ossil remains from ~100 million years ago (Ma) show that snakes were widely distributed across the world by the late Cretaceous period 1. During the course of their evolution, snakes lost their limbs, acquiring a serpentine body 2. Some also evolved or co-opted venom systems to help subdue, capture and digest their prey 2,3. The Colubroides clade of advanced snakes encompasses >3,000 extant species including >600 venomous species 4. The most venomous snakes include the true vipers and pit vipers, both members of the Viperidae family, and cobras, kraits, mambas and sea snakes from the Elapidae family 5. Although humans are not an intended target, accidental contact with venomous snakes can be deadly. Snakebite envenoming is a serious neglected tropical disease that affects ~5 million people worldwide annually, leading to ~400,000 amputations and >100,000 deaths 6. In India alone, the high rural population density combined with the presence of the 'big four' deadly snakes, namely the Indian cobra (Naja naja), Russell's viper (Daboia russelli), sawscaled viper (Echis carinatus) and common krait (Bungarus caeruleus), results in >46,000 snakebite-related deaths annually 7. Snake venom is a potent lethal cocktail rich in proteins and peptides, secreted by specialized venom gland cells. Venom components can be broadly classified as neurotoxic, cytotoxic, cardiotoxic or hemotoxic, and the composition can vary both between and within species 8-11. Currently, snake antivenom is the only treatment effective in the prevention or reversal of the effects of envenomation. Since 1896, antivenom has been developed by immunization of large mammals, such as the horse, with snake venom to generate a cocktail of antibodies that are used for therapy 12. Given the heterologous nature of these antibodies, they often elicit adverse immunological responses when treating snakebite victims 13. Moreover, the antivenom composition is not well defined and its ability to neutralize the venom

Using GWAS in a case-control design, 7 we recently identified rs3918226 as a new hypertension susceptibility Abstract-A case-control study revealed association between hypertension and rs3918226 in the endothelial nitric oxide synthase (eNOS) gene promoter (minor/major allele, T/C allele). We aimed at substantiating these preliminary findings by target sequencing, cell experiments, and a population study. We sequenced the 140-kb genomic area encompassing the eNOS gene. In HeLa and HEK293T cells transfected with the eNOS promoter carrying either the T or the C allele, we quantified transcription by luciferase assay. In 2722 randomly recruited Europeans (53.0% women; mean age 40.1 years), we studied blood pressure change and incidence of hypertension in relation to rs3918226, using multivariable-adjusted models. Sequencing confirmed rs3918226, a binding site of E-twenty six transcription factors, as the single nucleotide polymorphism most closely associated with hypertension. In T compared with C transfected cells, eNOS promoter activity was from 20% to 40% (P<0.01) lower. In the population, systolic/diastolic blood pressure increased over 7.6 years (median) by 9.7/6.8 mm Hg in 28 TT homozygotes and by 3.8/1.9 mm Hg in 2694 C allele carriers (P≤0.0004). The blood pressure rise was 5.9 mm Hg systolic (confidence interval [CI], 0.6-11.1; P=0.028) and 4.8 mm Hg diastolic (CI, 1.5-8.2; P=0.0046) greater in TT homozygotes, with no differences between the CT and CC genotypes (P≥0.90). Among 2013 participants normotensive at baseline, 692 (34.4%) developed hypertension. The hazard ratio and attributable risk associated with TT homozygosity were 2.04 (CI, 1.24-3.37; P=0.0054) and 51.0%, respectively. In conclusion, rs3918226 in the eNOS promoter tags a hypertension susceptibility locus, TT homozygosity being associated with lesser transcription and higher risk of hypertension. Salvi et al Hypertension and eNOS 845locus. This locus lays in the promoter of the endothelial nitric oxide synthase (eNOS) gene, which encodes the enzyme that produces nitric oxide, a strong vasodilator with a key role in the regulation of systemic vascular resistance. GWAS usually points to genomic regions of interest in relation to a trait, but seldom directly identifies the causal or functional variant. In the present study, we aimed at consolidating the role of eNOS as a hypertension susceptibility gene by fine mapping the DNA sequence tagged by rs3918226, by studying the transcriptional functionality of the rs3918226 alleles in vitro, and by relating the change in BP over time to rs3918226 in a randomly recruited population sample. Methods Target SequencingFrom the HYPERGENES study, 7 we selected 44 hypertensive patients carrying ≥1 T allele and 48 healthy controls homozygous for the C allele. Analyses of the genetic data confirmed that all patients and controls were of continental Italian descent. We sequenced a 140-kb DNA region of chromosome, 7 which, in addition to eNOS, included KCNH2 mapping upstream and 6 genes mapping downstream: ATG...

Background Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of ‘the right drug in the individual essential hypertensive patient’ remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient’s genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. Methods and results We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. Conclusion This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case–control study.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.