Biomedical subjects

Dirk S Paul

Publications and source records attributed to Dirk S Paul.

3 recordsLinked to original sources

PubMed2026

Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant.

IMPORTANCE: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. OBJECTIVE: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. EXPOSURES: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. MAIN OUTCOME AND MEASURE: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). RESULTS: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. CONCLUSIONS AND RELEVANCE: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Humans↗

PubMed2025

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities.

Genomics can provide insight into the etiology of type 2 diabetes and its comorbidities, but assigning functionality to non-coding variants remains challenging. Polygenic scores, which aggregate variant effects, can uncover mechanisms when paired with molecular data. Here, we test polygenic scores for type 2 diabetes and cardiometabolic comorbidities for associations with 2,922 circulating proteins in the UK Biobank. The genome-wide type 2 diabetes polygenic score associates with 617 proteins, of which 75% also associate with another cardiometabolic score. Partitioned type 2 diabetes scores, which capture distinct disease biology, associate with 342 proteins (20% unique). In this work, we identify key pathways (e.g., complement cascade), potential therapeutic targets (e.g., FAM3D in type 2 diabetes), and biomarkers of diabetic comorbidities (e.g., EFEMP1 and IGFBP2) through causal inference, pathway enrichment, and Cox regression of clinical trial outcomes. Our results are available via an interactive portal ( https://public.cgr.astrazeneca.com/t2d-pgs/v1/ ).

Humans↗

PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗