Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies.
Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies.
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DOI：
10.1371/journal.pgen.0020069
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发表时间：
2006-05
期刊：
影响因子：
4.5
通讯作者：
Peltonen L
中科院分区：
文献类型：
--
作者：
Komulainen K;Alanne M;Auro K;Kilpikari R;Pajukanta P;Saarela J;Ellonen P;Salminen K;Kulathinal S;Kuulasmaa K;Silander K;Salomaa V;Perola M;Peltonen L
上游转录因子1（USF 1）是一种广泛表达的转录因子，控制着脂质和葡萄糖代谢中的几个关键基因。在USF 1调控的约40个基因中，有几个参与了心血管疾病（CVD）的分子发病机制。虽然USF 1基因已被证明在家族性混合型高脂血症的病因学中具有关键作用，该家族性混合型高脂血症易患早期CVD，但该基因在人群水平上作为CVD事件的危险因素的潜在作用尚未确定。在这里，我们报告了一项前瞻性遗传流行病学研究的结果，该研究在两个大型芬兰队列中对USF 1变异体、CVD和死亡率之间的关联进行了研究。在1992-2001年和1997-2003年随访的两个不同队列的前瞻性病例队列设计中，对暴露USF 1所有常见等位基因变体的单倍型标记单核苷酸多态性进行基因分型。在14，140名个体中，随访年总数为112，435年，其中2，225人根据病例队列研究策略选择进行基因分型。在调整传统的危险因素后，我们观察到USF 1与女性CVD和死亡率的相关性。在两个队列的联合分析中，USF 1风险单倍型的女性携带者发生CVD事件的风险增加2倍（风险比[HR] 2.02; 95%置信区间[CI] 1.16-3.53; p = 0.01），全因死亡风险增加（HR 2.52; 95% CI 1.46-4.35; p = 0.0009）。还鉴定了USF 1的推定保护性单倍型。我们的研究表明，在特殊家庭中发现的基因在人群水平上也很重要，这意味着USF 1的等位基因变异显著影响女性CVD甚至全因死亡率的预期风险。更好地表征导致心血管疾病（CVD）的分子事件需要阐明CVD的遗传背景。在基于家族的研究或病例对照研究中确定CVD候选基因后，需要基于人群的前瞻性研究来证明等位基因变异对人群水平CVD风险的任何潜在影响。本研究探讨了上游转录因子1（USF 1）基因的不同等位基因的作用，USF 1基因编码一种转录因子，最初与罕见的多个受影响个体的家族性混合型高脂血症有关。USF 1的产物调节许多脂质和葡萄糖代谢的基因，作者在大量人群中表明，USF 1的特定等位基因与女性CVD和全因死亡率的风险相关。这项研究意味着一个有趣的女性特定的风险效应，并应刺激在不同人群中的性别特异性CVD风险基因的额外研究。
Upstream transcription factor 1 (USF1) is a ubiquitously expressed transcription factor controlling several critical genes in lipid and glucose metabolism. Of some 40 genes regulated by USF1, several are involved in the molecular pathogenesis of cardiovascular disease (CVD). Although the USF1 gene has been shown to have a critical role in the etiology of familial combined hyperlipidemia, which predisposes to early CVD, the gene's potential role as a risk factor for CVD events at the population level has not been established. Here we report the results from a prospective genetic–epidemiological study of the association between the USF1 variants, CVD, and mortality in two large Finnish cohorts. Haplotype-tagging single nucleotide polymorphisms exposing all common allelic variants of USF1 were genotyped in a prospective case-cohort design with two distinct cohorts followed up during 1992–2001 and 1997–2003. The total number of follow-up years was 112,435 in 14,140 individuals, of which 2,225 were selected for genotyping based on the case-cohort study strategy. After adjustment for conventional risk factors, we observed an association of USF1 with CVD and mortality among females. In combined analysis of the two cohorts, female carriers of a USF1 risk haplotype had a 2-fold risk of a CVD event (hazard ratio [HR] 2.02; 95% confidence interval [CI] 1.16–3.53; p = 0.01) and an increased risk of all-cause mortality (HR 2.52; 95% CI 1.46–4.35; p = 0.0009). A putative protective haplotype of USF1 was also identified. Our study shows how a gene identified in exceptional families proves to be important also at the population level, implying that allelic variants of USF1 significantly influence the prospective risk of CVD and even all-cause mortality in females. Better characterization of molecular events resulting in cardiovascular disease (CVD) requires elucidation of genetic background of CVD. After a CVD candidate gene is identified in family-based studies or case-control studies, population-based prospective studies are needed to demonstrate any potential impact of allelic variants on the CVD risk at the population level. This study addresses the role of different alleles of the upstream transcription factor 1 (USF1) gene, encoding a transcription factor and originally associated with familial combined hyperlipidemia in rare families with multiple affected individuals. The product of USF1 regulates numerous genes of lipid and glucose metabolism, and the authors show in large population cohorts that specific alleles of USF1 are associated with the risk of CVD and all-cause mortality among females. The study implies an interesting female-specific risk effect, and should stimulate additional studies of the sex-specific CVD risk genes in different populations.
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