Sex differences in the genetics of sarcoidosis across European and African ancestry populations

BackgroundSex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren’s syndrome (LS) and non-Löfgren’s syndrome (non-LS).MethodsA meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex.ResultsWe identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified.ConclusionOur findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis

Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis

This study was supported by the National Institute of Allergy, Immunology and Infectious Diseases, Office of Research on Women’s Health, National Institute of General Medical Sciences, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers U01AI101934, R01AI024717, U19AI082714, U54GM104938, P30GM103510, P30GM110766, P30AR053483, RC1AR058554, U34AR067392, and HHSN266200500026C. This publication is the sole responsibility of the authors and does not represent the views of the National Institutes of Health.Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-β, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms.Yeshttp://www.plosone.org/static/editorial#pee

Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects. These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease

Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans

Purpose: Identify genes associated with ocular sarcoidosis (OS).Methods: We genotyped 1.1 million genetic variants to identify significant OS associations, defined as those that achieved p \u3c 5 x 10(-8) in a genome-wide comparison of OS cases to healthy controls in our European- or African-American cohorts (EA, AA). Potential functional roles of all associated variants were assessed.Results: Eight significant non-HLA variants were found in AA OS cases compared to healthy controls and confirmed as at least suggestive when comparing OS to non-OS cases. Seven of these were within MAGI1 and include transcription factor binding sites and expression quantitative trait loci. Our EA cohort, while showing similar effect sizes at variants within MAGI1, had no significant variants. Association analysis of HLA-DRB1 alleles confirmed association to OS in EA to *04:01.Conclusion: Our results support organ-specific genetic risk in OS in a compelling candidate, MAGI1, known to be associated with barrier function and autoimmunity

Human Milk Exosomal MicroRNA: Associations with Maternal Overweight/Obesity and Infant Body Composition at 1 Month of Life

Among all the body fluids, breast milk is one of the richest sources of microRNAs (miRNAs). MiRNAs packaged within the milk exosomes are bioavailable to breastfeeding infants. The role of miRNAs in determining infant growth and the impact of maternal overweight/obesity on human milk (HM) miRNAs is poorly understood. The objectives of this study were to examine the impact of maternal overweight/obesity on select miRNAs (miR-148a, miR-30b, miR-29a, miR-29b, miR-let-7a and miR-32) involved in adipogenesis and glucose metabolism and to examine the relationship of these miRNAs with measures of infant body composition in the first 6 months of life. Milk samples were collected from a cohort of 60 mothers (30 normal-weight [NW] and 30 overweight [OW]/obese [OB]) at 1-month and a subset of 48 of these at 3 months of lactation. Relative abundance of miRNA was determined using real-time PCR. The associations between the miRNAs of interest and infant weight and body composition at one, three, and six months were examined after adjusting for infant gestational age, birth weight, and sex. The abundance of miR-148a and miR-30b was lower by 30% and 42%, respectively, in the OW/OB group than in the NW group at 1 month. miR-148a was negatively associated with infant weight, fat mass, and fat free mass, while miR-30b was positively associated with infant weight, percent body fat, and fat mass at 1 month. Maternal obesity is negatively associated with the content of select miRNAs in human milk. An association of specific miRNAs with infant body composition was observed during the first month of life, suggesting a potential role in the infant’s adaptation to enteral nutrition

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis

Genotypic Associations between <i>IFIH1</i> and Immune Mediators.

<p>Zoom plots of associations between SNPs in <i>IFIH1</i> and box-cox transformed plasma levels of (<b>A</b>) IL-6, (<b>B</b>) TNF-α, (<b>C</b>) IFN-β, (<b>D</b>) IP-10, (<b>E</b>) anti-dsDNA, and (<b>F</b>) total number of positive lupus-associated autoantibody specificities (dsDNA, chromatin, Ro/SSA, La/SSB, Sm, SmRNP, and nRNP, as described in <i>Materials and Methods</i>), displayed as negative log transformed p-values (y-axis). Red dots indicate SNPs within Exon 13. LD map of <i>IFIH1</i> SNPs is presented (<b>G</b>).</p

Altered IL-6 and IP-10 levels in SLE patients and lupus relatives.

<p>Plasma levels of IL-6 (<b>A, C</b>) and IP-10 (<b>B, D</b>) were assessed in SLE patients (case), unaffected first-degree relatives of SLE patients (FDR), and unrelated, unaffected controls with no family history of SLE (Ctl). IL-6 (<b>C</b>) and IP-10 (<b>D</b>) levels are compared by genotype of associated SNPs rs76162067 and rs79711023, respectively. Data are presented as mean <u>+</u> SEM. *<i>p<0</i>.<i>05</i>, **<i>p<0</i>.<i>01</i>, ***<i>p<0</i>.<i>001</i>, ****<i>p<0</i>.<i>0001</i> by Kruskal-Wallis test with Dunn’s multiple comparison for all groups assessed (Case/FDR/Ctl [<b>A-B</b>]; Case/FDR/Ctl carrying major (CC) or minor (TC) alleles [<b>C-D</b>]). Only comparisons found to be statistically significant were marked.</p