Refining genome-wide associated loci for serum uric acid in individuals with African ancestry.

OBJECTIVE: Serum uric acid is the end-product of purine metabolism and at high levels is a risk factor for several human diseases including gout and cardiovascular disease. Heritability estimates range from 0.32 to 0.63. Genome-wide association studies (GWAS) provide an unbiased approach to identify loci influencing serum uric acid. Here, we performed the first GWAS for serum uric acid in continental Africans, with replication in African Americans. METHODS: Africans (n = 4126) and African Americans (n = 5007) were genotyped on high-density GWAS arrays. Efficient mixed model association, a variance component approach, was used to perform association testing for a total of ~ 18 million autosomal genotyped and imputed variants. CAVIARBF was used to fine map significant regions. RESULTS: We identified two genome-wide significant loci: 4p16.1 (SLC2A9) and 11q13.1 (SLC22A12). At SLC2A9, the most strongly associated SNP was rs7683856 (P = 1.60 × 10-44). Conditional analysis revealed a second signal indexed by rs6838021 (P = 5.75 × 10-17). Gene expression and regulatory motif data prioritized a single-candidate causal variant for each signal. At SLC22A12, the most strongly associated SNP was rs147647315 (P = 6.65 × 10-25). Conditional analysis and functional annotation prioritized the missense variant rs147647315 (R (Arg) > H (His)) as the sole causal variant. Functional annotation of these three signals implicated processes in skeletal muscle, subcutaneous adipose tissue and the kidneys, respectively. CONCLUSIONS: This first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12. The combination of weak linkage disequilibrium in Africans and functional annotation led to the identification of candidate causal SNPs for all three signals. Each candidate causal variant implicated a different cell type. Collectively, the three associations accounted for 4.3% of the variance of serum uric acid.

Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.

Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2-/- mice. Mutant mice had left atrial enlargement and Micu2-/- cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2-/- ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2-/- vs. wild type, P = 7.8 × 10-40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that Micu2-/- and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that Micu2-/- mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from Micu2-/- mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that Micu2-/- mice recapitulate features of diastolic heart disease and define previously unappreciated roles for Micu2 in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.

Elevated retinol binding protein 4 contributes to insulin resistance in spontaneously hypertensive rats.

Retinol binding protein 4 (RBP4) is an adipokine secreted by adipose tissue and liver and contributes to insulin resistance (IR) in animals. Although several human studies indicated that RBP4 is positively correlated with blood pressure and is elevated in untreated hypertensive subjects, the role of RBP4 in IR of hypertensive animals still remains obscure. In this study, spontaneously hypertensive rats (SHR) were used to investigate the relationship between RBP4 levels and IR. We found that at 7 weeks old, SHR had significantly increased plasma RBP4 levels and RBP4 expression in liver and epididymal adipose tissue accompanied by worsening of IR as compared with Wistar-Kyoto (WKY) control rats. Administration of fenretinide in SHR to increase urinary RBP4 excretion significantly decreased plasma RBP4 levels and improved IR. Moreover, treatment with valsartan markedly reduced blood pressure, circulating RBP4 and adiponectin levels, and IR in SHR. Valsartan also reversed the increase of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the decrease of type 4 glucose transporter (GLUT4) in adipose tissue. In conclusion, these results suggest that RBP4 contributes, at least partly, to the pathogenesis of IR in SHR. Furthermore, the decrease of blood pressure caused by valsartan not only decreased RBP4 levels, but also improved IR in SHR.

Effects of overweight and the PLA2G7 V279F polymorphism on the association of age with systolic blood pressure.

This prospective study aimed to determine the effects of the persistence of overweight for three years and the PLA2G7 V279F polymorphism, as well as the interaction between these factors, on the association of age with blood pressure (BP). Healthy middle-aged subjects with normotensive BP were divided into the normal-weight and overweight groups. The PLA2G7 V279F genotype, BP, lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, and oxidized low-density lipoprotein (ox-LDL) were determined. Lp-PLA2 activity was lower in the F allele subjects (n = 111) than in those with the VV genotype (n = 389). The overweight individuals with the F allele had lower Lp-PLA2 activity and ox-LDL at both baseline and after three years and lower systolic and diastolic BP and LDL cholesterol after three years compared with those with the VV phenotype. After three years, the overweight subjects with the VV phenotype exhibited greater increases in Lp-PLA2 activity, systolic BP, and ox-LDL than those with the F allele and normal-weight subjects with the VV phenotype. A multivariate analysis revealed that the PLA2G7 V279F genotype, baseline BMI, changes in Lp-PLA2 activity and ox-LDL remained independently and positively associated with changes in systolic BP. The simultaneous presence of the PLA2G7 279VV genotype and persistence of overweight synergistically increases the risk for hypertension, whereas lower Lp-PLA2 activity in PLA2G7 279F allele carriers might offer certain protection against hypertension, even in individuals who have been overweight for over three years.

Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study.

BACKGROUND: Nitric oxide is involved in the regulation of vascular basal tone and blood pressure. Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension. OBJECTIVE: To look for linkage and association of three di-allelic polymorphisms (Glu298Asp, intron 4 VNTR and T-786C) and the intron 13 CA-repeat of NOS3 with blood pressure as a continuous trait. METHODS: Genotyping was performed in 110 dizygotic white twin pairs from Flanders, Belgium. The influence of NOS3 polymorphisms on conventional and ambulatory blood pressure was assessed by sib-pair analysis and haplotype association analysis. RESULTS: Genotype frequencies were similar to those previously reported in white populations. Sib-pair analysis did not show a significant influence of either polymorphism on blood pressure. Haplotype analysis disclosed a significant association between NOS3 haplotypes and daytime ambulatory diastolic (P = 0.02) and systolic (P < 0.0001) blood pressure, the latter remaining significant after multiple testing was taken into account (P = 0.032). The association between daytime ambulatory systolic blood pressure and NOS3 haplotypes was mainly attributable to four haplotypes accounting for 11.9% of all represented haplotypes. CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders. These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients. They indicate the importance of ambulatory blood pressure and haplotype analysis in revealing the moderate effect of polymorphisms on blood pressure.

PhenoMiner: a quantitative phenotype database for the laboratory rat, Rattus norvegicus. Application in hypertension and renal disease.

Rats have been used extensively as animal models to study physiological and pathological processes involved in human diseases. Numerous rat strains have been selectively bred for certain biological traits related to specific medical interests. Recently, the Rat Genome Database (http://rgd.mcw.edu) has initiated the PhenoMiner project to integrate quantitative phenotype data from the PhysGen Program for Genomic Applications and the National BioResource Project in Japan as well as manual annotations from biomedical literature. PhenoMiner, the search engine for these integrated phenotype data, facilitates mining of data sets across studies by searching the database with a combination of terms from four different ontologies/vocabularies (Rat Strain Ontology, Clinical Measurement Ontology, Measurement Method Ontology and Experimental Condition Ontology). In this study, salt-induced hypertension was used as a model to retrieve blood pressure records of Brown Norway, Fawn-Hooded Hypertensive (FHH) and Dahl salt-sensitive (SS) rat strains. The records from these three strains served as a basis for comparing records from consomic/congenic/mutant offspring derived from them. We examined the cardiovascular and renal phenotypes of consomics derived from FHH and SS, and of SS congenics and mutants. The availability of quantitative records across laboratories in one database, such as these provided by PhenoMiner, can empower researchers to make the best use of publicly available data. Database URL: http://rgd.mcw.edu.

Synergistic effects of the MTHFR C677T polymorphism and hypertension on spatial navigation.

Navigation skills deteriorate with age, but the mechanisms of the decline are poorly understood. Part of the decrement may be due to age-related vascular risk factors. The T allele in a C677T variant in methylenetetrahydrofolate reductase (MTHFR) gene is associated with elevated plasma homocysteine, which is detrimental to vascular integrity and has been linked to cognitive decline. We inquired if a combination of physiological (hypertension) and genetic (MTHFR 677T) vascular risks has a synergistic negative impact on cognitive performance in otherwise healthy adults. We tested 160 participants (18-80 years old) on a virtual water maze. Advanced age, female sex, and hypertension were associated with poorer performance. However, hypertensive carriers of the T allele performed significantly worse than the rest of the participants at all ages. These findings indicate that hypertension combined with a genetic vascular risk factor may significantly increase risk for cognitive impairment.

Home blood pressure monitoring in diabetes.

Forty three children with diabetes were recruited to evaluate home blood pressure monitoring using an electronic oscillometric sphygmomanometer (Philips HP5330). This device was found to be simple to use and reliable. It fulfilled the accuracy criteria of the American Association for the Advancement of Medical Instrumentation for both systolic and diastolic blood pressure and those of the British Hypertension Society for systolic blood pressure. Thirty eight children successfully measured their own blood pressure at home and taught other family members to do the same. The results indicate that home blood pressure monitoring is of value in the management of diabetic children.

Molecular biology of Na+ absorption.

Aldosterone controls the activity of the amiloride-sensitive epithelial Na+ channel located in the apical membrane of epithelial cells from the distal colon and kidney collecting duct. This channel is a key element in the antinatriuretic response to aldosterone. It consists of three homologous subunits, alpha-ENaC, beta-ENaC, and gamma-ENaC (for epithelial Na+ channel), which share significant identity with degenerins, a family of proteins found in the nematode Caenorhabditis elegans, and with ligand-gated cation channels, such as FaNaC [Phe-Met-Arg-Phe-NH2 (i.e., FMRF-amide) Na+ channel] or ASIC (acid-sensing ion channel), two neuronal ionotropic receptors for Phe-Met-Arg-Phe-NH2 and H+, respectively. All of these proteins contain a large extracellular loop located between two large hydrophobic domains. The NH2- and COOH-terminal domains are cytoplasmic and contain potential regulatory motifs. Gain-of-function mutations affecting beta-ENaC and gamma-ENaC genes can cause Liddle syndrome, a rare from of genetic hypertension. Loss-of-function mutations affecting alpha-ENaC or beta-ENaC genes can cause pseudohypoaldosteronism type 1. Steroids strongly increase beta-ENaC and gamma-ENaC transcription in rat distal colon. A different situation is observed in rat kidney, in which the large stimulation of ENaC activity is mainly via posttranslational mechanisms. In both tissues, aldosterone increases cell surface expression of the ENaC subunits.