👤 Kathrin Budde

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Immune checkpoint inhibitors have transformed melanoma therapy but frequently cause immune-related adverse events (irAEs), including colitis, that limit treatment. Reliable biomarkers predicting toxicity remain lacking. In this retrospective, multicenter study, we analyzed pretreatment serum samples from 331 patients with metastatic melanoma treated with anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab or nivolumab), or combination ipilimumab/nivolumab. IgG autoantibody reactivity against 832 human protein antigens, including autoimmune targets, cytokines, tumor-associated antigens, and cancer pathway proteins, was profiled using multiplex bead-based arrays. Statistical analysis (Significance Analysis of Microarrays and Cox regression) identified autoantibody signatures associated with subsequent irAEs and immune-related colitis (ir-colitis). We detected 47 autoantibodies predictive of irAEs, with KRT7, RPLP2, UBE2Z, and GPHN emerging as the strongest markers. Anti-KRT7 and anti-GPHN were specifically predictive in patients receiving PD-1 monotherapy, whereas anti-RPLP2 was associated with irAEs in ipilimumab/nivolumab combination therapy. For ir-colitis, 38 autoantibodies were identified, with five (PIAS3, RPLP0, UBE2Z, KRT7, and SDCBP) showing consistent predictive value across treatment groups. Anti-PIAS3 and anti-RPLP0 increased ir-colitis risk, while anti-SDCBP conferred protection. Notably, predictive profiles differed between PD-1-based and CTLA-4-based regimens, underscoring divergent mechanisms of toxicity. Several autoantibodies predictive of irAEs or ir-colitis also correlated with clinical outcome. ATG4D, MAGEB4, and IL4R were associated with prolonged progression-free and overall survival, whereas FGFR1 predicted both reduced irAE risk and inferior survival, consistent with the link between heightened immune activation, toxicity, and therapeutic benefit. This study, to our knowledge, is the largest pretreatment autoantibody screen in melanoma immunotherapy, demonstrates that serum autoantibody profiles can stratify patients at risk for irAEs and ir-colitis. The identified signatures connect tumor-related and immunity-related antigens, stress-response pathways, and autoimmune mechanisms. Pretreatment autoantibody profiling offers a promising biomarker-driven approach for individualizing risk assessment, improving patient selection, and guiding early intervention strategies to enhance the safety of immune checkpoint blockade in melanoma. Beyond toxicity prediction, our findings also suggest that specific autoantibodies may reflect underlying immune activation states linked to therapeutic response. Show less

The diagnosis of Sjögren's disease (SjD) in patients without autoantibodies against Ro/SSA is a major challenge. We aimed to identify novel autoantibodies in SjD that may facilitate the diagnostic procedure for Ro/SSA negative SjD. IgG and IgA autoantibody reactivity of 94 potential candidate autoantigens for SjD, selected from a discovery screen of 1,629 human antigens coupled to Luminex beads and prior knowledge about potential biological relevance, were examined in serum of SjD patients (n=347) using Luminex and ELISA technology. Healthy (HC, n=118) and non-Sjögren's sicca syndrome (NSS, n=44) individuals served as controls. To assess disease specificity, the novel autoantibodies were also measured in serum of patients with Rheumatoid Arthritis (RA, n=50), Systemic Lupus Erythematosus (SLE, n=49), and Systemic Sclerosis (SSc, n=37). 45 novel autoantibodies were significantly (p ≤ 0.05) more prevalent in SjD than in HC and were detected in up to 19% of the SjD cohort. The most common autoantibodies were against CCL4, M5, TMPO and OAS3. Some of the novel autoantibodies were associated with extraglandular disease manifestations, such as anti-TONSL or anti-IL6 with pulmonary involvement. We have developed a three and five marker panel for the detection of Ro/SSA negative patients, consisting of anti-FNBP4, anti-SNRPC, anti-CCL4, anti-M3 and anti-KDM6B, which had a sensitivity of up to 46% with a specificity of 95% (SjD vs. HC). Both panels discriminate these patients from HC, whereas the three-marker more effectively differentiates between Ro/SSA negative patients and NSS. Novel autoantibodies will facilitate the diagnosis of Ro/SSA negative patients with SjD, in particular our predictive panel will be useful in the diagnosis and differentiation of these patients from healthy and NSS individuals in a clinical context. In addition, the autoantibodies may also be useful for risk stratification of extraglandular manifestations. Show less

In contrast to lung adenocarcinoma (LUAD), targetable genetic alterations are less frequently detected in squamous cell carcinoma of the lung (LUSC). Over the last years, gene fusions have become promising targets in many solid cancers. Here, we analysed a cohort of LUSC, identified recurrent fusion genes and functionally characterised these tumour genomes. A subset of 1608 squamous cell carcinomas of the lung was analysed by means of the FusionPlex® Lung Panel to identify potentially targetable gene fusions using targeted next-generation sequencing. Cases harbouring recurrent gene fusions were further analysed using FISH, Cytoscan HD arrays and cell culture experiments. We found both, known and novel gene fusions in about 3 % of the cases. Known fusions occurring in lung cancer included ALK::EML4, EGFRvIII, EZR::ROS1 and FGFR3::TACC. We further identified recurrent gene fusions of currently unknown biological function, involving EGFR::VSTM2A and NSD3::FGFR1 and showed that the occurrence of the EGFR::VSTM2A fusion is accompanied by high-level amplification of EGFR. Our analyses further revealed that the genomes of these LUSC patients are chromosomally unstable, which leads us to believe that such non-actionable genomic rearrangements may be a result of "chromosomal chaos" most probably not representing exclusive cancer-driving genes in this cancer entity. We emphasise that caution should be taken when novel fusions are found and that the appearance of new gene fusions should always be interpreted in the molecular context of the respective disease. Show less

We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens-DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)-and in the tocilizumab arm against one antigen-neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm-G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor-positive versus-negative or anti-cyclic citrullinated test-positive versus test-negative rheumatoid arthritis (p ≥ 0.06). Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare. Show less

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype. Show less

Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases. Show less