Background. Evidence has shown that a large proportion of SARS-CoV-2 infected individuals do not experience symptomatic disease. Owing to its critical role in immune response, we hypothesized that variation in the human leukocyte antigen (HLA) loci may underly asymptomatic infection. Methods. We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Among 21,893 individuals who completed the baseline survey, our discovery (N=640) and replication (N=788) cohorts were comprised of self-identified White subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci (HLA-A, -B, -C, -DRB1, -DQB1) with asymptomatic vs. symptomatic infection. Results. HLA-B*15:01 was significantly increased in asymptomatic individuals in the discovery cohort compared to symptomatic (OR = 2.45; 95%CI 1.38-4.24, p = 0.0016, pcorr = 0.048), and we reproduced this association in the replication cohort (OR= 2.32; 95%CI = 1.10-4.43, p = 0.017). We found robust association of HLA-B*15:01 in the combined dataset (OR=2.40 95% CI = 1.54-3.64; p = 5.67 x10-5) and observed that homozygosity of this allele increases more than eight times the chance of remaining asymptomatic after SARS-CoV-2 infection (OR = 8.58, 95%CI = 1.74-34.43, p = 0.003). Finally, we demonstrated the association of HLA-B*15:01 with asymptomatic SARS-Cov-2 infection is enhanced by the presence of HLA-DRB1*04:01 Conclusion. HLA-B*15:01 is strongly associated with asymptomatic infection with SARS-CoV-2 and is likely to be involved in the mechanism underlying early viral clearance.
The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.
Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/ HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (p c = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.
The killer-cell immunoglobulin-like receptor ( KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.
HLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between severity of SARS-CoV-2 disease and HLA type in 3,235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Age, BMI, asthma status, and autoimmune disorder status were predictive of severity across multiple age and individual ancestry stratificiations. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.
HLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between the severity of SARS-CoV-2 disease and HLA type in 3235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.
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