Geeniinfo väärtus südame-veresoonkonnahaiguste riski hindamisel

Väitekirja elektrooniline versioon ei sisalda publiktasiooneFakt, et südame-veresoonkonnahaigused on peamiseks suremuse põhjustajaks maailmas, rõhutab vajadust edendada ja täiustada olemasolevaid haiguse ennetus- ja ennustusstrateegiaid. Südame-veresoonkonnahaiguste riski hindamine põhineb tänases kliinilises praktikas klassikalisi fenotüübilisi riskitegureid arvestavatel riski hindamise mudelitel. Kuigi nimetatud strateegia võimaldab kõrge riskiga indiviide suhteliselt hästi tuvastada, jääb pea kolmandiku riski hinnang ebatäpseks ning ravimääramine ebaselgeks. Lisaks eelnevale peegeldub mudelite piiratud kasutus selles, et riskifaktorite loetlemisega hinnatakse tegelikkuses molekulaarsel tasandil juba toimunud muutusi. Seega leevendatakse praeguse strateegia kasutamisel pigem patoloogia progresseerunud kulgu, kui pärsitakse või ennetatakse molekulaarsete mehhanismide häirumist varases staadiumis. Üheks võimalikuks edasiarenduse meetmeks pakutakse haiguse geneetilise informatsiooni arvestamist. Seda eeskätt seetõttu, et südame-veresoonkonnahaiguste geneetiliste seoste uuringutega on täna jõutud hinnanguteni, millel on potentsiaali muuta oluliselt täpsemaks nii tervete indiviidide varast haigusriski hindamist kui ka haigete kliinilist käsitlust. Selle doktoritöö peamiseks eesmärgiks on anda ülevaade tänastest südame-veresoonkonnahaiguste riski hindamise meetmetest ning sellest, kas ja kuidas geneetilise informatsiooni kaasamine igapäeva kliinilistesse otsustesse neid edendada võiks. Lisaks toon näiteid, kuidas kõrge resolutsiooniga genoomi järjestusandmestik võimaldaks tunnusega seotud põhjuslikke geenivariante täpsemini tuvastada ning kuidas populatsiooni-põhise biopanga andmete kasutamine tõhustaks kõrge riskiga indiviidide kliinilist käsitlust.Cardiovascular diseases are the main cause of morbidity and mortality worldwide, underscoring the requisite for improved strategies for disease prevention and risk prediction. The main approach applied in today's clinical practice to identify those at increased cardiovascular risk relies on the utilization of phenotypic risk models that facilitate the estimation of one's disease risk based on traditional risk factors. While this strategy is beneficial for avoiding disease incidence and it does on the whole target individuals at high risk for treatment sufficiently well, a third of individuals, who experience an adverse event, are misclassified into a lower risk category and are therefore advocated treatment ambiguously. Importantly, the current approach lacks in providing accurate estimation for primordial prevention, that is estimating risk before risk factors emerge. To overcome this issue and seek for approaches to enhance risk estimation, attention has now been turned to genetics with the aim of incorporating genetic information into established risk prediction strategies. The scrutiny of the genetic architecture of cardiovascular diseases conducted in recent decades has today resulted in estimates that can be of clinical utility and value. This doctoral thesis aims to give an overview of the status quo of the genomic research on cardiovascular diseases and contemplate on what the advances in molecular technology, computational capacities and large-scale initiatives have enabled, what the progress of these endeavours entail and whether these do bestow incremental value for clinical utility. Furthermore, I will bring examples of how the utilization of high-coverage sequencing data can enhance the search for the genetic underpinnings of cardiovascular disease-associated phenotypes, and how the use of large-scale cohorts and population-based biobanks can enable the anticipated improvement in disease risk estimation, especially when integrated into a national healthcare system.https://www.ester.ee/record=b522706

Südame isheemiatõve riski ennustamine geneetiliste markerite abil

Südame isheemiatõbi on komplekshaigus, mille avaldumises on roll keskkonnal, eluviisil, pärilikkusel ja nende koosmõjudel. Haiguse tekkeriski võimalikult varajane ja täpne hindamine on ennetava ravi määramise nurgakiviks. Kasutusel olevates riskiskoorides ei ole võetud arvesse pärilikkust, kuigi selle osakaalu südame isheemiatõve kujunemisel hinnatakse 40–60%-ni.Uute meetodite jõudmine geneetiliste uuringute paletti on toonud kaasa enam kui 50 südame isheemiatõve avaldumise riskiga soetud geneetilise markeri tuvastamise. Leitud markerite kombineerimine võimaldab koostada polügeense riskiskoori, mis aitab seni klassikalistel riskiteguritel põhinenud riski hindamist ja ravi määramist oluliselt täpsemaks muuta. On ootuspärane, et lähitulevikus kuulub südame isheemiatõve tervikliku käsitluse hulka lisaks klassikalistele riskiteguritele ka geneetiliste markerite hindamine.Eesti Arst 2015; 94(9):522–52

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

An amendment to this paper has been published and can be accessed via a link at the top of the paper