👤 Thomas W Blackwell

Hypertensive disorders of pregnancy (HDP) are associated with future cardiovascular disease but mechanisms are not well defined. We examined the association between HDP and atherosclerotic cardiovascular disease (ASCVD) biomarkers 5-10 years after childbirth. Secondary analysis of the NICHD MFMU Network Gestational Diabetes (GDM) Trial Follow-Up study. Participants were recruited and biospecimens obtained 5-10 years after the original trial of treatment for mild GDM. Patients were included if a biospecimen was available and their HDP status was known. We compared patients who experienced HDP to normotensive controls. Outcomes included unadjusted medians and mean concentrations of ASCVD serum biomarkers Apolipoprotein B (ApoB), high-sensitivity C-reactive protein (hs-CRP), and creatinine. Generalized linear models were used to compare concentrations between groups. Of 740 participants in this analysis, 78 had been diagnosed with HDP. Mean duration of follow up after delivery was 7.1 ± 1.3 years for both groups. Unadjusted means of each biomarker were not different between groups. After adjusting for obesity, mean serum creatinine was elevated in women who had been diagnosed with HDP (0.77 mg/dL 95%CI (0.72, 0.82)) compared to controls (0.71 mg/dL 95%CI (0.69, 0.72)), p = 0.02. Adjusted means for ApoB between women with HDP and controls were 64.2 mg/dL (95%CI (59.3, 69.5)) and 60.6 mg/dL (95%CI (58.9, 62.3)), (p = 0.18), and for hs-CRP mg/L were 14.6 (95%CI (11.4, 19.1)) and 14.5 mg/L (95%CI (13.3, 15.9)), (p = 0.91). In patients with HDP compared to normotensive controls, serum creatinine, but not ApoB or hs-CRP, was modestly elevated within 10 years of childbirth. Show less

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia. Show less

The main laminin-binding integrins α3β1, α6β1 and α6β4 are co-expressed in the developing kidney collecting duct system. We previously showed that deleting the integrin α3 or α6 subunit in the ureteric bud, which gives rise to the kidney collecting system, caused either a mild or no branching morphogenesis phenotype, respectively. To determine whether these two integrin subunits cooperate in kidney collecting duct development, we deleted α3 and α6 in the developing ureteric bud. The collecting system of the double knockout phenocopied the α3 integrin conditional knockout. However, with age, the mice developed severe inflammation and fibrosis around the collecting ducts, resulting in kidney failure. Integrin α3α6-null collecting duct epithelial cells showed increased secretion of pro-inflammatory cytokines and displayed mesenchymal characteristics, causing loss of barrier function. These features resulted from increased nuclear factor kappa-B (NF-κB) activity, which regulated the Snail and Slug (also known as Snai1 and Snai2, respectively) transcription factors and their downstream targets. These data suggest that laminin-binding integrins play a key role in the maintenance of kidney tubule epithelial cell polarity and decrease pro-inflammatory cytokine secretion by regulating NF-κB-dependent signaling. Show less

The objective of this study was to assess the relationship between single-nucleotide polymorphisms associated with restless legs syndrome and periodic limb movements of sleep in a population cohort of elderly individuals. Single-nucleotide polymorphisms previously associated with periodic limb movements of sleep or restless legs syndrome were analyzed in 2356 white male participants in the Osteoporotic Fractures in Men Sleep Study cohort. The associations between single-nucleotide polymorphisms and polysomnographically measured periodic limb movement index ≥15 were examined with logistic regression adjusted for age, ancestry markers, and periodic limb movements of sleep risk factors. Of the men in this cohort, 61% had a periodic limb movement index ≥15. Significant associations were observed between a periodic limb movement index ≥15 and the number of risk alleles for the two BTBD9 single-nucleotide polymorphisms (rs9357271[T], odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.20-1.58; and rs3923809[A], OR = 1.43, 95% CI 1.26-1.63), one of the MEIS1 single-nucleotide polymorphisms (rs2300478[G], OR = 1.31, 95% CI 1.14-1.51) and the mitogen-activated protein kinase kinase 5 (MAP2K5)/Ski family transcriptional corepressor 1 (SKOR1) single-nucleotide polymorphism (rs1026732[G], OR = 1.16, 95% CI 1.02-1.31). In a multivariable model controlling for each of the two MEIS1 single-nucleotide polymorphisms, the rs6710341[A] single-nucleotide polymorphism became a significant risk allele (OR = 1.59, 95% CI 1.26-2.00). Our findings confirm an association between the BTBD9, MEIS1, and MAP2K5/SKOR1 single-nucleotide polymorphisms and periodic limb movements of sleep in an elderly cohort not selected for the presence of restless legs syndrome. Show less