Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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.
BackgroundParaoxonase 1 (PON1) gene polymorphisms and polyphenols intake have been reported independently associated to lipid profile and susceptibility to atherosclerosis and cardiovascular disease. However, the interaction between these factors remains to be investigated. We performed an observational nutrigenetic study to examine whether the interaction between polyphenols and anthocyanins intake and PON1 genetic variants can modulate biomarkers of cardiovascular health in an Italian healthy population.MethodsWe recruited 443 healthy volunteers who participated in the EC funded ATHENA project (AnThocyanin and polyphenols bioactive for Health Enhancement through Nutritional Advancement). Data collection included detailed demographic, clinical, dietary, lifestyle, biochemical and genetic data. Polyphenols and anthocyanins intake was measured by 24 h dietary recall repeated three times a year in order to get seasonal variations. We tested the interaction between 18 independent tagging SNPs in PON1 gene and polyphenols intake on HDL, LDL, cholesterol, triglycerides and atherogenic index of plasma.ResultsWithout considering the genetic background, we could not observe significant differences in the lipid profile between high and low polyphenols and anthocyanins intake. Using a nutrigenetic approach, we identified protective genotypes in four independent polymorphisms that, at Bonferroni level (p ≤ 0.0028), present a significant association with increased HDL level under high polyphenols and anthocyanins intake, compared to risk genotypes (rs854549, Beta = 4.7 per C allele; rs854552, Beta = 5.6 per C allele; rs854571, Beta = 3.92 per T allele; rs854572, Beta = 3.94 per C allele).ConclusionsWe highlight the protective role of genetic variants in PON1 towards cardiovascular risk under high polyphenols and anthocyanins consumption. PON1 variants could represent novel biomarkers to stratify individuals who might benefit from targeted dietary recommendation for health promotion and strategies of preventive medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0941-6) contains supplementary material, which is available to authorized users.
This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure response to hydrochlorothiazide was performed in 1739 white hypertensives from six clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS), making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8) and the suggestive regions (P<10−5) were cross-validated in two black cohorts treated with hydrochlorothiazide. Additionally, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in blood pressure regulation or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified two suggestive regulatory regions linked to GJA1 and FOXA1, relevant for cardiovascular and kidney function. With the gene-based approach, we identified HSD3B1 as significantly associated with blood pressure response (P<2.28×10−4). HSD3B1 encodes the 3beta-HSD enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of blood pressure response to hydrochlorothiazide, and using two different analytical approaches, we identified three novel loci influencing blood pressure response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, and which was not identified in the single-SNP analysis due to high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.
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