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A 37-year old man had suffered palmar hyperhidrosis since he was fifteen years old. In the last year, he has been treated with tolvaptan for autosomic polycystic kidney disease (ADPKD). The start of tolvaptan therapy was associated with a complete resolution of palmar hyperhidrosis and a sensation of relaxation. During the year on which the patient took tolvaptan, he had to suspend the drug twice. The suspension of tolvaptan was associated with the reappearance of palmar hyperhidrosis followed by sudden remission after the drug reintroduction. Palmar sweating also known as ‘emotional sweating’ is not related to thermoregulation but allows an adequate adjustment of the frictional force to perform fine hand movements. Palmar hyperhidrosis is a chronic neurologic disorder characterized by excessive sweating of eccrine glands due to overactivity of the sympathetic nervous system. Palmar sweating and emotional processing are controlled by the limbic system. In this case report reduction of palmar sweating was associated with a sense of well-being. Corticotropin releasing factor (CRF) and adrenocorticotropic hormone (ACTH) are the two main hypothalamic hormones that interact with both the limbic system and the peripheral sympathetic nervous system. Tolvaptan is an arginine vasopressin (AVP) antagonist. AVP has effects on the sympathetic nervous system through both central and peripheral actions. Centrally AVP is a well-known ACTH secretagogue. Remission of palmar hyperhidrosis is probably mediated by tolvaptan acting on central ACTH secretion.

BackgroundUric acid has been associated with blood pressure and hypertension. During the final stage of purine metabolism xanthine oxidoreductase (XOR) produces uric acid, while at the same time reactive oxygen species are formed. We hypothesized that uric acid production, as assessed indirectly from XOR variants, is associated with hypertension (figure 1).ObjectivesThe aim of the present study is to investigate the association of variants in the XOR gene with blood pressure and the development of hypertension.MethodsAnalyses were conducted in the prospective Flemish FLEMENGHO and European EPOGH study. Among 2769 participants (48.3% men; mean age 40.7 years) we genotyped 25 XOR SNPs and measured blood pressure at baseline and follow-up (median 8.8 years). The relation between variants of the XOR gene with changes in pulse pressure and mean arterial pressure over time; and incidence of hypertension, were analysed using multivariable mixed models and cox-regression, respectively.ResultsCompared with major allele homozygotes, pulse pressure increased approximately 2 mm Hg more in minor allele carriers of rs11904439 (P=value 0.01), whereas mean arterial pressure and diastolic blood pressure increased approximately 1 mm Hg less in minor allele carriers of rs2043013 (P=0.01). In 2050 participants normotensive at baseline, hazard ratios contrasting risk of hypertension in minor allele carriers vs. major allele homozygotes was 1.31 (95% confidence interval [CI] 1.03–1.68) for rs11904439 and 1.69 (95% CI 1.11–2.57) for rs148756340. With the false discovery rate set at 0.25, the aforementioned associations retained significance. The changes in systolic blood pressure from baseline to follow-up and the serum levels of uric acid at baseline (n=1949) were not associated with XOR.ConclusionsIn conclusion, pending confirmation in appropriately powered cohort studies, our findings suggest that variation in uric acid production, as captured by genetic variation in XOR, might be a predictor of changes in pulse pressure, mean arterial pressure and in the risk of hypertension.AcknowledgementThe authors gratefully acknowledge the clerical assistance of Mrs Renilde Wolfs.Disclosure of InterestNone declared

We recently identified rs3918226 as a hypertension susceptibility locus (-665 C>T), TThomozygosity being associated with higher hypertension risk. T compared with C allele transfected cells had lower endothelial nitric oxide synthase (eNOS) expression. In the family-based Flemish Study on Environment, Genes and Health Outcomes (50.9% women; mean age 40.3 years), we investigated whether 32 TT homozygotes had worse outcomes than 2787 C allele carriers. Over 15 years (median), total and cardiovascular mortality and cardiovascular and coronary events amounted to 269 (9.5%), 98 (3.5%), 247 (8.8%) and 120 (4.3%), respectively. While accounting for family clusters, the hazard ratios associated with TT homozygosity were 4.11 (P = 0.0052) for cardiovascular mortality (4 deaths), 2.75 (P = 0.0067) for cardiovascular events (7 endpoints) and 3.10 (P = 0.022) for coronary events (4 endpoints). With adjustment for cardiovascular risk factors, these hazard ratios were 6.01 (P = 0.0003), 2.64 (P = 0.0091) and 2.89 (P = 0.010), respectively. Analyses unadjusted for blood pressure and antihypertensive treatment produced consistent results. For all fatal plus nonfatal cardiovascular events, the positive predictive value, attributable risk and population-attributable risk associated with TT homozygosity were 21.9, 61.5 and 2.0%, respectively. In conclusion, TT homozygosity at the position -665 in the eNOS promoter predicts adverse outcomes, independent of blood pressure and other risk factors. Journal of Human Hypertension (2015) 29, 167-172; doi: 10.1038/jhh.2014.66; published online 7 August 2014

We recently identified rs3918226 as a hypertension susceptibility locus ( −665 C>T ), TT homozygosity being associated with higher hypertension risk. T compared with C allele transfected cells had lower endothelial nitric oxide synthase ( eNOS ) expression. In the family-based Flemish Study on Environment, Genes and Health Outcomes (50.9% women; mean age 40.3 years), we investigated whether 32 TT homozygotes had worse outcomes than 2787 C allele carriers. Over 15 years (median), total and cardiovascular mortality and cardiovascular and coronary events amounted to 269 (9.5%), 98 (3.5%), 247 (8.8%) and 120 (4.3%), respectively. While accounting for family clusters, the hazard ratios associated with TT homozygosity were 4.11 ( P =0.0052) for cardiovascular mortality (4 deaths), 2.75 ( P =0.0067) for cardiovascular events (7 endpoints) and 3.10 ( P =0.022) for coronary events (4 endpoints). With adjustment for cardiovascular risk factors, these hazard ratios were 6.01 ( P =0.0003), 2.64 ( P =0.0091) and 2.89 ( P =0.010), respectively. Analyses unadjusted for blood pressure and antihypertensive treatment produced consistent results. For all fatal plus nonfatal cardiovascular events, the positive predictive value, attributable risk and population-attributable risk associated with TT homozygosity were 21.9, 61.5 and 2.0%, respectively. In conclusion, TT homozygosity at the position − 665 in the eNOS promoter predicts adverse outcomes, independent of blood pressure and other risk factors.

Background Genes involved in cytoskeletal assembly and water/electrolyte balance have been previously linked to hypertension, but recent evidences suggest a role also in the development of inflammation and autoimmunity [1-2]. Systemic Lupus Erythematosus is a prototypic multi-organ autoimmune disease, characterized by polymorphic clinical features and a complex polygenic background. Renal disease in SLE occurs in 40-70% of lupus patients and is responsible of an high burden of morbidity and mortality. Despite substantial efforts, less is known about the role of specific genetic factors in conferring susceptibility to SLE and its complications, including lupus nephritis (LN) [3]. Objectives With these premises we sought if an association between known hypertension-related polymorphisms and development of SLE and LN existed. Methods 106 patients (96 females, 10 males) diagnosed with SLE (n=51) or LN (n=55), 23 patients with Sjoegren's Syndrome and 62 healthy controls were enrolled. Patients and controls were genotyped for polymorphisms in α-, β- and γ-adducin (ADD1,2,3 respectively), angiotensin converting enzyme, transient receptor potential cation channel-subfamily C, solute carrier family 8 (sodium-calcium exchanger) member 1 (SLC8A1), solute carrier family 24 (sodium/potassium/calcium exchanger) member 3, PKD2 calcium channel and PRKG1 kinase genes. Results Beta-adducin (ADD2) rs4984 CT heterozygosis was significantly more frequent in SLE patients than in LN patients (χ2 =6.154; p=0.013). No patient had the ADD2 rs4984 TT genotype in accordance with a low prevalence of the ADD2 C1797T homozygosity in the population. Seven patients with SLE (n=3) or LN (n=4), but none of the control groups carried the AA variant of sodium/calcium exchanger 1 (SLC8A1) rs11893826 SNP (χ2 =11.771; p=0.019). Conclusions Genes involved in the control of electrolyte/water balance and cytoskeletal plasticity could affect the pathogenic background of SLE/LN. Larger studies are required to confirm these data and attempt correlations between genetic data and specific clinical features. References Tintinger GR, et al., Drug Des Devel Ther, 2009 Kleinewietfeld M, et al., Nature, 2013 Ramos PS, et al., Semin Nephrol, 2010 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3378

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10–11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6–19.0), P = 0.038 and 13.4 (25.4–2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10–11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Background Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated MGP (dp—µcMGP). The risk associated with dp—µcMGP in the population is unknown. Methods In a Flemish population study, we measured circulating dp—µcMGP at baseline (1996–2011), genotyped MGP and recorded adverse health outcomes until December 31,2012. We assessed the multivariable-adjusted association of adverse health outcomes with dp—µcMGP and we applied a Mendelian randomization analysis based on MGP genotypes. Results Among 2318 participants, baseline dp—µcMGP averaged 3.61 µg/liter. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 form cardiovascular disease, and 85 participants experienced coronary events. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9–25.3) and by 21.5% (11.1–32.9) fora doubling of the nadir: 1.43 and 0.97 µg/liter, respectively. With higher dp—µcMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp—µcMGP doubling, 1.14[1.01–1.28]; P = 0.027), but coronary events log-linearly decreased (0.93 [0.88–0.99]; P = 0.021). dp—µcMGP levels were associated ( P ≤0.001) with MGP variants rs2098435, rs4236 and rs2430692. For non-cancer mortality and coronary events ( P ≤0.022), but not for total and cardiovascular mortality ( P ≥0.13), the Mendelian randomization analysis suggested causality. In a nested case-control study, 64 patients with coronary events had lower dp—µcMGP than 107 matched controls (3.51 vs. 4.54 µg/liter; P = 0.012). Conclusions Higher dp—µcMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.

Background The X-linked AT2R G1675A polymorphism is located in the short intron 1 of the AT2R gene within a sequence motif conforming to a splice branch site. AT2R is expressed in the human retina, but no previous study examined the association between retinal microvascular phenotypes and the AT2R G1675A polymorphism. Methods In 340 subjects randomly selected from a Flemish population (mean age, 51.9 years; 51.5% women), we post-processed retinal images (Canon CrDGi) using IVAN software to generate the retinal arteriole and venule equivalents (CRAE and CRVE) and the arteriole-to-venule-ratio (AVR). DNA fragments including the AT2R G1675A, AT1R A1166C, ACE I/D and CYP11B2 C– 344T polymorphisms, were amplified by PCR. We applied a mixed model to assess phenotype-genotype associations while accounting for relatedness and covariables. Results CRAE, CRVE and AVR averaged 151.9 µm, 215.2 µm and 0.710, respectively. CRAE was 5.5 µm greater in women than men and decreased with age ( P <0.05). In multivariable-adjusted analyses, CRAE was higher in hemizygous and homozygous carriers of the AT2R A allele than in their G allele counterparts in both sexes combined (+4.49 µm; P = 0.014) and in men (+4.91 µm; P = 0.032) with a similar trend in women (+3.41 µm; P = 0.14). AVR was increased in the presence of the AT2R A allele compared with AT2R G hemizygotes and homozygotes (+0.024; P = 0.0082). The associations of CRAE and CRVE with other polymorphisms was not significant. Conclusions: Pending confirmation in experimental and epidemiological studies, our findings suggest that diameter of the retinal arterioles might be associated with the AT2R 1675G/A polymorphism.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin–angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 ( Gly460Trp ), AGT ( C–532T and G–6A ) and AT1R ( A1166C ). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes ( P -value for interaction ⩽0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm 2  kPa −1 ; P =0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 × 10 −3  kPa −1 ; P =0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml −1  h −1 ) were increased ( P⩽ 0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 × 10 −3  kPa −1 ; P =0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.