network-based analysis of the sphingolipid metabolism in hypertension

analisis berbasis jaringan metabolisme sfingolipid pada hipertensi

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ID: 234382
2015
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Abstract
Common diseases like essential hypertension or diabetes mellitus are complex as they are polygenic in nature, such that each genetic variation only has a small influence on the disease. Genes operates in integrated networks providing the blue-print for all biological processes and conditional of the complex genotype determines the state and dynamics of any trait, which may be modified to various extent by non-genetic factors. Thus, diseases are heterogenous ensembles of conditions with a common endpoint. Numerous studies have been performed to define genes of importance for a trait or disease, but only a few genes with small effect have been identified. The major reasons for this modest progress is the unresolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition. Here, a two-step procedure is presented in which physiological heterogeneity is disentangled and genetic effects are analysed by variance decomposition of genetic interactions and by an information theoretical approach including 162 single nucleotide polymorphisms (SNP) in 84 genes in the sphingolipid metabolism and related networks in blood pressure regulation. As expected, almost no genetic main effects were detected. In contrast, two-gene interactions established the entire sphingolipid metabolic and related genetic network to be highly involved in the regulation of blood pressure. The pattern of interaction clearly revealed that epistasis does not necessarily reflects the topology of the metabolic pathways i.e. the flow of metabolites. Rather, the enzymes and proteins are integrated in complex cellular substructures where communication flows between the components of the networks, which may be composite in structure. The heritabilities for diastolic and systolic blood pressure were estimated to be 0.63 +/- 0.01 , which may in fact be the maximum heritabilities of these traits.
Penyakit umum seperti hipertensi esensial atau diabetes melitus bersifat kompleks karena secara alami merupakan penyakit poligenik, sehingga setiap variasi genetik hanya memberikan pengaruh kecil terhadap penyakit tersebut. Gen beroperasi dalam jaringan terintegrasi yang menyediakan cetak biru bagi semua proses biologis, dan kondisi genotipe yang kompleks menentukan keadaan serta dinamika dari setiap sifat (*trait*), yang dapat dimodifikasi dalam berbagai tingkatan oleh faktor non-genetik. Dengan demikian, penyakit merupakan kumpulan heterogen dari berbagai kondisi dengan titik akhir yang sama. Banyak penelitian telah dilakukan untuk mengidentifikasi gen-gen penting bagi suatu sifat atau penyakit, tetapi hanya sedikit gen dengan efek kecil yang berhasil diidentifikasi. Alasan utama dari kemajuan yang terbatas ini adalah heterogenitas regulasi tekanan darah yang belum terurai serta keterbatasan pendekatan monogenik yang umum digunakan dalam menangkap efek genetik pada kondisi poligenik. Dalam studi ini, disajikan suatu prosedur dua langkah untuk menguraikan heterogenitas fisiologis dan menganalisis efek genetik melalui dekomposisi varians dari interaksi genetik serta pendekatan teori informasi yang mencakup 162 polimorfisme nukleotida tunggal (*single nucleotide polymorphism*/SNP) pada 84 gen dalam metabolisme sfingolipid dan jaringan terkait pada regulasi tekanan darah. Sesuai dugaan, hampir tidak ditemukan adanya efek utama genetik yang terdeteksi. Sebaliknya, interaksi dua gen membuktikan bahwa keseluruhan jaringan genetik metabolisme sfingolipid dan jaringan terkait sangat terlibat dalam regulasi tekanan darah. Pola interaksi ini secara jelas mengungkapkan bahwa epistasis tidak selalu mencerminkan topologi jalur metabolisme, yaitu aliran metabolit. Enzim dan protein justru terintegrasi dalam substruktur seluler kompleks tempat terjadinya aliran komunikasi antar-komponen jaringan, yang strukturnya dapat bersifat komposit. Heritabilitas untuk tekanan darah diastolik dan sistolik diperkirakan sebesar 0,63 +/- 0,01, yang sebenarnya mungkin merupakan heritabilitas maksimum dari sifat-sifat tersebut.
Reference Key
efenger2015frontiersnetwork-based Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Mogens eFenger
Journal chemical record (new york, ny)
Year 2015
DOI
10.3389/fgene.2015.00084
URL
http://journal.frontiersin.org/Journal/10.3389/fgene.2015.00084/full
Keywords
hypertension mutual information sphingolipids epistasis

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