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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EPrior studies indicate that genetic factors are important in the formation and rupture of intracranial aneurysms [Broderick JP et al. \u003Cem\u003EBMC Med Genet\u003C\/em\u003E 2005]. This article discusses the initial results from the Familial Intracranial Aneurysm Study II [FIA II; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00071565\u0026amp;atom=%2Fspmdc%2F12%2F1%2F18.atom\u0022\u003ENCT00071565\u003C\/a\u003E].\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EIschemia Clinical Trials Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EPrior studies indicate that genetic factors are important in the formation and rupture of intracranial aneurysms (IAs) [Broderick JP et al. \u003Cem\u003EBMC Med Genet\u003C\/em\u003E 2005]. Joseph P. Broderick, MD, University of Cincinnati, Cincinnati, Ohio, USA, presented initial results from the Familial Intracranial Aneurysm Study II [FIA II; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00071565\u0026amp;atom=%2Fspmdc%2F12%2F1%2F18.atom\u0022\u003ENCT00071565\u003C\/a\u003E].\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EMost deaths from subarachnoid hemorrhage (SAH) are due to rapid and massive brain injury from the initial bleeding; therefore, prevention of aneurysm formation is of paramount importance. Scientific evidence suggests that a genetic component plays an important role in the development of IAs, but the specific genes that are involved have not been identified.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe purposes of FIA II were to identify genes that may increase the risk of aneurysm development in the brain and to determine the effect of environmental factors, such as cigarette smoking and high blood pressure, on the expression of those genes.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EAccording to Dr. Broderick, approaches to dissect the genetic contribution to IAs have had mixed results. Linkage has been largely unsuccessful and, to this point, has not identified genetic variants that are associated with a risk of IA. Genomewide association studies (GWAS) have been somewhat successful, identifying several replicated genes with modest effect size (OR approximately 1.2 to 1.3), but again have yet to identify specific variants within these genes that are causally related to IA.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EWhole exome sequencing (WES) is a promising new approach that focuses on the coding region of the genome (the exome). This method is designed to find variants that affect protein structure or function, which are relatively common in Mendelian disorders. WES complements GWAS but is best suited to the identification of rare (r) variants of moderate to large effect size, while GWAS finds common variants that are typically of smaller effect size.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe authors reviewed families with a dense history of IA and available DNA. Seven families that met their criteria (two or more affected pairs of siblings, three or more family members with IA, or individuals with a confirmed IA but without a family history) were identified. DNA from affected individuals was sent to the Center for Inherited Disease Research (CIDR) (ie, 32 exomes from 32 individuals who were sequenced).\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EQuality filtering produced 93,635 single-nucleotide variants (SNVs). Biologic filters, which retain only the variants that meet the biological hypothesis (ie, rare exonic and amino acid-altering alleles that segregate in Mendelian fashion may contribute to IA pathology), reduced that figure to 871 SNVs. Variants were kept if they were observed in at least three affected individuals in a single family if the SNVs were autosomal dominant or recessive. Of the 871 SNVs, 31 were in the gene otology pathways of interest, such as collagen.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EVariants in two collagen genes were identified in at least three family members in one of these IA families (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). These variants are predicted to potentially cause abnormal function in these proteins. Collaborators from Poland have demonstrated that both of these genes are expressed differently in aneurysmal tissue as compared with vascular tissue of the middle meningeal arteries. \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E shows the presence of these variants in affected family members, all of whom were also smokers\u2014the most important environmental risk factor for IA. Further work will need to be done to see whether these gene variants are truly causal in the development of IA. Ultimately, the interplay of three factors\u2014environment (smoking, hypertension), common variants of individual small effects (GWAS), and rare variants with medium to large effects (WES)\u2014likely contributes to disease susceptibility.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Collagen Variants.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-781717648\u0022 data-figure-caption=\u0022Collagen Variants.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12717\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-10\u0022 class=\u0022first-child\u0022\u003ECollagen Variants.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from J. Broderick, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022One Family and Collagen.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-781717648\u0022 data-figure-caption=\u0022One Family and Collagen.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/1\/18\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12718\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EOne Family and Collagen.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from J. Broderick, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EThe identification of susceptibility genes, along with a better understanding of environmental interactions, such as cigarette smoking, may prevent the development of IAs and IA ruptures in people who are at risk for this condition.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/1\/18.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzniwq\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzniwq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}