SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types.

Essential hypertension (EH) is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. We studied an isolated Sardinian village (Talana) in which the prevalence of hypertension is comparable to that in most Western populations. Talana exhibits features, such as slow demographic growth, high inbreeding, a low number of founders, stable lifestyle and culture, and accurate genealogical records, that make it suitable for the study of complex disorders. Clinical assessment of the entire adult population (N= approximately 1,000) identified approximately 100 hypertensive subjects. For our study, we selected the individuals with the most-severe EH (i.e., diastolic blood pressure >100 mm Hg), belonging to a single deep-rooted pedigree (12 generations), whose common ancestors lived in the 17th century. We performed a three-stage genomewide search using 36 affected individuals, by means of parametric linkage and allele-sharing approaches. LOD scores >1 were observed on chromosomes 1, 2, 13, 15, 17, and 19 (stage I). The most striking result was found in a 7.57-cM region on chromosome 2p24-p25. All five nonparametric linkage statistics estimated by the SimWalk2 program lie above the significance threshold of P<.008 for the whole region. Similar significance was obtained for 2p24-25 when parametric linkage (LOD score 1.99) and linkage disequilibrium mapping (P=.00006) were used, suggesting that a hypertension-susceptibility locus is located between D2S2278 and D2S168. This finding is strengthened by a recent report of linkage with marker D2S168 in a hypertensive sib-pair sample from China.

Recently, a major locus on chromosome 7q was found in association with the taste sensitivity to phenylthiocarbamide (PTC) in humans. This region contains the TAS2R38 gene that encodes a member of the TAS2R bitter taste receptor family. Three SNPs within this gene demonstrated a strong association with taster status in Utah families and in an additional sample of 85 unrelated individuals. We studied a small isolated village in eastern Sardinia and carried out a genome-wide scan to map the genetic basis of PTC perception in this population. We performed both qualitative and quantitative PTC-taste linkage analysis. Qualitative analysis was carried out by defining a cut-off from the bimodal distribution of the trait and classifying subjects as tasters and non-tasters (75 and 25%, respectively). Linkage analysis on 131 subjects belonging to a unique large multi-generation pedigree comprising 239 subjects confirmed significant evidence for linkage at 7q35 also in our population. Haplotype analyses of the three SNPs inside the PTC gene allowed us to identify only two haplotypes that were associated with the non-taster phenotype (80% AVI homozygous) and to taster phenotype (40% PAV homozygous and 56% PAV/AVI heterozygous). Sex, age and haplotype effect explained 77.2 % of the total variance in PTC sensitivity.

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity.We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.

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.