), rs17513722 (FAM161A) and rs4788084), with HFC after adjusting for the effects of covariates (p-value < 0.0005). rs738409, rs2281135 (PNPLA3), and rs3761472 (SAMM50) were associated with hepatocyte ballooning, lobular and portal inflammation and non-alcoholic steatohepatitis (NASH) (p-value < 0.05). rs4788048 is an eQTL for IL27 and SULT1A2 genes, both of which are highly expressed in healthy livers and are likely to be involved in NAFLD pathogenesis. CONCLUSIONS: Our study identified the novel association of rs4788084 with HFC, which regulates the expression of IL-27, an immune regulatory gene. We further showed that adiposity affected the HFC, irrespective of the genetic predisposition.

Pre-therapeutic Biomarkers for Ranibizumab Therapy among Type 2 Diabetic Patients with Diabetic Macular Edema.

SIGNIFICANCE: A differential outcome in randomized controlled trials of anti-vascular endothelial growth factor (anti-VEGF) therapy, including ranibizumab, for diabetic macular edema is a major dilemma for planning, optimizing, and managing clinical usage. The variable outcome of the therapeutics necessitates the importance of finding a predictive biomarker for anti-VEGF therapy to improve subject selection. PURPOSE: Our study correlates the baseline pro- and anti-VEGF isoforms and its three receptors (VEGFReceptor1, VEGFReceptor2, and VEGFReceptor3) for circulatory candidate protein molecules among diabetic patients with macular edema, with the clinical outcome of ranibizumab therapy. METHODS: This study included 86 individuals who were anti-VEGF naive at the time of ascertainment but have completed the standardized therapy regimen of the clinic. Plasma proteins for pro- and anti-VEGF isoforms and its three receptors were determined in replicate by an enzyme-linked immunosorbent assay. RESULTS: The study demonstrated that 56 (65.12%) individuals benefited from the therapy in terms of letter gain (Snellen chart). Baseline plasma soluble VEGF receptor 2 (sVEGFR-2) was significantly higher among responders (65.10 pg/mL; 95% confidence interval, 55.41 to 74.80 pg/mL) compared with nonresponders (46.38 pg/mL; 95% confidence interval, 38.69 to 54.07 pg/mL; PFDR = .03). Diffuse diabetic macular edema with proliferative diabetic retinopathy increases the risk of nonresponse to the therapy by 3.03-fold (PFDR = .04). CONCLUSIONS: The present study postulates that diffuse diabetic macular edema with proliferative diabetic retinopathy and baseline circulatory soluble VEGF receptor 2 may be potential candidates as therapy-stratifying markers for ranibizumab treatment among patients with diabetic macular edema.

Hepatic transcriptome signature correlated with HOMA-IR explains early nonalcoholic fatty liver disease pathogenesis.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is multistage with heterogeneous outcomes. We studied the influence of insulin resistance (IR) on the hepatic transcriptome of early NAFLD stages, to understand disease development. MATERIALS AND METHODS: In this cross-sectional study, possible clinicopathological risk factors were compared between mild-NAFL (N = 72) and non-alcoholic steatohepatitis (NASH; N = 51) patients. Liver tissue-transcriptome difference was studied between a subset of 25 mild-NAFL and 20 NASH biopsies and validated on another subset of 12 mild-NAFL and 13 NASH biopsies, using RT-PCR. The relationship between IR driven gene expression changes with fibrosis in NASH was investigated. RESULTS: Significantly higher weight (p = 0.005) and elevated levels of HbA1c (p = 0.009), FBG (p = 0.03) and HOMA-IR (p = 0.009) were found in NASH patients. Five differentially expressed genes (DEGs, fold change > 1.5) were identified in NASH-FABP4, FABP5L2, CD24, PRAP1, and SPP1. The DEGs were positively associated with disease severity and HOMA-IR, and were found to be efficient classifiers of mild-NAFL and NASH. Additional 1218 genes identified related to IR (IrCGs), which can classify NASH-with-fibrosis patients separately from mild-NAFL and NASH patients. IrCGs can promote intra-hepatic fat accumulation, dysregulation of the lipid metabolism, lipotoxicity, and activation of cell survival pathways including activation of cell proliferation and differentiation pathways. CONCLUSIONS: Hepatic expression of genes associated with insulin resistance may drive NAFLD development and progression.

Multifaceted genome-wide study identifies novel regulatory loci in SLC22A11 and ZNF45 for body mass index in Indians.

Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants-rs6913677 in BAI3 gene (p = 1.08 × 10-8) and rs2078267 in SLC22A11 gene (p = 4.62 × 10-8) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10-7) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10-7), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.