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Paul L Auer

Publications and source records attributed to Paul L Auer.

3 recordsLinked to original sources
PubMed2026

Inherited Predisposition to Increased Systemic Inflammation Predicts a Broad Class of Disease Phenotypes.

Chronic, low-grade systemic inflammation is a polygenic trait captured with the INFLA-score, a composite of C-reactive protein, platelet count, leukocyte count, and granulocyte-to-lymphocyte ratio. We derived a polygenic risk score from the INFLA-score (iPRS) in a multi-ancestry population from the UK Biobank (n=421,368), then evaluated and used it in a phenome-wide association study among participants in the All of Us Research Program (AoU). The multi-ancestry iPRS was tested for association with the INFLA-score in AoU (N=4,833 with biomarker data) via linear regression, adjusting for age, sex, and genetically-determined principal components (PCs) and with 2,821 phecodeX-defined phenotypes in AoU (N=265,068) via logistic regression, adjusting for sex, age, EHR length, race, ethnicity and PCs. The iPRS predicted the INFLA-score (R-squared=0.026, beta=0.980, p<2x10-16) and was associated with 47 phenotypes (Bonferroni-corrected p<0.05). The strongest associations were with blood-related phenotypes: elevated white blood cell count (OR=1.19, p=3.85x10-66), thrombocytopenia (OR=0.86, p=5.70x10-44), platelet defects (OR=0.86, p=2.47x10-43), neutropenia (OR= 0.86, p=5.52x10-18), myeloproliferative disorder (OR= 1.2, p=2.77x10-15). Others included celiac disease (OR=0.713, p=2.98x10-46), ankylosing spondylitis (OR=1.4, p=1.33 x 10-17), hypertension (OR=1.04, p=4.56x10-15), rheumatoid arthritis (OR=1.09, p=1.02x10-13), hematuria (OR=1.05, p=1.96x10-10). Removing major-histocompatibility-complex SNPs abolished associations with known autoimmune diseases, while all other associations remained. We replicated 17 (42.5%) of 40 significant phenotypes available in the Vanderbilt University Medical Center's BioVU. Our findings demonstrate that systemic inflammation can be predicted using the iPRS across multiple ancestries, and the iPRS is associated with numerous clinical endpoints. This multi-ancestry iPRS may have future utility in stratifying risk for inflammation-driven conditions across diverse populations.

Journal Article↗
PubMed2025

Association of Genetic Predisposition to Inflammation With Cancer-Related Cognitive Impairment and Fatigue in Women Who Received Chemotherapy for Nonmetastatic Breast Cancer.

PURPOSE: Cancer-related cognitive impairment (CRCI) and cancer-related fatigue (CRF) are reported by approximately 75% of patients receiving chemotherapy for breast cancer and both have been linked to inflammation. We sought to test whether an inflammation polygenic risk score (iPRS) might be associated with CRCI and/or CRF. METHODS: Using data from the UK Biobank, we developed an iPRS for the INFLA-Score, a composite measure of C-reactive protein, white cell count, platelet count, and neutrophil-lymphocyte ratio. The iPRS was evaluated for association with CRCI and CRF among women with nonmetastatic breast cancer enrolled in two completed multisite clinical trials: URCC08106 and URCC10055. CRCI and CRF were measured before and after standard-of-care chemotherapy using the FACT-Cog and Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), respectively. Linear regression evaluated the change in FACT-Cog and MFSI scores; logistic regression evaluated binary outcomes of any versus no worsening of scores. Analyses were adjusted for patient and treatment factors. We also performed exploratory genome-wide analyses. RESULTS: The cohort included 802 women who received chemotherapy (anthracycline-based = 51.8%; previous surgery = 85.0%) at a median age of 55 years (range = 22-81). The iPRS was associated with a significant decrease in MFSI-SF score (&#x3b2; = -3.29 [95% CI, -6.25 to -0.34]; P = .029) and lower odds of decreased MFSI-SF score (odds ratio, 0.66 [95% CI, 0.47 to 0.93]; P = .016) following chemotherapy. This negative relationship was partially explained by a positive correlation of the iPRS with prechemotherapy MFSI-SF score (&#x3b2; = 4.33 [95% CI, 0.23 to 8.43]; P = .038). The iPRS was not associated with a change in FACT-Cog score (&#x3b2; = -1.12; P = .627), but single nucleotide polymorphism rs9365961 was (&#x3b2; = -10.05; P = 1.46 &#xd7; 10-8). CONCLUSION: If validated, the iPRS could identify patients in need of supportive care interventions to reduce CRF.

Humans↗
PubMed2025

Genetic study of von Willebrand factor antigen levels &#x2264; 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (&#x2264; 50 IU/dL) in the general population is underexplored. OBJECTIVES: To identify genetic variants influencing VWF:Ag levels &#x2264; 50 IU/dL. METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels &#x2264; 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS: Variants at 2 loci were associated (P < 5 &#xd7; 10-9) with VWF:Ag levels &#x2264; 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels &#x2264; 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels &#x2264; 50 IU/dL, bleeding, and VWD.

Humans↗