Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19

The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.

Association and Gene–-Gene Interactions Study of Late-Onset Alzheimer’s Disease in the Russian Population

Alzheimer’s disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated subjects were genotyped for 63 SNPs using iPLEX Assay and real-time PCR. We identified five genetic loci that were significantly associated with LOAD risk for the Russian population (TOMM40 rs2075650, APOE rs429358 and rs769449, NECTIN rs6857, APOE ε4). The results of the analysis based on comparison of the haplotype frequencies showed two risk haplotypes and one protective haplotype. The GMDR analysis demonstrated three significant models as a result: a one-factor, a two-factor and a three-factor model. A protein–protein interaction network with three subnetworks was formed for the 24 proteins. Eight proteins with a large number of interactions are identified: APOE, SORL1, APOC1, CD33, CLU, TOMM40, CNTNAP2 and CACNA1C. The present study confirms the importance of the APOE-TOMM40 locus as the main risk locus of development and progress of LOAD in the Russian population. Association analysis and bioinformatics approaches detected interactions both at the association level of single SNPs and at the level of genes and proteins.

Evidence of New Intragenic HBB Haplotypes Model for the Prediction of Beta-Thalassemia in the Malaysian Population

This study sought to determine the potential role of HBB haplotypes for the prediction of beta-thalassemia in the Malaysian population. A total of 543 archived samples were reviewed and selected for this study. Five tagging SNPs in the beta-globin gene (HBB; NG_000007.3) were recorded and analysed for SNP-based and haplotype association using SHEsis online software. Single-SNP-based association analysis showed three tagging SNPs have statistical significant association with beta-thalassemia; IVS2-16G>C (p=0.036), IVS2-666C>T (p=0.032) and 3’UTR +314G>A (p=0.004). However, two tagging SNPs assigned as IVS2-74T>G and 3’UTR +233G>C did not yield significant association with p-value 0.099 and 0.211, respectively. In a further investigation, combined five tagging SNPs for haplotype association analysis revealed three susceptible haplotypes with significant p-values of which, assigned as haplotypes 1-2-2-1-1 (p=6.49x10-7, OR=10.371 [3.345~32.148]), 1-2-1-1-1 (p= 0.009, OR=1.423 [1.095~1.850] and 1-1-1-1-1 (p=1.39x10-4, OR=10.221 [2.345~44.555]). Another three haplotypes were found to be protective haplotype with significant p-value of which assigned as haplotypes 2-2-1-1-1 (p=0.006, OR=0.668 [0.500~0.893]), 1-1-2-2-1 (p=0.013, OR=0.357 [0.153~0.830]) and 1-1-2-1-1 (p=0.033, OR=0.745 [0.567~0.977]). This study has identified the potential use of intragenic polymorphic markers in the HBB gene, which were significantly associated with beta-thalassemia. A combination of these five tagging SNPs defined a new haplotype model for beta-thalassemia and further evaluation for the prediction of severity in beta-thalassemia.

Alternative splicing of OAS1 alters the risk for severe COVID-19

A locus containing OAS1/2/3 has been identified as a risk locus for severe COVID-19 among Europeans ancestry individuals, with a protective haplotype of ~75 kilobases derived from Neanderthals. Here, we show that among several potentially causal variants at this locus, a splice variant of OAS1 occurs in people of African ancestry independently of the Neanderthal haplotype and confers protection against COVID-19 of a magnitude similar to that seen in individuals without African ancestry.

Increased islet antigen–specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes–protective haplotype

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)–specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127−FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen–specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope–specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10–producing T effectors and CD25+CD127−FOXP3+ regulatory T cells.

MicroRNA 146a Polymorphisms and Expression in Indian Children with Acute Lymphoblastic Leukemia

Background MicroRNAs (miR) have been reported to be involved in hematopoiesis and in the pathogenesis of several hematological malignant neoplasms. Single-nucleotide polymorphisms (SNPs) in human miR genes may alter the expression of those genes and influence the predisposition to childhood leukemia. Objective To evaluate the association of rs2910164 G>C, rs57095329 A>G and the expression of miRNA-146a in ethnic South Asian children with acute lymphoblastic leukemia (ALL). Method Genotyping and expression analysis using TaqMan Small RNA Assay was performed on 71 patients with pathologically confirmed ALL and 74 control individuals. Results No statistically significant association was found between the 2 SNPs, its expression levels, and ALL risk. Conclusion Haplotype analysis indicated a combination of allele A of rs57095329 and allele G of rs2910164 could represent a risk haplotype and an allele combination of G of rs57095329 and G of rs2910164 could represent a protective haplotype for ALL.

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed “MHC-I-opathy” family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n=360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: OR[95% CI]=2.07[1.58-2.71], p=1.24 × 10(−7)) and rs2287987 (OR[95% CI]: =2.01 [1.51-2.67], p=1.41 × 10(−6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 × 10(−9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.