Analysis of protein-coding genetic variation in 60,706 humans.

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

PRECISION MEDICINE FOR METABOLIC DISORDERS IN LOW- AND MIDDLE-INCOME COUNTRIES: AREAS OF OPPORTUNITY AND CHALLENGES FOR THE FUTURE.

The purpose of this perspective is to analyze the use of precision medicine and its potential for the next few decades with a special focus on the low- and middle-income countries, using diabetes as a paradigm. Precision medicine has improved the diagnosis, prevention, treatment, and prognosis of several malignant neoplasia. Furthermore, this approach is useful in the management of monogenic diabetes. However, its impact in the current practice for the majority of the cases of diabetes is quite limited. Precision medicine has not fulfilled the expectations because it implies a long-term process composed by several feedback loops, and a number of internal and external validations and calibrations to target specific populations. If we want to obtain the expected benefits, the academic community and science agencies should work together to create the budgets and infrastructure that warrant the transfer of knowledge to the whole of society.

Prediction of incident hypertension and arterial stiffness using the non-insulin-based metabolic score for insulin resistance (METS-IR) index.

Hypertension is associated with insulin resistance (IR), metabolic syndrome (MS), and arterial stiffness. Non-insulin-based IR indexes were developed as tools for metabolic screening. Here, we aimed to evaluate the novel non-insulin-based Metabolic Score for IR (METS-IR) index for the prediction of incident hypertension and arterial stiffness evaluated using pulse wave velocity (PWV) analysis, compared with other non-insulin-based IR indexes. We evaluated two populations, a cross-sectional evaluation of high-risk individuals (n = 305) with a wide range of metabolic comorbidities and dyslipidemia in whom PWV measurement was performed and a 3-year prospective cohort of normotensive individuals (N = 6850). We observed a positive correlation between METS-IR and PWV in the cross-sectional cohort, which was higher compared with other non-insulin-based fasting IR indexes; furthermore, PWV values >75th percentile were associated with the upper tercile of METS-IR values. In the prospective cohort, we observed an increased risk for incident hypertension for the upper METS-IR tercile (METS-IR ≥ 46.42; HR: 1.81, 95% CI: 1.41-2.34), adjusted for known cardiovascular risk factors, and observed that METS-IR had greater increases in the predictive capacity for hypertension along with SBP and the Framingham Hypertension Risk Prediction Model compared with other non-insulin-based IR indexes. Therefore, METS-IR is a novel non-insulin-based IR index which correlates with arterial stiffness and is a predictor of incident hypertension, complementary to previously validated risk prediction models.

PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis.

AIM: To identify gene mutations in PRSS1 and SPINK1 in individuals with early onset idiopathic chronic or recurrent acute pancreatitis. METHODS: The cationic trypsinogen gene (PRSS1; exons 2 and 3) and the serine protease inhibitor Kazal 1 gene (SPINK1; exon 3) were selectively amplified and sequenced from blood samples of 19 patients admitted to the Pancreas Clinic at our institution with chronic pancreatitis and/or idiopathic recurrent acute pancreatitis that were diagnosed or with onset before age 35. Fifty healthy volunteers served as controls. Whole blood samples were collected and gene specific sequences were amplified by polymerase chain reaction (PCR). All PCR products were subsequently sequenced in order to identify the presence of any mutations. RESULTS: Nineteen patients with pancreatitis (14 males; median age 24 years, range 15-48 years) were included in this study, of which five showed the presence of gene mutations. Direct sequencing results indicated the presence of two previously unidentified mutations in exon 2 of PRSS1 (V39E and N42S) in two patients with recurrent acute pancreatitis. Two cases had the N34S SPINK1 mutation. Analysis of the relatives of one patient homozygous for this mutation showed that five of the six family members carried the N34S SPINK1 mutation. Of these members, three were healthy heterozygous carriers and two were homozygotes (one sibling had diabetes, the other was healthy). Another patient was heterozygous for a novel SPINK1 mutation located on exon 3 (V46D). All members from this patient's family had normal genotypes, indicating that it was a de novo mutation. No mutations in either gene were present in the control subjects. CONCLUSION: Two novel PRSS1 mutations and one novel SPINK1 mutation were identified in Mexican patients with early onset idiopathic recurrent acute pancreatitis.