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Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population 总被引:6,自引:0,他引:6
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Helgadottir A Gretarsdottir S St Clair D Manolescu A Cheung J Thorleifsson G Pasdar A Grant SF Whalley LJ Hakonarson H Thorsteinsdottir U Kong A Gulcher J Stefansson K MacLeod MJ 《American journal of human genetics》2005,76(3):505-509
Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases. 相似文献
2.
Genes contributing to risk for common forms of stroke 总被引:4,自引:0,他引:4
Gulcher JR Gretarsdottir S Helgadottir A Stefansson K 《Trends in molecular medicine》2005,11(5):217-224
The quest for disease genes that confer risk for stroke is now being undertaken using three complementary approaches. Positional cloning using rare Mendelian phenocopies of stroke has found genes that contribute to rare forms of stroke but, so far, not to the common forms of stroke. Candidate-gene case-control association studies using the common forms of stroke have found suggestive associations of modest effect. However, positional cloning using hundreds of Icelandic families affected by the common forms of stroke has recently found two genes conferring substantial risk for ischemic stroke that have apparently been confirmed in the USA and other European populations. Both genes encode enzymes, phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (FLAP), which suggest novel treatment strategies for stroke prevention. 相似文献
3.
Bown MJ Jones GT Harrison SC Wright BJ Bumpstead S Baas AF Gretarsdottir S Badger SA Bradley DT Burnand K Child AH Clough RE Cockerill G Hafez H Scott DJ Futers S Johnson A Sohrabi S Smith A Thompson MM van Bockxmeer FM Waltham M Matthiasson SE Thorleifsson G Thorsteinsdottir U Blankensteijn JD Teijink JA Wijmenga C de Graaf J Kiemeney LA Assimes TL McPherson R;CARDIoGRAM Consortium;Global BPgen Consortium;DIAGRAM Consortium;VRCNZ Consortium Folkersen L Franco-Cereceda A Palmen J Smith AJ 《American journal of human genetics》2011,89(5):619-627
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10−5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10−5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10−10, odds ratio 1.15 [1.10–1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04–1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 相似文献
4.
In the sperm whale (Physeter macrocephalus) two different repeat types (A
and B) of the common cetacean DNA satellite were identified. The evolution
of each group of repeats appears to be independent from that of the other.
The sequence similarity between the two groups is less than the similarity
between group A and repeats of the satellite in related whale species. The
systematic relationship within and between the families Physeteridae (sperm
whales) and Ziphiidae (beaked whales) was addressed by both sequence
analysis of the satellite and comparisons with the families Delphinidae and
Phocoenidae. The mysticete blue whale (Balaenoptera musculus) was used as
an outgroup in the comparisons. The molecular phylogeny, when
maximum-parsimony analysis and the neighbor-joining method were used,
grouped together species of each family. At the family level the ziphiids
grouped closet to the families Phocoenidae and Delphinidae. The
similarities between the common cetacean satellite of the blue whale and
the sperm whale were greater than those between the blue whale and the
other odontocetes included, suggesting that the evolution of the satellite
is slower in the sperm whale than in the other odontocetes.
相似文献
5.
Arnason U Gullberg A Gretarsdottir S Ursing B Janke A 《Journal of molecular evolution》2000,50(6):569-578
Extant cetaceans are systematically divided into two suborders: Mysticeti (baleen whales) and Odontoceti (toothed whales).
In this study, we have sequenced the complete mitochondrial (mt) genome of an odontocete, the sperm whale (Physeter macrocephalus), and included it in phylogenetic analyses together with the previously sequenced complete mtDNAs of two mysticetes (the
fin and blue whales) and a number of other mammals, including five artiodactyls (the hippopotamus, cow, sheep, alpaca, and
pig). The most strongly supported cetartiodactyl relationship was: outgroup,((pig, alpaca),((cow, sheep),(hippopotamus,(sperm
whale,(baleen whales))))). As in previous analyses of complete mtDNAs, the sister-group relationship between the hippopotamus
and the whales received strong support, making both Artiodactyla and Suiformes (pigs, peccaries, and hippopotamuses) paraphyletic.
In addition, the analyses identified a sister-group relationship between Suina (the pig) and Tylopoda (the alpaca), although
this relationship was not strongly supported. The paleontological records of both mysticetes and odontocetes extend into the
Oligocene, suggesting that the mysticete and odontocete lineages diverged 32–34 million years before present (MYBP). Use of
this divergence date and the complete mtDNAs of the sperm whale and the two baleen whales allowed the establishment of a new
molecular reference, O/M-33, for dating other eutherian divergences. There was a general consistency between O/M-33 and the
two previously established eutherian references, A/C-60 and E/R-50. Cetacean (whale) origin, i.e., the divergence between
the hippopotamus and the cetaceans, was dated to ≈55 MYBP, while basal artiodactyl divergences were dated to ≥65 MYBP. Molecular
estimates of Tertiary eutherian divergences were consistent with the fossil record.
Received: 12 July 1999 / Accepted: 28 February 2000 相似文献
6.
Palsdottir A Helgason A Palsson S Bjornsson HT Bragason BT Gretarsdottir S Thorsteinsdottir U Olafsson E Stefansson K 《PLoS genetics》2008,4(6):e1000099
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease. 相似文献
7.
Styrkarsdottir U Halldorsson BV Gudbjartsson DF Tang NL Koh JM Xiao SM Kwok TC Kim GS Chan JC Cherny S Lee SH Kwok A Ho S Gretarsdottir S Kostic JP Palsson ST Sigurdsson G Sham PC Kim BJ Kung AW Kim SY Woo J Leung PC Kong A Thorsteinsdottir U Stefansson K 《PloS one》2010,5(10):e13217
Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10−9), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10−5), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10−5), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10−5), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians. 相似文献
8.
Localization of a susceptibility gene for common forms of stroke to 5q12 总被引:21,自引:0,他引:21
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Gretarsdottir S Sveinbjörnsdottir S Jonsson HH Jakobsson F Einarsdottir E Agnarsson U Shkolny D Einarsson G Gudjonsdottir HM Valdimarsson EM Einarsson OB Thorgeirsson G Hadzic R Jonsdottir S Reynisdottir ST Bjarnadottir SM Gudmundsdottir T Gudlaugsdottir GJ Gill R Lindpaintner K Sainz J Hannesson HH Sigurdsson GT Frigge ML Kong A Gudnason V Stefansson K Gulcher JR 《American journal of human genetics》2002,70(3):593-603
Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9×10-6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke. 相似文献
9.
Jarngerdur Gretarsdottir Asa L. Aradottir Vigdis Vandvik Einar Heegaard H. J. B. Birks 《Restoration Ecology》2004,12(2):268-278
The long‐term effects (20–45 years) of reclamation treatments on plant succession are examined at two localities in Iceland that were fertilized and seeded from 1954 to 1979 with perennial grasses or annual grasses, or left untreated. The areas that underwent reclamation treatments had significantly higher total plant cover (7–100%) than the untreated control plots (<5%), and floristic composition was usually significantly different between treated and untreated plots. Dwarf‐shrubs (Calluna vulgaris and Empetrum nigrum), bryophytes, biological soil crust, grasses, and shrubs characterized the vegetation in the treated plots, but low‐growing herbs that have negligible effects on the environment, such as Cardaminopsis petraea and Minuartia rubella, and grasses characterized the control plots. The seeded grass species had declined (<10%, the perennials) or disappeared (the annuals) but acted as nurse species that facilitated the colonization of native plants. It seems that by seeding, some factors that limit plant colonization were overcome. Soil nutrients, vegetation cover, litter, and biological soil crust were greater in the treated areas than the control plots. This may have enhanced colonization through an increase in soil stability and fertility, increased availability of safe microsites, increased moisture, and the capture of wind‐blown seeds. This study demonstrates the importance of looking at the long‐term effects of reclamation treatments to understand their impact on vegetation succession. 相似文献
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