New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Importanza del mappaggio genetico fine per la definizione farmacogenomica : esempio dell&apos;ACE e risposta a LOSARTAN

RAZIONALE. L'allele D del gene ACE \ue8 associato a maggior rischio cardio-renale. I dati sono controversi per la risposta alla terapia antiipertensiva. Abbiamo eseguito uno studio farmacogenomico tra locus ACE e risposta a Losartan in ipertesi na\uefve (EH), mai trattati prima, per evitare ogni effetto carry-over. CASISTICA E METODI. Analisi della struttura di linkage disequilibrium (LD) di ACE per individuare SNPs tagging I/D, su 1013 soggetti etnicamente omogenei, caratterizzati anche per I/D. Gli SNP rs4341, rs4342, rs1987692 sono in LD assoluto con I/D, quindi tag. Farmacogenomica: 388 EH caucasici, genotipizzati con ILLUMINA 1MDuo. Imputazione con aplotipi CEU 1000Genomes. Fenotipo: caduta pressoria sistolica dopo 4 settimane di terapia con Losartan (\u394SBP), analizzata con regressione lineare, modello additivo, correggendo per et\ue0, sesso ed etnia. RISULTATI. I tre tag SNP sono significativamente associati a \u394SBP (p=3x10). Estendendo l'analisi a tutto il locus (400 kbp), abbiamo analizzato 110 SNP, notando un progressivo aumento di significativit\ue0 alla regione flanking-3\u2019 del gene (rs4461142, p=5.86x10 -2 ) a circa 2.000 bp dal codone di stop di ACE, associato a una caduta pressoria di 3.7 mmHg nei CC rispetto ai portatori dell\u2019allele T. Il polimorfismo \ue8 solo in debole LD con I/D (r =0.6). A conferma della specificit\ue0 per Losartan, ripetendo lo stesso espe- 2 rimento in 180 EH trattati con placebo e 660 con idroclorotiazide, -3 non \ue8 stato osservato nessun effetto attribuibile al genotipo (p=0.84 e p=0.97). CONCLUSIONI. Nonostante siano passati pi\uf9 di 20 anni dalla prima segnalazione, \ue8 probabile che il polimorfismo I/D non abbia un ruolo funzionale ma che sia solo un proxy di altri non ancora identificati. Questo studio di mappaggio fine punta alla regione flanking-3\u2019 che potrebbe essere connessa a un sito regolatore per il gene ACE, localizzata a circa 6.000 bp dallo pseudogene ACE3p

alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives

Erythrocyte membrane alterations mirror those of vascular smooth muscle and renal tubular cell membrane. The interaction between adducin and Na-K pump is the most likely biochemical mechanism responsible for the increased tubular Na reabsorption and hypertension in Milan hypertensive strain (MHS) rats. To substantiate this hypothesis in humans, we tested to see if alpha-adducin Gly460Trp genotype is associated with erythrocyte sodium transport rate in a new cohort of n=268 never-treated North Sardinian primary hypertensives. Plasma renin activity and blood pressure response to hydrochlorothiazide were also measured to evaluate the relationship between sodium transport rate and two intermediate phenotypes with a higher degree of genetic complexity. Na-K pump, Na-K-Cl cotransport, and Li-Na countertransport at V(max) were faster (P<0.0001), whereas intracellular Na concentration was lower (P<0.0001) in patients carrying one or two 460Trp alleles. Such behavior was mirrored by opposite changes of intracellular Na concentration. Plasma renin activity and blood pressure response to diuretic treatment, on the other hand, showed a weaker association with the sodium transport rate. In conclusion, our findings are consistent with the hypothesis that the Gly460Trp alpha-adducin polymorphism may affect renal Na handling through an alteration in ion transport across the cell membrane mirrored by erythrocytes. These results may also have clinical relevance because the Gly460Trp alpha-adducin polymorphism may explain, at least in part, the variability of blood pressure response to diuretics in primary hypertensive patients

Changes in plasma atrial natriuretic factor during sequential fluid removal and biochemical correction in end-stage chronic renal failure patients

Plasma immunoreactive atrial natriuretic factor (ANF) levels, their chromatographic profiles (high-performance liquid chromatography; HPLC) and changes during sequential ultrafiltration (UF; 1 litre/h) and biochemical correction without fluid removal (BC; 3 h) were studied in 8 end-stage chronic renal failure patients on intermittent haemodialysis (greater than 1 year). Patients entered randomly the UF-BC or BC-UF protocols that were reversed after 1 week. HPLC showed a single peak of ANF immunoreactivity in plasma of end-stage chronic renal failure patients before dialysis sessions. ANF at the end of fluid removal fell by 31 +/- 2% (p less than 0.01) during UF-BC and by 30 +/- 2% (p less than 0.01) at the end of BC during BC-UF. In both sequences a further slight reduction in plasma ANF was observed during the second phase: it was 8.5 +/- 5% (n.s.) during BC of the BC-UF and 12.5 +/- 2% (p less than 0.05) during fluid removal of BC-UF. Plasma ANF was not significantly removed by the machinery. BC did not modify the microhaematocrit in the BC-UF sequence while the microhaematocrit was significantly increased by UF (13 +/- 1 and 14 +/- 1%, p less than 0.005 vs. basal, respectively), and decreased by BC in the UF-BC sequence (-5 +/- 2% vs. end UF, p less than 0.05). Serum creatinine and urea decreased significantly during BC in both protocols while they were unmodified during UF. No significant changes were seen in PRC during either protocol.(ABSTRACT TRUNCATED AT 250 WORDS

NATRIURETIC EFFECT OF ACUTE NIFEDIPINE ADMINISTRATION IS NOT MEDIATED BY THE RENAL KALLIKREIN-KININ SYSTEM

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 x 106 KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at -10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume (+47%), Na+ (+54%) and Cl- (+58%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ (+38%) and K+ (+29%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans

The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study

The basic requirement for declaring an association study positive is that the "hypertension-favoring" allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations by using the alpha-adducin polymorphism as a paradigm. Four hundred ninety hypertensives and 176 normotensives enrolled in Sassari, Italy, and 468 hypertensives and 181 normotensives enrolled in Milano, Italy, were genotyped for the alpha-adducin Gly460Trp polymorphism. The blood pressure response to 2 months of hydrochlorothiazide therapy could be evaluated in 143 (85 in Sassari and 58 in Milano) hypertensives with and without the 460Trp alpha-adducin allele. The alpha-adducin 460Trp allele was not significantly more frequent in hypertensives in the Sassari population but was more frequent in hypertensives than in normotensives in Milano (P=0.019). Basal plasma renin activity was lower and blood pressure fall after diuretic therapy more pronounced (P<0.01) in hypertensives carrying at least one 460Trp allele than in Gly460Gly homozygotes, irrespective of their membership in the Sassari or Milano cohort. The effect of alpha-adducin genotype in predicting basal plasma renin activity and blood pressure decrease with diuretic treatment is similar in Sassari and Milano, despite the lack of association of the alpha-adducin genotype with hypertension in Sassari