👤 Jeffrey L Gunter

Associations of Alzheimer's disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier vs later an individual's progression on plasma and PET Alzheimer's disease biomarkers is associated with earlier vs later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed effects models to estimate how much earlier vs later each individual progresses on plasma p-tau217, amyloid PET, tau PET, and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs, and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cutpoints, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R=0.38-0.47) in the MCSA and stronger (R=0.74-0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET AD biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer's disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer's disease co-pathologies. Show less

COVID-19 is associated with cardiometabolic complications, including lipid abnormalities, but its effect on lipoprotein(a) [Lp(a)] remains unclear. This pilot cohort study was conducted at an academic tertiary hospital and a primary healthcare facility (6 July-31 August 2021). It included a cross-sectional baseline comparison of patients hospitalised with COVID-19, diabetic controls, and healthy controls, with COVID-19 patients additionally followed for three months post-discharge. The study evaluated the relationship between lipid profiles, Lp(a), disease severity, and recovery. Among 169 participants, patients with COVID-19 ( The online version contains supplementary material available at 10.1038/s41598-026-37439-5. Show less

Moderate-to-vigorous physical activity (MVPA) is inversely associated with risks of cancer, cardiovascular diseases (CVD), type 2 diabetes (T2D), and their co-occurrence, defined as multimorbidity; however, the underlying biological pathways remain unclear. In 33,806 UK Biobank participants with 2911 measured blood proteins, a proteomic signature of MVPA was derived with linear and LASSO regressions. Multivariable Cox models, adjusted for MVPA, estimated prospective associations with cancer, CVD, T2D, and multimorbidity. We show that after multiple testing corrections, 220 proteins are retained in the MVPA signature. Proteins related to food intake, metabolism, and cell growth (e.g., LEP, MSTN) are inversely associated, while those involved in immune cell migration and musculoskeletal integrity (e.g., integrins, COMP) are positively associated with MVPA. Several proteins positively associated with MVPA are inversely associated with disease risk (e.g., integrins, CLEC4A for cancer; LPL, LEP for T2D), while proteins negatively associated with MVPA are positively associated with disease risk (e.g., CD38, TGFA for CVD). The proteomic signature score is inversely associated with cancer risk (hazard ratio per interquartile range: 0.87; 95% confidence interval: 0.78, 0.96) and T2D (0.66; 0.60, 0.72). For multimorbidity, proteins inversely related to MVPA align with expected risk patterns (e.g., GGT1, HR: 1.32; 95% CI: 1.12, 1.57), but the proteomic signature score is not associated. This study identifies several proteins associated with MVPA that are also associated with cancer, CVD, T2D, and the multimorbidity of these conditions. Further studies investigating the causal nature of these associations are welcome. Show less

Numerous genetic variants have been identified by genome-wide association studies as being associated with colorectal cancer (CRC) risk. Metabolome-wide association analysis was performed for 187 CRC-associated genetic variants using genomic data and untargeted Show less

Coronary artery disease (CAD) and cancer are 2 leading global causes of mortality, with shared modifiable risk factors, yet the genetic and molecular mechanisms underlying their comorbidity remain poorly understood. We performed a genome-wide pleiotropy analysis to identify shared genetic mechanisms across CAD and 4 common cancers that share modifiable risk factors with CAD (breast, colorectal, lung, prostate). Using genome-wide pleiotropy and colocalization analysis, we identified 60 colocalized susceptibility loci shared by CAD and site-specific cancer, of which 43 are novel, including loci at Our findings highlight shared and opposing genetic loci between CAD and cancer and provide insight into molecular intermediates mediating joint disease risk. Importantly, they indicate potential drug repurposing opportunities for dual CAD and cancer prevention while highlighting possible adverse and divergent effects of existing medications across both conditions. Show less

The role of lipid-perturbing medications in cancer risk is unclear. We employed cis-Mendelian randomization and colocalization to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, and PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, and prostate). We triangulated findings using pre-diagnostic protein measures in prospective analyses in EPIC (977 colorectal cancer cases, 4080 sub-cohort members) and the UK Biobank (860 colorectal cancer cases, 50 177 controls). To gain mechanistic insight into the role of ANGPTL4 in carcinogenesis, we examined the impact of the ANGPTL4 p. E40K loss-of-function variant on differential gene expression in normal colon tissue in BarcUVa-Seq. Finally, we evaluated the association of colon tumor ANGPTL4 expression with cancer-specific mortality in TCGA. In analysis of 78 473 cases and 107 143 controls, genetically proxied circulating ANGPTL4 inhibition was associated with reduced colorectal cancer risk (ORSD decrease = 0.76, 95% confidence interval [CI] = 0.66 to 0.89, P = 5.52 × 10-4, PPcolocalization = 0.83). This association was replicated using pre-diagnostic circulating ANGPTL4 concentrations in EPIC (hazard ratio [HR]log10 decrease = 0.91, 95% CI = 0.84 to 0.98, P = .01) and the UK Biobank (HRSD decrease = 0.93, 95% CI = 0.86 to 0.99, P = .03). In gene-set enrichment analysis of differential gene expression in 445 colon tissue samples, ANGPTL4 loss-of-function down-regulated several cancer-related biological pathways (PFDR < .05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 tumor expression was associated with reduced colorectal cancer-specific mortality risk (HRlog2 decrease = 0.66, 95% CI = 0.50 to 0.87, P = 2.92 × 10-3). Our integrative proteogenomic and observational analyses suggest a potential protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4 as a therapeutic target for colorectal cancer prevention. Show less

Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in Show less

Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects. Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284). Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS. These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS. Show less

Fatty acids (FAs) have been postulated to impact adiposity, but few epidemiological studies addressing this hypothesis have been conducted. This study investigated the association between serum phospholipid FAs (S-PLFAs) and indicators of obesity. BMI and waist-to-hip ratio (WHR) were collected from 372 healthy Mexican women included as controls in a case-control study. S-PLFA percentages were determined through gas chromatography. Desaturation indices, SCD-16, SCD-18, FA desaturase (FADS)1, and FADS2, biomarkers of endogenous metabolism, were proxied respectively as 16:1n-7/16:0, 18:1n-9/18:0, 20:4n-6/20:3n-6, and 22:6n-3/20:5n-3. Multiple linear regressions adjusted for relevant confounders and corrected for multiple testing were conducted to determine the association between S-PLFA, desaturation indices, and indicators of adiposity. SCD-16 (β = 0.034, Show less

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. Show less