<a><i>Objective</i>: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters: Beta cell, Proinsulin, Obesity, Lipodystrophy, and Liver/Lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. </a> <p><i>Research Design and Methods</i>: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in twelve studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n=454,193) and tested for cross-sectional association with T2D-related outcomes including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). </p> <p><i>Results</i>: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. <a>Increased Obesity and Lipodystrophy cluster pPS’s, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The Lipodystrophy and Liver/Lipid cluster pPS’s were each associated with CAD, with increasing and decreasing effects respectively. An increased Liver/Lipid cluster pPS was also significantly associated with reduced renal function. </a>The Liver/Lipid cluster includes known loci linked to liver lipid metabolism (e.g. <i>GCKR</i>, <i>PNPLA3,</i> and <i>TM6SF2)</i>, and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. </p> <p><i>Conclusion</i>: Our findings support that genetically-driven pathways leading to T2D also predispose differentially to clinical outcomes. </p> <b><br> </b> <p><b> </b></p>
Abstract Per- and polyfluoroalkyl substances (PFAS) are widely used and persistent chemicals, leading to ubiquitous exposure. Although high PFAS levels have been associated with an adverse cardiovascular risk profile, the distribution of levels and relations with cardio-metabolic risk markers in the general population have not been fully characterized. We assessed the association between blood levels of perfluorooctaneic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) and a range of lipoproteins and metabolites as well as clinical lipid measurements. We used data from participants of the Netherlands Epidemiology of Obesity study (NEO) ( n = 584) and the Rhineland Study ( n = 1962), jointly spanning an age range of 30 to 89 years. PFAS were measured with the Metabolon HD4 platform, and lipoprotein and metabolite profiles were measured using Nightingale’s nuclear magnetic resonance-spectroscopy platform, and mainly comprised lipoprotein markers. Using linear regression analyses, we quantified age-, sex-, and education-adjusted associations of PFOA, PFOS, and PFHxS with clinical lipid measurements and 224 lipoproteins and metabolites. Higher levels of PFAS, particularly PFOS and PFHxS, were associated with higher concentrations of total lipid, cholesterol and phospholipid content in most HDL, IDL, LDL, and VLDL subclasses. The effect sizes were age-dependent for the majority of the associations, with the deleterious effects of PFAS being generally stronger in people below compared to those above median age. Our observation that in the general population even low PFAS concentrations are associated with an unfavorable lipid profile, calls for further critical regulation of PFAS substances.
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