Type 2 diabetes (T2D) and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analysed large-scale multiomic data to uncover genetic factors underlying T2D and blood pressure (BP) comorbidity. We curated 1,304 independent single-nucleotide variants (SNVs) associated with T2D/BP, grouping them into five clusters related to metabolic syndrome, inverse T2D-BP risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalisation with tissue-specific gene expression highlighted significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores (PGS) derived from these clusters improved risk prediction for T2D-hypertension comorbidity, identifying individuals with more than twice usual susceptibility. These results reveal complex genetic basis of shared T2D and BP mechanistic heterogeneity, enhancing comorbidity risk prediction. Partitioned PGSs offer promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions, supporting precision medicine and public health initiatives. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been conducted using the UK Biobank Resource under application number 236. This project was in part funded by the Agence Nationale de la Recherche under the Programme d'Investissement d'Avenir (PreciDIAB, ANR-18-IBHU-0001 and RHU PreciNASH ANR-16-RHUS-0006), by the European Union through the "Fonds Europeen de Developpement Regional" (FEDER), by the "Conseil Regional des Hauts-de-France" (Hauts-de-France Regional Council), by the "Metropole Europeenne de Lille" (MEL, European Metropolis of Lille), and by the European Research Council (ERC OpiO - 101043671, to AB) The authors would like to thank all the investigators from different consortia that built and shared the GWAS meta-analysis, eQTLs, and scATAC-seq atlases used in this study, as well as the UK Biobank participants and dedicated staff. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The GWAS used in this study are all publicly available and listed in Supplementary Table 4. The UK Biobank Resource (UKB, https://ukbiobank.ac.uk/) was accessed using the Application Number 236. GTEx (https://www.gtexportal.org/home/datasets/) and TIGER (http://tiger.bsc.es/) eQTLs are publicly available. The ATAC-seq data from CATLAS are publicly available http://catlas.org/humanenhancer/. Data from the ABOS cohort are not publicly available, as the study is ongoing. The Biological Atlas of Severe Obesity (Atlas Biologique de l'Obesité Sévère [ABOS]) cohort (ClinicalTrials.gov: [NCT01129297][1]) is an ongoing prospective study that aims to identify the determinants of bariatric surgery outcomes. Patients were recruited at the Centre Hospitalier Universitaire de Lille (France), as previously described in DOI: 10.1097/SLA.0000000000000945, DOI: 10.1016/S2213-8587(22)00005-5, and DOI: 10.1038/s41467-024-51078-2. All human procedures were ethically approved by the Comité de Protection des Personnes Nord Ouest IV or by the ethics committee of Liège University Hospital. The analysis performed in this study aligned with the original scopes and objectives of the ABOS and Liège cohort studies; therefore, no additional ethical approval was requested. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GWAS used in this study are all publicly available and listed in Supplementary Table 4. The UK Biobank Resource (UKB, https://ukbiobank.ac.uk/) was accessed using the Application Number 236. GTEx (https://www.gtexportal.org/home/datasets/) and TIGER (http://tiger.bsc.es/) eQTLs are publicly available. Data from the ABOS cohort are not publicly available, as the study is ongoing. The ATAC-seq data from CATLAS are publicly available http://catlas.org/humanenhancer/. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01129297&atom=%2Fmedrxiv%2Fearly%2F2025%2F03%2F06%2F2025.03.02.25323190.atom

Abstract: We postulated that T2D predisposes to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (methylationEPIC arrays) of the exocrine pancreas of 141 donors, assessing the impact of T2D. Epigenome-wide association study (EWAS) for T2D identified a hypermethylation in an enhancer of the Pancreatic-Lipase-Related-Protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (in 191K participants of the UKbiobank) associated with elevated glycemia and LDL-cholesterol. Mendelian Randomisation using 2.5M SNP OmniArrays in 111 donors evidenced that T2D was causal of PNLIPRP1 hypermethylation, which was causal for LDL-cholesterol. Further AR42J rat exocrine cell studies demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known pre-pancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and on exocrine pancreas function with potential implications for pancreatic diseases. Article Highlights: a. Why did we undertake this study? We performed this study to identify epigenetic changes with T2D in the pancreas. b. What is the specific question(s) we wanted to answer? This study addresses whether T2D induce epigenetic changes that could explain why T2D individuals are more prone to pancreas disease. c. What did we find? We found a hypermethylation at PNLIPRP1 associated with T2D and revealed a role of this gene in cholesterol metabolism. d. What are the implications of our findings? This study has important implications in the prevention of pancreatic diseases as their molecular mechanisms remain largely unknown.

ABSTRACT OBJECTIVE Diverse measures of obesity relate to cancer risk differently. Here we assess the relationship between overall and central adiposity and cancer. METHODS We constructed z-score weighted polygenic scores (PGS) for two obesity-related phenotypes; body mass index (BMI) and BMI adjusted waist-to-hip ratio (WHRadjBMI) and tested for their association with five cancers in the UK Biobank: overall breast (BrC), post-menopausal breast (PostBrC), prostate (PrC), colorectal (CrC) and lung (LungC) cancer. We utilised publicly available data to perform bi-directional Mendelian randomization (MR) between BMI/WHRadjBMI and BrC, PrC and CrC. RESULTS PGS BMI had significant multiple testing-corrected inverse association with PrC (OR[95%CI]=0.97[0.95-0.99], P =0.0012) but PGS WHRadjBMI was not associated with PrC. PGS BMI was associated with PostBrC (OR[95%CI]=0.97[0.96-0.99], P =0.00203) while PGS WHRadjBMI had nominal association with BrC. PGS BMI had nominal positive association with LungC. MR analyses showed significant multiple testing-corrected protective causal effect of BMI on PrC (OR[95%CI]=0.993[0.988-0.998], P =4.19×10 −3 ). WHRadjBMI had a nominal causal effect on higher PrC risk (OR[95%CI]=1.022[1.0067-1.038], P =0.0053). We also report nominal causal protective effect of WHRadjBMI on breast cancer (OR[95%CI]=0.99[0.98-0.997], P =0.0068). Neither PGS nor MR analyses were significant for CrC. CONCLUSIONS Higher overall adiposity appears protective from PrC while higher central adiposity is a potential risk factor for PrC but protective from BrC. STUDY IMPORTANCE What is already known about this subject? Observational studies suggest obesity is associated with higher risk of certain cancers and at the same time is protective of other cancers. The direction of association is in part influenced by the anthropometric trait used to assess obesity. Higher BMI appears protective from prostate, breast and lung cancers but is a risk factor for post-menopausal breast, pancreatic and colorectal cancers. What are the new findings in your manuscript? We implement Mendelian randomization approach using large scale datasets and show a protective causal effect of higher BMI from prostate cancer but suggest that higher WHRadjBMI is causal for prostate cancer. We also show nominal evidence of WHRadjBMI being causally protective from breast cancer. How might your results change the direction of research or the focus of clinical practice? We demonstrate the importance of partitioning obesity into discrete types depending on the area of fat deposition rather than using an overall measure. Our results show that diverse measures of obesity relate differently to cancer risk. In fact, even for the same type of cancer, overall and central obesity measures may impact in opposite direction in terms of risk to cancer.

Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal adiposity, using BMI adjusted waist-to-hip ratio (WHRadjBMI) by utilising polygenic scores (PGS) and Mendelian randomisation (MR) analyses. We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics, we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGS BMI was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.0804[1.025–1.14], P = 0.0037). The significance of association declined after T2D adjustment (OR[95%CI] = 1.073[1.018–1.13], P = 0.00904). PGS WHRadjBMI association with pancreatic cancer was at the margin of statistical significance (OR[95%CI] = 1.047[0.99–1.104], P = 0.086). T2D adjustment effectively lost any suggestive association of PGS WHRadjBMI with pancreatic cancer (OR[95%CI] = 1.039[0.99–1.097], P = 0.14). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011–1.0018], P = 0.027) but not for BMI on pancreatic cancer. Overall, we show that abdominal adiposity measured using WHRadjBMI, may be a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.

Background Type 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism. Methods We explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank. Results Methylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer in PNLIPRP1 , an acinar-specific gene. PNLIPRP1 expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreased Pnliprp1 in response to a diabetogenic treatment, and 2/ in Pnliprp1 knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rare PNLIPRP1 null variants associated with increased glucose, BMI and LDL-cholesterol. Conclusions/interpretation We present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC.