Allelic Association Research Articles

Association of C4 Null Alleles and Persistently Low C4 in Asian Indian Patients With Systemic Lupus Erythematosus.

The association between heterozygous C4 deficiency and systemic lupus erythematosus (SLE) is unclear. There is a lack of data in South Asian Indians on any possible association of C4A and C4B null alleles with lupus. We aimed to study the prevalence of C4A and C4B null alleles in a cohort of SLE patients with persistently low C4 levels compared to healthy controls (HC). Patients with SLE and HC were recruited for this prospective observational study. C4 (C4AQ and C4BQ) polymorphisms were tested using a touch-down polymerase chain reaction protocol. One hundred and three SLE patients and 103 HC were included in the study. Persistently low C4 levels were observed in 25 (23.6%) of SLE. The frequency of C4A and C4B null alleles was similarly distributed across SLE and HC (4% and 3.8%, respectively). Univariate analysis showed a low age, higher proportion of elevated dsDNA, and higher positive anti-SSA (Sjogren's syndrome-related antigen A) antibodies at presentation were associated in SLE patients with the null allele group on comparison without the null allele group. However, these associations did not persist in the multivariate analysis. In conclusion, C4 null allele frequency was similar in SLE and HC. No characteristic associations were observed in SLE with C4 null alleles was observed. Therefore, C4 null allele is an unlikely explanation for persistently low C4 in South Indian Asian patients with lupus.

The evaluation of targeted exome sequencing of candidate genes in a Han Chinese population with primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), known as a common ocular disease with genetic heterogeneity, is characterized by progressive optic disc atrophy and visual field defects. This study aimed to assess the contribution of previously reported POAG-associated genes and investigate potential functional variations and genotype-phenotype correlations in a Han Chinese population. DNA from 500 cases and 500 controls was pooled and sequenced using a customized panel of 398 candidate genes. After prioritization, 21 SNPs from 16 genes were genotyped in the first replication cohort (500 cases and 500 controls), and 9 SNPs were genotyped in the second replication cohort (500 cases and 500 controls). Allelic associations and odds ratios were adjusted for age and sex, while linear regression assessed SNP correlations with POAG endophenotypes. Haplotype analysis and linkage disequilibrium were performed using Haploview. In silico prediction tools were used to predict pathogenicity and function. SNPs from MFN2, DGKG, PKHD1, PTPRJ, and LTBP2 were associated with POAG in at least one cohort, and SNPs from EXOC2, PTPRJ, and LTBP2 showed significant correlations with intraocular pressure. Additionally, haplotype analysis revealed a significant association between the EXOC2 TGC haplotype and POAG risk. We validated several candidate genes and identified novel SNPs, providing further insight into the genetic architecture of POAG in the Han Chinese population.

Association of NOS2A Gene Polymorphisms with Susceptibility to Tuberculosis in Manipuri Population of Northeast India.

Single nucleotide polymorphisms (SNPs) have been reported to influence the activity of specific genes involved with the innate immune response to Mycobacterium; hence, they are crucial in tuberculosis (TB) susceptibility studies. The study aimed to investigate the polymorphism in the NOS2A (Nitric oxide synthase 2A)geneand its association with susceptibility to TB in the Manipuri population of northeast India. This case-control study includes 495 subjects- 220TB patients and 275 control individuals. TaqMan allelic discrimination assay was used to study the gene polymorphism, and Griess's test was employed to determine the serum nitric oxide (NO) levels. Serum NO levels were analysed to correlate with the functional changes associated with the polymorphisms. Two SNPs of the gene,NOS2A(rs8078340 and rs2274894), were studied. For the SNP-rs8078340, a significant difference in the genotypic and allelic frequencies was observed between the cases and control groups (p = 0.001; AA genotype OR = 30.288, 95% CI: 1.703-538.44 and A allele OR = 2.937, 95%CI: 1.762-4.896). However, for the SNP-rs2274894, only the T allele (with OR = 1.464; 95%CI: 1.080-1.983, p = 0.014) was associated with susceptibility to TB. Serum levels of NO were significantly different between the cases and control groups (p < 0.05). Significant associations of both homozygous AA genotype and allele A of the NOS2A (rs8078340) and minor allele T of NOS2A (rs2274894) were observed with susceptibility to TB. Patients with the AA genotype of NOS2A show a higher NO level, suggesting its role in greater expression of the NOS2A gene.

Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

Effect of serotonin receptor gene variants on substance use disorders

Background Substance use disorders are multifaceted conditions influenced by both genetic and environmental factors. Serotonergic pathways are known to be involved in substance use disorder susceptibility, with genetic markers within serotonin receptor genes identified as potential risk factors. Methods To further explore this relationship, we conducted a study to investigate the association between several polymorphisms in five serotonin receptor genes (HTR1B, HTR2A/B, HTR3A/B) and substance use disorders (SUD) in Jordanian males by sequencing genotypes in 496 SUD patients and 496 healthy controls. Results Our findings revealed an allelic association between rs9567735 in the HTR2A gene and rs17586428 in the HTR2B gene with SUD. Haplotype analysis also showed that one haplotype of the HTR2A gene and four haplotypes of the five included genes were significantly associated with SUD risk. Moreover, we found that motives for substance use were correlated with single nucleotide polymorphisms SNPs rs1923882 and rs1150226, with the latter SNP also being associated with smoking. Conclusion These findings suggest that genetic variants of human 5-HT receptor genes may affect individual susceptibility to SUD in Jordan. However, further studies with larger sample sizes and additional variants in the same or different genes must confirm these findings.

Association of APOE alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease neuroimaging markers.

TOMM40 and APOC1 variants can modulate the APOE-ε4-related Alzheimer's disease (AD) risk by up to fourfold. We aim to investigate whether the genetic modulation of ε4-related AD risk is reflected in brain morphology. We tested whether 27 magnetic resonance imaging-derived neuroimaging markers of neurodegeneration (volume and thickness in temporo-limbic regions) are associated with APOE-TOMM40-APOC1 polygenic profiles using the National Alzheimer's Coordinating Center Uniform Data Set linked to the AD Genetic Consortium data. All brain regions studied using structural phenotypes were smaller in individuals with AD. The ε4 allele was associated with smaller limbic (entorhinal, hippocampus, parahippocampus) brain volume and cortical thickness in AD cases than controls. There were significant differences in the associations for the higher-risk and lower-risk ε4-bearing APOE-TOMM40-APOC1 profiles with temporo-limbic region markers. The APOE-AD heterogeneity may be partly attributed to the modulating role of the TOMM40 and APOC1 genes in the APOE cluster. The ε4 allele is associated with smaller values of neuroimaging markers in AD cases. Larger values of neuroimaging markers may protect against AD in the ε4 carriers. TOMM40 and APOC1 variants differentiate AD risk in the ε4 carriers. The same variants can differentiate the links between ε4 and neuroimaging markers.

The association of rs25487 of theXRCC1geneandrs13181 of theERCC2genepolymorphisms with the ovarian cancer risk.

Ovarian cancer (OC) is the most lethal gynecological cancer worldwide. DNA damage plays an important role in cancer development, and the proteins encoded by XRCC1 and ERCC2 are important components of the DNA repair system. This study aimed to examine the relationship between the rs25487 XRCC1 and rs13181 ERCC2 polymorphisms and the risk of OC development in women from the Moscow region. DNA was isolated from the blood of 129 healthy donors and tissues and blood samples from 125 patients with OC and studied using real-time PCR. An increase in odds ratios (OR) was obtained for OC tissue and blood for both T (OR = 1.46, 95% confidence interval [CI] = 1.22-1.76, P = 0.00005), and for T/T of rs25487 XRCC1. The most significant OR values were found for the T/T genotype using the codominant model (OR = 2.11, 95% CI = 1.44-3.07, P = 0.00006) and dominant model (OR = 3.13, 95% CI = 1.44-6.79, P = 0.0025) for the pooled blood and tissue groups. For rs13181 ERCC2, differences were observed for the T/G genotype in OC tissues (OR = 0.69, 95% CI = 0.51-0.92, P = 0.011) in the codominant model. In this study, the association of allele T and genotypes of rs25487 XRCC1 and T/G of rs13181 ERCC2 with OC was shown. Our results indicate that these polymorphisms may be involved in the pathogenesis of OC and are promising for further studies on therapeutic applications in OC.

HLA Class I and II Alleles in Anti-Acetylcholine Receptor Antibodies Positive and Double-Seronegative Myasthenia Gravis Patients of Romanian Descent.

Background: Several significant associations between certain Human Leukocyte Antigen (HLA) alleles and myasthenia gravis (MG) subtypes were established in populations from Western Europe and North America and, to a lesser extent, from China and Japan. However, such data are scarcely available for Eastern Europe. This study aimed to analyze the associations of HLA Class I and II alleles with MG and its serological subtypes (with anti-acetylcholine receptor autoantibodies, RAch+MG, and double-seronegative, dSNMG) in myasthenic patients of Romanian descent. Methods: We consecutively enrolled adult Romanian unrelated myasthenic patients, which were genotyped by next-generation sequencing for HLA-A, -B, -C, -DRB1 and -DQB1. The descent-matched controls were represented by two separate groups of random normal subjects genotyped for the main five HLA loci at the two-digit and four-digit levels, respectively, collected from the Allele Frequency Net Database. Results: A total of 40 patients (females: 80.00%; median age at onset: 42.5 years, range: 1-78; RAch+MG: 75.00%; dSNMG: 22.50%) were included. We were able to confirm previously acknowledged allelic associations: positive for HLA-B*08, DRB1*14:54 and DRB1*16:01 and negative for DRB1*13. However, we found some potential novel significant positive associations between MG and the HLA-A*02:36, B*47, B*73, B*44:27 and B*57:02 alleles. All alleles positively associated with MG remained significantly associated with RAch+MG, regardless of the patients' clinical and thymic heterogeneity. We found significant positive associations between dSNMG and the HLA-B*47, B*44:27 and DRB1*14:54 alleles that are shared with RAch+MG. Conclusions: These results suggest both distinct and common etiopathogenic mechanisms between dSNMG and RAch+MG. Our study pioneers allele associations in Romanian MG patients.

High KIR diversity in Uganda and Botswana children living with HIV.

Killer-cell immunoglobulin-like receptors (KIRs) are essential components of the innate immune system found on the surfaces of natural killer (NK) cells. The KIRs encoding genes are located on chromosome 19q13.4 and are genetically diverse across populations. KIRs are associated with various disease states including HIV progression, and are linked to transplantation rejection and reproductive success. However, there is limited knowledge on the diversity of KIRs from Uganda and Botswana HIV-infected paediatric cohorts, with high endemic HIV rates. We used next-generation sequencing technologies on 312 (246 Uganda, 66 Botswana) samples to generate KIR allele data and employed customised bioinformatics techniques for allelic, allotype and disease association analysis. We show that these sample sets from Botswana and Uganda have different KIRs of different diversities. In Uganda, we observed 147 vs 111 alleles in the Botswana cohort, which had a more than 1 % frequency. We also found significant deviation towards homozygosity for the KIR3DL2 gene for both rapid (RPs) and long-term non-progressors (LTNPs)in the Ugandan cohort. The frequency of the bw4-80I ligand was also significantly higher among the LTNPs than RPs (8.9 % Vs 2.0%, P-value: 0.032). In the Ugandan cohort, KIR2DS4*001 (OR: 0.671, 95 % CI: 0.481-0.937, FDR adjusted Pc=0.142) and KIR2DS4*006 (OR: 2.519, 95 % CI: 1.085-5.851, FDR adjusted Pc=0.142) were not associated with HIV disease progression after adjustment for multiple testing. Our study results provide additional knowledge of the genetic diversity of KIRs in African populations and provide evidence that will inform future immunogenetics studies concerning human disease susceptibility, evolution and host immune responses.

Enabling efficient analysis of biobank-scale data with genotype representation graphs.

Computational analysis of a large number of genomes requires a data structure that can represent the dataset compactly while also enabling efficient operations on variants and samples. However, encoding genetic data in existing tabular data structures and file formats has become costly and unsustainable. Here we introduce the genotype representation graph (GRG), a fully connected hierarchical data structure that losslessly encodes phased whole-genome polymorphisms. Exploiting variant-sharing across samples enables GRG to compress 200,000 UK Biobank phased human genomes to 5-26 gigabytes per chromosome, also enabling graph-traversal algorithms to reuse computed values in random access memory. Constructing and processing GRG files scales to a million whole genomes. Using allele frequencies and association effects as examples, we show that computation on GRG via graph traversal runs the fastest among all tested alternatives. GRG-based algorithms have the potential to increase the scalability and reduce the cost of analyzing large genomic datasets.

Association of BoLA-DRB3 Alleles with the Progression of Bovine Leukosis in the Lucerna Breed

Association of BoLA-DRB3 Alleles with the Progression of Bovine Leukosis in the Lucerna Breed

Multi-locus high-risk alleles association from interleukin’s genes with female infertility and certain comorbidities

Objective There is evidence that cytokine genes’ single nucleotide polymorphisms could be the reasons behind female infertility. This study aimed to identify the role for Interleukin33 rs1048274 (G > A) and rs16924243 (T > C), Interleukin22 rs1397852121 (C > T), rs1295978671 (C > T) and rs2227483 (A > T), Interleukin17A rs2275913 (G > A,C) and Interleukin17F rs763780 (T > C), Interleukin13 1512 (A > C) and IL13 2044 (G > A), and Interleukin4 rs2243250 (C > T) and rs2070874 (C > T) gene polymorphisms in female infertility to gain a richly more detailed understanding of its genetic predisposition. Five distinct groups, each comprising 200 infertile women and 200 age-matched fertile controls, were recruited to each Interleukins (33, 22, 17, 13 and 4) in this case–control study and were genotyped by using an amplification refractory mutation system. Statistical analysis is conducted by SPSS software V. 22 and using Chi-square (χ2) and logistic regression tests. Strength of association was estimated by multiple-comparison correction, population structure test and Haplotype analysis. The study was approved by the Academic Ethics Committee and each enrolled patient signed an informed consent.Results Our statistical results revealed risk alleles in all of the substitution lines for women infertility. Current findings provided evidence that in the presence of Interleukin33 Ap-value rs1048274 = 0.002 and Cp-value rs16924243 < 0.0001, Interleukin 22Tp-value rs1397852121 < 0.0001 and Tp-value rs2227483 = 0.000, Interleukin17A Ap-value rs2275913 = 0.003 and Interleukin17F Cp-value rs763780 = 0.000 and Interleukin13 Cp-value 1512 = 0.000 and Ap-value 2044 = 0.003, Interleukin4 Tp-value rs2243250 = 0.001 and Tp-value rs2070874 = 0.009 risk alleles, risk genotype also were significantly associated with increased chances of developing infertility. The relationship between risk genotypes and several well-established infertility risk factors including, polycystic ovary syndrome, premature ovarian failure, oophorectomy, diminished ovarian reserve, endometriosis, uterine fibroids, ovarian cysts, uterine polyps, fallopian tube blockage and thyroid dysfunction, also exhibited. This study suggests the significant role of interleukin gene polymorphisms in human reproductive success.

Pleiotropic Associations with Alzheimer's Disease and Physical Activity: Sex Differences and the Effects of Environment.

Physical activity (PA) is a modifiable factor in mitigating/preventing Alzheimer's disease (AD). It is crucial to identify the conditions under which PA's effects on AD risk would be beneficial. This study aims to gain insights into pleiotropic predisposition to AD and PA within and across sexes and environmental effects. We performed a genome-wide association study (GWAS) of pleiotropic AD-PA associations in individuals (65 years and older) of European ancestry in a US sample (14,628 individuals), for men and women separately and combined, and contrasted them with the UK biobank (204,789 individuals) to elucidate the effects of the environment. Fisher's method and Wald's test were used for estimating the significance of pleiotropic associations and differences between the samples. We identified genetic markers in 60 loci with significant pleiotropic associations. Of them, 91.7% of loci exhibited antagonistic relationships characterized by a misalignment of the signs of the associations of the same alleles with AD and PA and a correlation between these phenotypes. Only 16.7% of associations were replicated in the UKB. Phosphorylation and the regulation of transcription were identified as more pronounced biological mechanisms of AD-PA pleiotropy in females and males, respectively. Our results demonstrate the intrinsic heterogeneity of AD-PA pleiotropy and suggest that PA should be used as an intervention against AD with caution, after identifying groups of individuals and combinations of gene-environment interactions with beneficial effects.

Revisiting the Link Between HLA-DRB1 Alleles and Autoantibodies in Rheumatoid Arthritis: Association of non-Shared Epitope Alleles *09 and *15 With High Levels of Anti-Citrullinated Peptide/Protein Antibodies.

Autoantibodies serve as essential clinical biomarkers and may indicate etiological mechanisms in rheumatic diseases. In light of the increasing knowledge concerning the diversity and biologic implications of anti-citrullinated peptide/protein antibodies (ACPAs), we have re-evaluated the association between the ACPA response and the HLA-DRB1 allelic groups, known to represent a major genetic risk factor for rheumatoid arthritis (RA). We explored a collection of 4,392 well-characterized incident patients with RA of White European descent from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) new-onset RA study, as well as 1,199 cases of patients with RA of Southeast Asian origin from the Malaysian EIRA study. We focused on a quantitative analysis of the levels of anti-cyclic citrullinated peptide IgG antibodies, including those falling below the diagnostic threshold. Our data show that non-shared epitope alleles HLA-DRB1*09 and *15 exhibit significant associations with ACPA levels. Notably, these novel associations were independent of ethnicity. To validate our findings, we conducted an additional replication study in an independent pool of 4,109 patients with RA of White European origin. These results indicate a new, previously overlooked, role for the HLA locus in the regulation of the levels of ACPA RA-specific autoantibodies that goes beyond the shared epitope-defined gene variants.

Genomic variants associated with type 2 diabetes mellitus among Filipinos.

Type 2 diabetes mellitus leads to debilitating complications that affect the quality of life of many Filipinos. Genetic variability contributes to 30% to 70% of T2DM risk. Determining genomic variants related to type 2 diabetes mellitus susceptibility can lead to early detection to prevent complications. However, interethnic variability in risk and genetic susceptibility exists. This study aimed to identify variants associated with type 2 diabetes mellitus among Filipinos using a case-control design frequency matched for age and sex. A comparison was made between 66 unrelated Filipino adults with type 2 diabetes mellitus and 121 without. Genotyping was done using a candidate gene approach on genetic variants of type 2 diabetes mellitus and its complications involving allelic association and genotypic association studies with correction for multiple testing. Nine (9) significant variants, mostly involved in glucose and energy metabolism, associated with type 2 diabetes mellitus in Filipinos were found. Notably, a CDKAL1 variant (rs7766070) confers the highest level of risk while rs7119 (HMG20A) and rs708272 (CETP) have high risk allele frequencies in this population at 0.77 and 0.66, respectively, making them potentially good markers for type 2 diabetes mellitus screening. The data generated can be valuable in developing genetic risk prediction models for type 2 diabetes mellitus to diagnose and prevent the condition among Filipinos.

Effect of FTO Gene polymorphism on anthropometric, hemodynamic, and autonomic variables in adolescents

Objective: The study aimed to analyze the influence of physical activity levels and the rs9939609 polymorphism (FTO gene) on anthropometric, hemodynamic, and cardiac autonomic variables in public school students. Methods: A total of 288 students (aged 11 to 18, both sexes) from public schools in São Luís, Maranhão, were divided into four groups: sedentary AA+AT (AA+AT sed), active AA+AT (AA+AT activ), sedentary TT (TT sed), and active TT (TT activ). Evaluations included the International Physical Activity Questionnaire, weight, height, body mass index (BMI), buccal cells collection for DNA extraction, systolic (SBP) and diastolic (DBP) blood pressure measurements, and heart rate variability (HRV) analysis. A chi-square test for allelic associations was applied a 5% significance level. Results: No significant differences were observed in DBP or heart rate (HR). The active groups (AA+AT activ and TT activ) exhibited reductions in weight and METs/min/week compared to their respective sedentary groups (P&lt;0.05). The TT activ group also demonstrated reductions in SBP and BMI compared to the TT sed group (P&lt;0.05). The TT activ group had higher HRV in the RR time domain (ms) compared to the TT sed group (P&lt;0.05), though no significant differences were found in other HRV variables. Conclusions: The FTO gene polymorphism influences cardiac autonomic modulation, while physical activity levels affect anthropometric variables.

Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis.

Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.

New Associations with the HIV Predisposing and Protective Alleles of the Human Leukocyte Antigen System in a Peruvian Population.

The accurate determination of an individual's unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to either increased protection or susceptibility in the context of infectious and autoimmune diseases. This study aimed to determine the frequency and association of HLA alleles between people living with HIV (PLHIV) as the case group and Peruvian individuals without HIV with high-risk behaviors of sexually transmitted diseases as the control group. Whole exome sequencing (WES) was used to determine high-resolution HLA allelotypes using the OptiType and arcas HLA tools. The HLA alleles present in HLA classes I (A, B, and C loci) and II (DPB1, DQA1, DQB1, and DRB1 loci) were determined in a cohort of 59 PLHIV (cases) and 44 individuals without HIV (controls). The most frequent HLA alleles were A*02:01, DPB1*04:02, and DQB1*03:419 at 36%, 30%, and 28% prevalence in general population. We found that C*07:01 (p = 0.0101; OR = 10.222, 95% IC: 1.40-74.55), DQA1*03:02 (p = 0.0051; OR = 5.297, 95% IC: 1.48-19.02), and DRB1*09:01 (p = 0.0119; OR = 4.788, 95% IC: 1.39-16.44) showed an association with susceptibility to HIV infection, while DQB1*03:419 (p = 0.0478; OR = 0.327, 95% IC: 0.11-0.96) was associated with protection from HIV infection. Our findings contribute to the knowledge of HLA allele diversity in the Peruvian population (around 70% South American indigenous ancestry) lays the groundwork for further valuable large-scale use of HLA typing and offers a novel association with HIV infection that is relevant to vaccine studies.

A genome-wide association study of adults with community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).MethodsWe performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.ResultsSix independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.ConclusionsWe completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

Genomic and Serological Rheumatoid Arthritis Biomarkers, MUC5B Promoter Variant, and Interstitial Lung Abnormalities.

Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples. Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans. Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry. The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status. RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.