Biomedical subjects

Sarah L Kerns

Publications and source records attributed to Sarah L Kerns.

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 (β = -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 (β = 4.33 [95% CI, 0.23 to 8.43]; P = .038). The iPRS was not associated with a change in FACT-Cog score (β = -1.12; P = .627), but single nucleotide polymorphism rs9365961 was (β = -10.05; P = 1.46 × 10-8). CONCLUSION: If validated, the iPRS could identify patients in need of supportive care interventions to reduce CRF.

Humans↗

PubMed2006

Geminin prevents rereplication during xenopus development.

To maintain a stable genome, it is essential that replication origins fire only once per cell cycle. The protein Geminin is thought to prevent a second round of DNA replication by inhibiting the essential replication factor Cdt1. Geminin also affects the development of several different organs by binding and inhibiting transcription factors and chromatin-remodeling proteins. It is not known if the defects in Geminin-deficient organisms are due to overreplication or to effects on cell differentiation. We previously reported that Geminin depletion in Xenopus causes early embryonic lethality due to a Chk1-dependent G(2) cell cycle arrest just after the midblastula transition. Here we report that expressing a non-Geminin-binding Cdt1 mutant in Xenopus embryos exactly reproduces the phenotype of geminin depletion. Expressing the same mutant in replication extracts induces a partial second round of DNA replication within a single S phase. We conclude that Geminin is required to suppress a second round of DNA replication in vivo and that the phenotype of Geminin-depleted Xenopus embryos is caused by abnormal Cdt1 regulation. Expressing a nondegradable Cdt1 mutant in embryos also reproduces the Geminin-deficient phenotype. In cell extracts, the nondegradable mutant has no effect by itself but augments the amount of rereplication observed when Geminin is depleted. We conclude that Cdt1 is regulated both by Geminin binding and by degradation.

Animals↗