Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p &lt; 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Mineral composition in cognate inclusions in Late Miocene-Early Pliocene potassic lamprophyres with affinities to lamproites from the Denizli region, Western Anatolia, Turkey: Implications for uppermost mantle processes in a back-arc setting

Mineral assemblages of both cognate inclusions and host-lamprophyres with lamproitic affinity in Kocapinar district (Denizli), Western Anatolia, consist of phlogopitic mica, diopsidic clinopyroxene, K-feldspar, apatite, opaque and carbonates (calcite-dolomite). Two distinct types of cognate inclusions have been defined in host lamprophyres: clinopyroxene-rich (CCI) and clinopyroxene-phlogopite-rich (CPCI). Whole-rock compositions of inclusions show a near-primitive nature with high MgO (7.56-15.1wt.%), Cr (195-2270ppm), Ni (213-335ppm) contents and a potassic character [K 2O (2.0-2.8wt.%)&gt;Na 2O (0.4-2.2wt.%)]. Data imply that the inclusions crystallized from magmas formed by melting of phlogopite-bearing pyroxenites in a peridotitic mantle source, however, the presence of reverse-zoning in clinopyroxenes with salitic Fe-rich green cores in host-lamprophyres and CPCI inclusions suggest that the Denizli lavas represent mixtures of distinct (probably ultrapotassic and alkali basaltic) magmas. Estimated geobarometric constraints inferred from clinopyroxene compositions in CCI and CPCI inclusions indicate moderate pressures of pyroxene crystallization (ranging between 1.7 and 2.2GPa and corresponding to 53-70km depths) under low pressure magma fractionation. Results reveal that i) the origin of Denizli lamprophyres with transitional (between arc-type and intra-plate-type) geochemical signatures is consistent with a shallow level mantle petrogenesis, rather than a deep-seated origin related to mantle convection, ii) the source was a highly refractory and metasomatized peridotitic mantle present at the base of the lower crust, iii) metasomatic agents that affected the mantle lithosphere beneath Denizli region are distinct from those beneath other western Anatolia orogenic centers, and iv) the transitional character of Kocapinar (Denizli) lamprophyric rocks were probably formed as a result of either underplating or contamination of asthenospheric magma at the base of the mantle lithosphere, or assimilation of delaminated continental edge-lithospheric mantle via ascending asthenosphere. Denizli lamprophyres are interpreted to have formed during the formation of a basin/graben structure in the Latest Miocene-Early Pliocene, just after Late Miocene exhumation of Menderes massif. © 2012 Elsevier B.V

Lower hepatic fat is associated with improved insulin secretion in a high-risk prediabetes subphenotype during lifestyle intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat. All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p&lt;0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (pinteraction&lt;0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes. Prediabetes is a heterogenous condition comprising subphenotypes with different risks of diabetes and its complications (1). From its two key features, insulin resistance and impaired insulin secretion, insulin resistance can be clearly improved by lifestyle intervention (LI); however, it is not known, if LI can improve insulin secretion in specific subphenotypes of reduced insulin secretion (2). Recently, we described 6 clusters of prediabetic metabolism (1). Two of these clusters (cluster 3 and 5) have high risk of progression to diabetes. Another group (cluster 6) has an intermediate risk of diabetes as these persons are capable of compensating insulin resistance via hyperinsulinemia over years. In this study, we retrospectively stratified participants of a large multi-center study into these novel clusters of prediabetic metabolism (1) and investigated whether LI improved their insulin secretion and other glycemic traits

Analysis for genetic modifiers of disease severity in patients with long QT syndrome type 2.

BACKGROUND: -Considerable interest exists in the identification of genetic modifiers of disease severity in the Long QT Syndrome (LQTS) as their identification may contribute to refinement of risk stratification. METHODS AND RESULTS: -We searched for single nucleotide polymorphisms (SNPs) that modulate the QTc-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1,201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies (GWAS) in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, p=9.5&times;10(-8); rs12143842, p=4.8&times;10(-7); rs2880058, p=8.6&times;10(-7)) were strongly associated with the QTc-interval with marked effects (&gt;12ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454, OR=1.85 [95% CI, 1.32-2.59], p=3&times;10(-4)) and KCNQ1 (rs12576239; OR=1.84 [95% CI, 1.31-2.60], p=5&times;10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multi-locus genetic risk score (GRSNOS1AP) uncovered a strong linear relationship between GRSNOS1AP and the QTc-interval (p=4.2&times;10(-7)). Furthermore, patients with a GRSNOS1AP in the lowest quartile had a lower relative risk of cardiac events compared to patients in the other quartiles combined (p=0.039). CONCLUSIONS: -We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time we linked common genetic variation at KCNQ1 with risk for LQTS

Empagliflozin effectively lowers liver fat content in well-controlled Type 2 Diabetes: A randomized, double-blind, phase 4, placebo-controlled trial.

OBJECTIVE To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA(1c) 6.6 +/- 0.5% [49 +/- 10 mmol/mol], known disease duration 39 +/- 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change -2.5 kg [-3.7, -1.4]; P &lt; 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (-74 mol/L [-108, -42]; P &lt; 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P &lt; 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D