Biology subjects

Austin, T. R.

Publications and source records attributed to Austin, T. R..

2 recordsLinked to original sources

bioRxiv2023

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

genetics↗

bioRxiv2021

Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status

Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18x10-8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14x10-65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

genetics↗