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Table S1. Common tagging SNPs in MEOX2. Table S2. MEOX2 and TCF15 SNPs and allele and genotype frequencies in unrelated founders. Table S3. MEOX2 and TCF15 allele and genotype frequencies in 2027 analysed participants. Table S4. Sex- and age-standardised CHD rates by MEOX2 SNPs. Table S5. Hazard ratios for CHD by MEOX2 SNPs in participants free of CHD at baseline. Table S6. Sex- and age-standardised CHD rates by MEOX2 haplotypes. Table S7. Hazard ratios for CHD by MEOX2 haplotypes reconstructed while accounting for pedigree information. Table S8. Hazard ratios for CHD by MEOX2 haplotypes in participants free of CHD at baseline. Table S9. Baseline characteristics of participants without blood left for genotyping compared with those included in the analyses. Figure S1. Plot of the MEOX2 gene and flanking regions on chromosome 7. Figure S2. Plot of the TCF15 gene and flanking regions on chromosome 20. Figure S3. Interaction between TCF15 rs12624577 and MEOX2 rs4532497. Figure S4. Incidence of coronary endpoints, myocardial infarction and coronary revascularisation in MEOX2 GTCCGC carriers and non-carriers.

In the recent years, several cytokines have been associated with Alzheimer's disease (AD) development and progression and many studies have correlated this risk with polymorphisms in the genes encoding these molecules. Also the type 1 cytokine interferon (IFN)-gamma belongs to a cytokine class that affects the immune function; in fact it plays a major role in defence against viruses and intracellular pathogens but also in the induction of the immune-mediated inflammatory response. The aim of this study was to evaluate the role of IFN-gamma in AD by studying the association of +874T--A IFN-gamma gene polymorphism with AD. We included in this study 115 AD patients (70 women, 45 men, mean age 80) and 90 sex and age-matched healthy controls (HC, 51 women, 39 men, mean age 82) from northern Italy. Genomic DNA was extracted with the salting-out method from whole blood of all subjects; the genotyping at IFN-gamma loci was assessed with ARMS-PCR. The data obtained from the +874T--A IFN-gamma gene polymorphism analysis of AD patients and HC lack of any statistically significant differences also when stratified according to gender. In conclusion these results confirm the previous shown lack of association between +874T--A IFN-gamma gene polymorphism and the risk of AD. However, other polymorphisms have been demonstrated to influence IFN-gamma transcription and since natural killer cells of AD patients show higher production of the cytokine, further analysis will be necessary to clarify the role of this gene in the pathogenesis of the disease.

Common tagging SNPs in PEAR1. Table S2. PEAR1 allele and genotype frequencies by SNP in unrelated founders. Table S3. PEAR1 allele and genotype frequencies by SNP in 1938 analysed participants. Table S4. Hazard ratios for all-cause mortality and the composite cardiovascular endpoint by PEAR1 SNPs. Table S5. Multivariable-adjusted hazard ratios associated with rs12566888 by antiplatelet treatment status. Table S6. Frequencies of haplotypes. Table S7. Multivariable-adjusted hazard ratios associated with the TTGATGGA haplotype by antiplatelet treatment status. Table S8. Minor allele frequencies in current study population and in European subjects in 1000 Genomes and HapMap. (DOC 211 kb)

Common tagging SNPs in PEAR1. Table S2. PEAR1 allele and genotype frequencies by SNP in unrelated founders. Table S3. PEAR1 allele and genotype frequencies by SNP in 1938 analysed participants. Table S4. Hazard ratios for all-cause mortality and the composite cardiovascular endpoint by PEAR1 SNPs. Table S5. Multivariable-adjusted hazard ratios associated with rs12566888 by antiplatelet treatment status. Table S6. Frequencies of haplotypes. Table S7. Multivariable-adjusted hazard ratios associated with the TTGATGGA haplotype by antiplatelet treatment status. Table S8. Minor allele frequencies in current study population and in European subjects in 1000 Genomes and HapMap. (DOC 211 kb)

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.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.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.

Objective: Endogenous Ouabain (EO) has been demonstrated to modulate the activity of Na+, K+-ATPase. Our purpose was to measure plasma levels of EO in Meniere's Disease (MD) subjects as a possible predisposing factor to developing and maintaining hydrops. Study Design: Case-control study. Settings: University hospital. Patients: Thirty-nine MD subjects and 29 controls with a lifetime negative history for vertigo and dizziness. Main Outcome Measures: Plasma levels of EO. Results: Plasma EO in MD subjects was in the range between 33 and 504 pmol/L (median, 135.5 pmol/L), whereas in the control group, plasma EO varied between 70 and 724 pmol/L (median, 205 pmol/L). The Mann-Whitney U test detected a statistically significant difference (p = 0.0001). Conclusion: Low plasma levels of EO have been proposed to augment Na-K pump activity, whereas high EO levels show an inhibitory effect on the pump activity. A proper pump activity may be necessary to keep the right ionic amount and osmolarity in endolymph. Although other possibilities may be considered, we suggest that altered control mechanisms of pump activity may be related to the pathogenesis and maintenance of MD.