Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.

Tulehdusta välittäviin sytokiineihin kuuluvan interleukiini 1β (IL-1β):n kohonneen systeemisen pitoisuuden on arveltu edesauttavan insuliiniresistenssin kehittymistä ja johtavan haiman β-solujen toimintahäiriöihin. IL-1β:n sisäsyntyisellä vastavaikuttajalla, interleukiini 1 reseptoriantagonistilla (IL-1RA), on puolestaan esitetty olevan suojaava rooli mainittujen fenotyyppien kehittymisessä päinvastaisten vaikutustensa ansiosta. IL-1RA:n suojaavan roolin havainnollistamiseksi työssä Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits tunnistettiin veren IL-1RA- pitoisuuteen assosioituvia geneettisiä variantteja, minkä jälkeen selvitettiin näiden yhteyttä glukoosi- ja insuliinimetaboliaan liittyvien muuttujien-, sekä immunologisten muuttujien pitoisuuksiin. Yhteensä 11 tutkimuskohorttia käsittäneessä genominlaajuisessa assosiaatioanalyysissä ja meta-analyysissä tunnistettiin kaksi toisistaan riippumatonta yhden nukleotidin polymorfismia (SNP), jotka assosioituivat itsenäisesti veren IL-1RA- pitoisuuteen: rs4251961 lokuksessa IL1RN (n = 13 955, P = 2,76e-21) ja rs6759676 lokuksen IL1F10 läheisyydessä (n = 13 994, P = 1,73e-17). Kyseisten varianttien yhteinen selitysosuus IL-1RA:n varianssista oli 2,0 %. Molemmat variantit assosioituivat mataliin C-reaktiivisen proteiinin (CRP) systeemisiin pitoisuuksiin. Tämän lisäksi rs6759676 assosioitui mataliin paastoinsuliinin pitoisuuksiin, sekä matalaan insuliiniresistenssiin (HOMA-IR). Tutkimuksemme osoittaa, että geneettisesti säädelty IL-1RA:n kohonnut pitoisuus saattaa suojata insuliiniresistenssin kehittymiseltä. Tulokset tukevat myös näkemystä elimistön tulehdusreaktion ja insuliiniresistenssin kehittymisen kausaliteetista, joskin lisätutkimukset ovat tarpeen ilmiön paremmaksi ymmärtämiseksi

Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.

Tulehdusta välittäviin sytokiineihin kuuluvan interleukiini 1β (IL-1β):n kohonneen systeemisen pitoisuuden on arveltu edesauttavan insuliiniresistenssin kehittymistä ja johtavan haiman β-solujen toimintahäiriöihin. IL-1β:n sisäsyntyisellä vastavaikuttajalla, interleukiini 1 reseptoriantagonistilla (IL-1RA), on puolestaan esitetty olevan suojaava rooli mainittujen fenotyyppien kehittymisessä päinvastaisten vaikutustensa ansiosta. IL-1RA:n suojaavan roolin havainnollistamiseksi työssä Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits tunnistettiin veren IL-1RA- pitoisuuteen assosioituvia geneettisiä variantteja, minkä jälkeen selvitettiin näiden yhteyttä glukoosi- ja insuliinimetaboliaan liittyvien muuttujien-, sekä immunologisten muuttujien pitoisuuksiin. Yhteensä 11 tutkimuskohorttia käsittäneessä genominlaajuisessa assosiaatioanalyysissä ja meta-analyysissä tunnistettiin kaksi toisistaan riippumatonta yhden nukleotidin polymorfismia (SNP), jotka assosioituivat itsenäisesti veren IL-1RA- pitoisuuteen: rs4251961 lokuksessa IL1RN (n = 13 955, P = 2,76e-21) ja rs6759676 lokuksen IL1F10 läheisyydessä (n = 13 994, P = 1,73e-17). Kyseisten varianttien yhteinen selitysosuus IL-1RA:n varianssista oli 2,0 %. Molemmat variantit assosioituivat mataliin C-reaktiivisen proteiinin (CRP) systeemisiin pitoisuuksiin. Tämän lisäksi rs6759676 assosioitui mataliin paastoinsuliinin pitoisuuksiin, sekä matalaan insuliiniresistenssiin (HOMA-IR). Tutkimuksemme osoittaa, että geneettisesti säädelty IL-1RA:n kohonnut pitoisuus saattaa suojata insuliiniresistenssin kehittymiseltä. Tulokset tukevat myös näkemystä elimistön tulehdusreaktion ja insuliiniresistenssin kehittymisen kausaliteetista, joskin lisätutkimukset ovat tarpeen ilmiön paremmaksi ymmärtämiseksi

Pharmacoepigenetics of hypertension : genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design

Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.Peer reviewe

MixFit : Methodology for Computing Ancestry-Related Genetic Scores at the Individual Level and Its Application to the Estonian and Finnish Population Studies

Ancestry information at the individual level can be a valuable resource for personalized medicine, medical, demographical and history research, as well as for tracing back personal history. We report a new method for quantitatively determining personal genetic ancestry based on genome-wide data. Numerical ancestry component scores are assigned to individuals based on comparisons with reference populations. These comparisons are conducted with an existing analytical pipeline making use of genotype phasing, similarity matrix computation and our addition-multidimensional best fitting by MixFit. The method is demonstrated by studying Estonian and Finnish populations in geographical context. We show the main differences in the genetic composition of these otherwise close European populations and how they have influenced each other. The components of our analytical pipeline are freely available computer programs and scripts one of which was developed in house.Peer reviewe

Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist–hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006–0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance

Gene x dietary pattern interactions in obesity : analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.Peer reviewe

Gene × dietary pattern interactions in obesity: Analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GR

The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies

Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms