Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits.
Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits.
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DOI：
10.1161/circgenetics.111.961482
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发表时间：
2012-04-01
期刊：
影响因子：
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通讯作者：
Salomaa V
中科院分区：
文献类型：
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作者：
Kristiansson K;Perola M;Tikkanen E;Kettunen J;Surakka I;Havulinna AS;Stancáková A;Barnes C;Widen E;Kajantie E;Eriksson JG;Viikari J;Kähönen M;Lehtimäki T;Raitakari OT;Hartikainen AL;Ruokonen A;Pouta A;Jula A;Kangas AJ;Soininen P;Ala-Korpela M;Männistö S;Jousilahti P;Bonnycastle LL;Järvelin MR;Kuusisto J;Collins FS;Laakso M;Hurles ME;Palotie A;Peltonen L;Ripatti S;Salomaa V
全基因组关联(GWA)研究已经确定了代谢综合征(METS)组分性状的几个易感基因座，但在识别作为一个实体的代谢综合征易感基因座方面取得了不同程度的成功。我们在四个芬兰队列中进行了一项关于蛋氨酸及其成分特征的GWA研究，该队列包括2637例蛋氨酸病例和7927名对照，均未患糖尿病，并在具有转录组和基于核磁共振的代谢组学数据的独立样本中跟踪最高基因座。此外，我们使用因子分析测试了与多个蛋氨酸组成性状相关的基因座，并建立了蛋氨酸的遗传风险分数。已知的ApoA1/C3/A4/A5基因聚集区(SNP Rs964184)与所有研究样本中的蛋氨酸相关(Meta分析P=7.23×10−9)。血清代谢物分析进一步支持了这种关联，rs964184与各种极低密度脂蛋白、甘油三酯和高密度脂蛋白代谢物相关(P=0.024-1.88×10−5)。在我们的GWA和因子分析中，重复了22个先前确定的针对单个蛋氨酸组成性状的易感基因座。其中大多数与脂类表型有关，没有与两种或两种以上不相关的蛋氨酸成分相关的。遗传风险分数，即与METS个体特征相关的基因座上的等位基因数量计算出来的，与METS状态密切相关。我们的发现表明，来自脂代谢途径的基因在蛋氨酸综合征的遗传背景中起着关键作用。我们发现几乎没有证据表明多效性将血脂异常和肥胖与其他蛋氨酸组分特征，如高血压和糖耐量异常联系在一起。
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS. A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.