Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Evaluation of how gene-job strain interaction affects blood pressure in the PAMELA study.

OBJECTIVE: To see whether there is interaction between single nucleotide polymorphisms (SNPs) belonging to candidate genes for hypertension and job strain and its components (job demand and job control) in an accurately phenotyped Italian cohort (Pressioni Arteriose Monitorate E Loro Associazioni). METHODS: From the Pressioni Arteriose Monitorate E Loro Associazioni cohort, we sampled 924 employed men and women who had completed a modified version of the Karasek questionnaire and for whom deoxyribonucleic acid information was available. We selected 1,510 common tagging and putative functional SNPs in 92 candidate autosomal genes involved in sympathetic nervous system, oxidative stress, renin-angiotensin-aldosterone system, and sodium balance. The interaction of each candidate SNP with the perceived job stress scores on ambulatory systolic and diastolic blood pressures was evaluated by adding product terms to a multiple regression linear model, adjusted for sex, age, total cholesterol, and body mass index. RESULTS: Among all the SNPs tested, the interaction of SNP rs11210278 located on the endothelin 2 gene and job control was statistically significant after controlling for multiple testing, using false discovery rate (unadjusted p = .00000661; p adjusted for false discovery rate = .0085), indicating an inverse association with systolic blood pressure for the homozygous wild-type allele (C/C) and a positive association for the variant genotypes (C/T and T/T). CONCLUSIONS: We show that the hypertensive response to job strain is present only in carriers of the rs11210278 wild-type genotype. The phenomenon is discussed in relationship to the controversial results of field studies on job strain and hypertension.

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Imaging of thyroid carcinoma with CT and MRI: approaches to common scenarios.

Computed tomography (CT) and magnetic resonance imaging (MRI) can play an important role in preoperative and post-treatment assessment of thyroid malignancy. The radiologist should be aware of the pathological behavior of thyroid carcinoma, and the characteristic imaging appearance of the primary tumor and metastases. This review describes the approach to imaging thyroid cancer on CT and MRI for four common scenarios: detection of the incidental thyroid nodule, evaluation of thyroid metastases, presurgical imaging for invasive disease, and evaluation for recurrence in the post-treatment neck.

Association between ADRA1A gene and the metabolic syndrome: candidate genes and functional counterpart in the PAMELA population.

OBJECTIVES: There is currently uncertainty about whether metabolic syndrome has a common underlying process. We performed a gene-centric association study of metabolic syndrome in 98 major cardiometabolic genes in the large, well phenotyped Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. We followed this with functional studies to elucidate a possible mechanism for the top association signal. METHODS: From the PAMELA cohort, we sampled 1407 individuals with information on the metabolic syndrome (ATPIII criteria). We analyzed 1324 tagging single-nucleotide polymorphisms (SNPs) in 98 candidate genes selected, based on known pathways involved in sympathetic nervous system, oxidative stress, renin-angiotensin system and sodium balance. RESULTS: The SNP rs17055869 near the alpha-1A-adrenoreceptor gene (ADRA1A) showed the strongest association with metabolic syndrome (odds ratio 1.7, CI 1.3-2.2; P = 0.00007, P = 0.000098 after permutation). In order to determine a functional basis for this association, we examined in a subgroup of metabolic syndrome patients whether the allelic distribution of the above-mentioned gene is different according to the different degree of the metabolic syndrome-related sympathetic activation, directly assessed by the gold standard method to assess neuroadrenergic drive, that is microneurographic recording of efferent postganglionic muscle sympathetic nerve traffic. All metabolic syndrome patients with a lesser degree of sympathetic activation were homozygous for the major allele (C), whereas those with a very pronounced sympathetic overdrive had an over-representation of the minor T allele (P < 0.0001). CONCLUSION: Thus, the rs17055869 SNP near the 3' end of ADRA1A is significantly associated with metabolic syndrome and it may be involved in determining a greater level of sympathetic activation in metabolic syndrome patients.

The effects of sex and method of blood pressure measurement on genetic associations with blood pressure in the PAMELA study.

BACKGROUND: Phenotypic accuracy and specificity are essential for a successful genetic association study. Blood pressure (BP) measurements show heterogeneity depending on the method and time of measurement, sexual dimorphism and measurement errors, making genetic dissection difficult. METHODS AND RESULTS: We studied 1550 adults aged 25-74 years, not on any antihypertensive treatment, resident in Monza, Italy (PAMELA study) all of whom had home, clinic and ambulatory BPs measured. We analysed 3705 single nucleotide polymorphisms (SNPs) (1324 typed and 2381 imputed) across 168 genes for association with these traits. No SNP achieved an experiment wide significance level of P less than 3 x 10 for any of the phenotypes studied. We selected 28 top candidate SNPs for further analysis of phenotypic heterogeneity and sexual dimorphism using a gene-centric strategy calculating empirical P values by permutations within each gene by including genic SNPs with an r less than 0.5. The association signals were not consistent across all the BP phenotypes, whether compared by genes or by physiological pathways. The top SNPs in WNK1, ADRA1A, ADRA1B, DRD1, NOS1 and PON3 showed significant sex interaction for BP and when analysed separately by sex showed evidence of dimorphism with opposite direction of effect for the same allele in the two sexes. CONCLUSION: In the largest study of its kind, we show that sex and BP measurement methods have a significant impact on association signals. These findings might explain previous inconsistencies in studies on cardiovascular candidate genes and should have major implications for the design and interpretation of association studies.

Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress.

Human essential hypertension is a classic example of a complex, multifactorial, polygenic disease with a substantial genetic influence in which the underlying genetic components remain unknown. The stroke-prone spontaneously hypertension rat (SHRSP) is a well-characterized experimental model for essential hypertension and endothelial dysfunction. Previous work, identified glutathione S-transferase mu type 1, a protein involved in detoxification of reactive oxygen species, as a positional and functional candidate gene. Quantitative real-time polymerase chain reaction showed a highly significant, 4-fold reduction of glutathione S-transferase mu type 1 mRNA expression in 5- and 16-week-old SHRSP compared with the congenic and normotensive Wistar Kyoto rats. This suggests that differential expression is not attributable to long-term changes in blood pressure. DNA sequencing identified one coding single nucleotide polymorphism (R202H) and multiple single nucleotide polymorphisms in the promoter region. mRNA expression changes were reflected at the protein level, with significant reductions in the SHRSP glutathione S-transferase mu type 1. Protein was colocalized with aquaporin 2 to the principle cells of the renal collecting ducts. Coupled to significant increases in nitrotyrosine levels in the kidney, this suggests a pathophysiological role of this protein in hypertension and oxidative stress. Similar processes may underlie oxidative stress in the vasculature.

Microarray analysis of rat chromosome 2 congenic strains.

Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of human essential hypertension, and a number of reproducible blood pressure regulation quantitative trait loci have been found to map to rat chromosome 2. The SP.WKYGla2c* congenic strain was produced by introgressing a region of rat chromosome 2 from the normotensive Wistar Kyoto (WKY) strain into the genetic background of the SHRSP. Systolic and diastolic blood pressures were significantly reduced in the SP.WKYGla2c* compared with the SHRSP parental strain (198/134+/-6.1/3.3 versus 172/120+/-3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013). Genome-wide microarray expression profiling was undertaken to identify differentially expressed genes among the parental SHRSP, WKY, and congenic strain. We identified a significant reduction in expression of glutathione S-transferase mu-type 2, a gene involved in the defense against oxidative stress. Quantitative reverse transcription-polymerase chain reaction relative to a beta-actin standard confirmed the microarray results with SHRSP mRNA at 8.56 x 10(-4) +/-1.6 x 10(-4) compared with SP.WKYGla2c* 3.67 x 10(-3)+/-2.8 x 10(-4) (95% CI -3.9 x 10(-3) to -1.8 x 10(-3); P=0.0034) and WKY 4.03 x 10(-3)+/-5.1 x 10(-4); (95% CI -5.4 x 10(-3) to -8.9 x 10(-4); P=0.027). We also identified regions of conserved synteny, each containing the Gstm2 gene, on mouse chromosome 3 and human chromosome 1.