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  • 1
    Keywords: MORTALITY ; RISK ; GENE ; MICE ; ASSOCIATION ; BLOOD-PRESSURE ; HYPERTENSION ; CARDIOVASCULAR-DISEASE ; METAANALYSIS ; HEART-FAILURE ; ADRENERGIC-RECEPTOR TRAFFICKING
    Abstract: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP
    Type of Publication: Journal article published
    PubMed ID: 21909110
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  • 2
    Keywords: DISEASE ; kidney ; TRIAL ; HEALTH ; OUTCOMES ; METAANALYSIS ; RENIN-ANGIOTENSIN SYSTEM ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIANTS ; D SUPPLEMENTATION
    Abstract: Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49 363), increased 25(OH) D concentration was associated with decreased systolic blood pressure (beta per 10% increase, -0.12 mm Hg, 95% CI -0.20.to -0.04; p=0.003) and reduced odds of hypertension (odds ratio [OR] 0.98, 95% CI 0.97-0.99; p=0.0003), but not with decreased diastolic blood pressure (beta per 10% increase, -0.02 mm Hg, -0.08 to 0.03; p=0.37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0.10 mm Hg in systolic blood pressure (-0.21 to -0.0001; p=0.0498) and a change of -0.08 mm Hg in diastolic blood pressure (-0.15 to -0.02; p=0.01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0.98, 0.96-0.99; p=0.001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH) D concentration was associated with a change of -0.29 mm Hg in diastolic blood pressure (-0.52 to -0.07; p=0.01), a change of -0.37 mm Hg in systolic blood pressure (-0.73 to 0.003; p=0.052), and an 8 1% decreased odds of hypertension (OR 0.92, 0.87-0.97; p=0.002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
    Type of Publication: Journal article published
    PubMed ID: 24974252
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  • 3
    Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to approximately 370,000 women, we identify 389 independent signals (P 〈 5 x 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain approximately 7.4% of the population variance in age at menarche, corresponding to approximately 25% of the estimated heritability. We implicate approximately 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 28436984
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  • 4
    Keywords: PATHWAY ; PATHWAYS ; DISEASE ; RISK ; PROTEIN ; ASSOCIATION ; VARIANTS ; DESIGN ; genetics ; meta-analysis ; inflammation ; interaction ; CORONARY-HEART-DISEASE ; METAANALYSIS ; metabolic syndrome ; myocardial infarction ; COMMON VARIANTS ; ALPHA-GENE ; CRP GENE ; EPIDEMIOLOGIC APPLICATIONS ; FRAMINGHAM ; GENETICALLY ISOLATED POPULATION ; genome-wide association study ; NETHERLANDS TWIN REGISTER
    Abstract: Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P 〈 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
    Type of Publication: Journal article published
    PubMed ID: 21300955
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  • 5
    ISSN: 1432-0983
    Keywords: mtDNA ; Recombination ; CMS ; N. sylvestris
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Two cytoplasmic male-sterile plants (CMSI and CMSII) were obtained by protoplast culture in Nicotiana sylvestris. Both plants showed large deletions (up to 50 kb) in their mitochondrial DNA. Restriction maps of the reorganized regions suggested that the deletions occurred via two homologous recombination events (rec. 1 and rec. 2) in the parental mitochondrial genome. With the exception of nad5, no mitochondrial DNA polymorphism could be detected between parental and CMS lines using different heterologous genes probes. A sequence homologous to the Oenothera nad5 mitochondrial gene was located close to the CMSI-specific rec. 2 region. Moreover, a cDNA probe corresponding to total mitochondrial RNA from the parent line was found to hybridize to mitochondrial DNA fragments involved in the rec. 1 event common to both CMS lines, suggesting that rec. 1 lies in a transcribed region. Cytoplasmic male sterility in the Nicotiana sylvestris CMS mutants could be due either to gene deletion or to a regulatory effect of such a deletion on mitochondrial gene expression, rather than to the presence of specific polypeptides as has been shown in the T cytoplasm of maize, or in CMS Petunia.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1617-4623
    Keywords: Protoplast culture ; Nuclear male sterility ; Mitochondrial DNA recombination ; Substoichiometric molecules ; Nicotiana sylvestris
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary ANicotiana sylvestris plant regenerated from protoplast culture was found to be mutated in both the mitochondrial (mt) and nuclear genomes. The novel mt DNA organization, called U, is due to the amplification of recombinant substoichiometric DNA sequences that preexist in the parent line. The recombination event involves two 404 by repeats, which hybridize to a 2.1 kb transcript. Although the sequence of both repeats was not altered by the recombination, an additional transcript of 2.5 kb was detected in U mitochondria. In addition to this mitochondrial reorganization, the protoclone carried a recessive nuclear mutation conferring male sterility (ms4). A possible role ofms4 in the appearance of the U mt DNA organization was investigated by introducing this gene into normalN. sylvestris cytoplasm. No mt DNA change could be found in homozygousms4/ms4 plants of the F2 generation.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1617-4623
    Keywords: Protoplast culture ; Nuclear and cytoplasmic male sterility ; Mitochondrial DNA and proteins ; Nicotiana sylvestris
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Male sterile plants appeared in the progeny of three fertile plants obtained after one cycle of protoplast culture from a fertile botanical line and two androgenetic lines ofNicotiana sylvestris. These plants showed the same foliar and floral abnormalities as the cytoplasmic male sterile (cms) mitochondrial variants obtained after two cycles of culture. We show that male sterility in these plants is controlled by three independent nuclear genes,ms1, ms2 andms3, while no changes can be seen in the mitochondrial genome. However, differences were found between thein organello mitochondrial protein synthesis patterns of male sterile and parent plants. Two reproducible changes were observed: the presence of a new 20 kDa polypeptide and the absence of a 40 kDa one. Such variations were described previously in mitochondrial protein synthesis patterns of the cms lines. Fertile hybrids of male sterile plants showed normal synthesis patterns. The male sterile plants are thus mutated in nuclear genes involved in changes observed in mitochondrial protein synthesis patterns.
    Type of Medium: Electronic Resource
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