Rintasyöpäriskin arviointiin uusia genomityökaluja

Vertaisarvioitu.Tutkimukset viimeksi kuluneen vuosikymmenen ajalta ovat osoittaneet rintasyövän perinnöllisen alttiuden monimuotoisuuden. Yksittäisten merkittävien rintasyövän alttiusgeenien mutaatioita seulotaan ja valikoitujen potilaiden osalta myös hyödynnetään, mutta testauskriteerit täyttävistäkin vain noin kuudennekselta löydetään tällainen mutaatio. Sairastumisriskin arvioimiseksi on viime vuosina kehitetty moniin tauteihin polygeenisiä riskisummia - tehokkaita algoritmeja, jotka huomioivat riskitekijöitä perimänlaajuisesti. Suuri rintasyövän polygeeninen riski lisää rintasyöpäriskiä huomattavasti ja rikastuu yksittäisten mutaatioiden tapaan sukuihin. Siksi rintasyövän geneettisen riskinarvioinnin tulisi olla nykyistä kokonaisvaltaisempaa. Polygeenisen riskiarvion lupaavimmat käyttökohteet ovat naisten, joiden rintasyöpäriski on suuri, tunnistaminen rintasyöpäpotilaiden lähisukulaisten joukosta, sekä yksittäisten merkittävien mutaatioiden kantajien riskiarvion tarkentaminen.Peer reviewe

Systematic comparison of family history and polygenic risk across 24 common diseases

Peer reviewe

Jätetäänkö sitten myös verenpaine mittaamatta?

Kommentt

Jätetäänkö sitten myös verenpaine mittaamatta?

Kommentt

Genomitiedon arkaluonteisuus on tiukassa elävä myytti

Aikuisen henkilön geeni- ja genomitieto ei sellaisenaan ole ¬kovinkaan arkaluonteista. Pelkän tietosuojan korostaminen vähentää tutkimuksen mahdollisuuksia: arvokkaatkin aineistot muuttuvat suljettuina arvottomiksi

Genomitiedon arkaluonteisuus on tiukassa elävä myytti

Aikuisen henkilön geeni- ja genomitieto ei sellaisenaan ole ¬kovinkaan arkaluonteista. Pelkän tietosuojan korostaminen vähentää tutkimuksen mahdollisuuksia: arvokkaatkin aineistot muuttuvat suljettuina arvottomiksi

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldSystemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes--the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes--we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system

Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

Lamin A/C mutation affecting primarily the right side of the heart

LMNA mutations are amongst the most important causes of familial dilated cardiomyopathy. The most important cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) is desmosomal pathology. The aim of the study was to elucidate the role of LMNA mutations among Finnish cardiomyopathy patients. We screened 135 unrelated cardiomyopathy patients for LMNA mutations. Because of unusual phenotype, two patients were screened for the known Finnish ARVC-related mutations of desmosomal genes, and their Plakophilin-2b gene was sequenced. Myocardial samples from two patients were examined by immunohistochemical plakoglobin staining and in one case by electron microscopy. We found a new LMNA mutation Phe237Ser in a family of five affected members with a cardiomyopathy affecting primarily the right side of the heart. The phenotype resembles ARVC but does not fulfill the Task Force Criteria. The main clinical manifestations of the mutation were severe tricuspid insufficiency, right ventricular enlargement and failure. Three of the affected patients died of the heart disease, and the two living patients received heart transplants at ages 44 and 47. Electron microscopy showed nuclear blebbing compatible with laminopathy. Immunohisto - chemical analysis did not suggest desmosomal pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes a phenotype different from traditional cardiolaminopathy. Our findings suggest that cardiomyopathy affecting primarily the right side of the heart is not always caused by desmosomal pathology. Our observations highlight the challenges in classifying cardiomyopathies, as there often is significant overlap between the traditional categories.Peer reviewe

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism