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Introduction Human leukocyte antigen (HLA) variability has been demonstrated to be associated with susceptibility/severity of COVID‐19. High‐resolution HLA genotyping to identify alleles associated with severe COVID‐19 in an Indian cohort was performed. Methods Quantitative reverse‐transcription polymerase chain reaction‐confirmed SARS‐CoV‐2‐positive patients with mild/moderate/severe disease ( n = 54) and asymptomatic ( n = 42) were recruited and genotyped for 11‐HLA loci on MiSeq using NGSgo®‐MX11‐3 and analyzed (NGSengine; GenDx). Results A significant difference in alleles between the groups was identified for HLA‐C*04:01:01:01, HLA‐DRB5*01:01:01:02, HLA‐DQA1*03:01:01:01, HLA‐DPB1*04:01:01:41, and HLA‐DPA1*01:03:01:02. Alleles namely, HLA‐C*04:01:01:01 (OR: 5.71; 95% CI: 1.2–27.14; p = .02), HLA‐DRB5*01:01:01:02 (OR: 2.94; 95% CI: 1.1–7.84; p = .03), DQA1*03:01:01:01 (OR: 22.47; 95% CI: 1.28–393.5; p = .03), HLA‐DPB1*04:01:01:41 (OR: 9.44; 95% CI: 0.5–175.81; p = .13), and HLA‐DPA1*01:03:01:02 (OR: 8.27; 95% CI: 2.26–30.21; p = .001) were associated with severe COVID‐19. Conclusion Genotyping for these alleles will enable identification of individuals at risk of severe disease and stratification for preferential vaccination.

AbstractSARS-CoV-2, a highly transmittable pathogen has infected over 3.8 million people around the globe. The spike glycoprotein of SARS-CoV-2 engages host ACE2 for adhesion, TMPRSS2 for activation and entry. With the aid of whole-exome sequencing, we report a variant rs12329760 in TMPRSS2 gene and its mutant V160M, which might impede viral entry. Furthermore, we identified TMPRSS2 cleavage sites in S2 domain of spike glycoprotein and report the structure of TMPRSS2 in complex with spike glycoprotein. We also report the structures of protease inhibitors in complex with TMPRSS2, which could hamper the interaction with spike protein. These findings advance our understanding on the role of TMPRSS2 and in the development of potential therapeutics.

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SummaryBackgroundRecent studies reported that Nudix Hydrolase 15(NUDT 15) gene variant (C415T) can better predict thiopurine induced leucopenia in Asian patients with inflammatory bowel disease (IBD) than thiopurine S‐methyl transferase (TPMT).AimTo evaluate the role of the NUDT variant compared with TPMT in predicting azathioprine induced leucopenia in Indian IBD patients.MethodsProspectively collected data of consecutive patients treated with azathioprine from a large IBD registry were analysed for side effects, discontinuation time, and initial and maximum dose tolerated. Genotyping of NUDT15 C415T (rs116855232; p.R139C) was carried out retrieving blood samples from bio‐repository employing real time polymerase chain reaction with age and sex‐matched healthy volunteers. The association of NUDT15 C415T with leucopenia (<3 × 109/L) and neutropenia (<1.5 × 109/L) was evaluated. TPMT genotyping was done in patients who developed leucopenia.ResultsAmong 1014 patients (mean age 35.84 ± 12.74 years; 61% males; 54% ulcerative colitis, 44% Crohn's disease and 2% IBD‐unclassified), 79 were excluded due to inadequate blood samples. Of the remaining 935, 81 (9%) developed leucopenia and 70 (7.5%) developed neutropenia. The variant “T” allele [heterozygous (CT) and homozygous (TT) versus wild type (CC)] was associated with a 19‐fold higher odds (OR19.35, 95% CI11.55‐32.42; P < 0.0001) of leucopenia and 21‐fold higher odds of neutropenia (OR21.41, 95% CI12.25‐37.41). There was significant difference in median dose tolerated between CC, CT and TT (1.35, 1.38 and 0.92 mg/kg body weight, respectively) (P = 0.037) and median duration of therapy (18, 15 and 10 months for CC/CT/TT) (P = 0.003). NUDT15 genotype was an independent risk factor for leucopenia (hazard ratio (HR): CT 11.31, 95% CI6.85‐18.03, P < 0.0001 and TT 31.283, 95% CI14.76‐66.30 compared to CC) and neutropenia (HR: CT 13.04, 95% CI7.65‐22.22, P < 0.0001 and TT 43.39, 95% CI20.21‐92.68 compared to CC). The sensitivities for predicting leucopenia and neutropenia by number of mutant NUDT 15 alleles based on additive predictive model were 66.67% and 70% with a receptor operator characteristic curve area under curve value of 0.791 and 0.807, respectively. Among patients with leucopenia, only 6.2% were heterozygous and none were homozygous for TPMT variants.ConclusionNUDT15 variant genotyping appears to be a better predictor for azathioprine‐induced leucopenia in an Indian population than TPMT with high accuracy and can be useful in optimizing azathioprine dosage.

Alpha-fetoprotein (AFP) is a glycoprotein that is produced by the liver and yolk sac during fetal development. Its levels are usually raised in malignant conditions. Hereditary persistence of AFP (HPAFP) is a rare benign condition with elevated levels of AFP. It is inherited in a dominant mode with complete penetrance and is usually not associated with any clinical disability. We report two individuals with elevated levels of AFP harboring the −119G>A polymorphism in the AFP gene. A genetic screening to rule out variants in the AFP gene is advised in cases with unexplained persistent AFP levels to avoid inappropriate treatment and surgical options.