Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.
Genome-wide association study identifies two novel regions at 11p15.5-p13 and 1p31 with major impact on acute-phase serum amyloid A.
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DOI：
10.1371/journal.pgen.1001213
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发表时间：
2010-11-18
期刊：
影响因子：
4.5
通讯作者：
Gieger C
中科院分区：
文献类型：
--
作者：
Marzi C;Albrecht E;Hysi PG;Lagou V;Waldenberger M;Tönjes A;Prokopenko I;Heim K;Blackburn H;Ried JS;Kleber ME;Mangino M;Thorand B;Peters A;Hammond CJ;Grallert H;Boehm BO;Kovacs P;Geistlinger L;Prokisch H;Winkelmann BR;Spector TD;Wichmann HE;Stumvoll M;Soranzo N;März W;Koenig W;Illig T;Gieger C
急性期血清淀粉样蛋白A（A-SAA）水平升高可引起淀粉样变性，是动脉粥样硬化及其临床并发症、2型糖尿病以及各种恶性肿瘤的危险因素。为了研究A-SAA水平的遗传基础，我们在三项基于人群的研究（KORA，TwinsUK，Sorbs）和一项前瞻性病例队列研究（LURIC）中对基线A-SAA浓度进行了首次全基因组关联研究，共包括4，212名欧洲血统的参与者，并在11p15.5-p13和1 p31处确定了两个新的遗传易感区域。11 p15.5-p13（rs 4150642; p = 3.20×10−111）区域包含血清淀粉样蛋白A1（SAA 1）和相邻的一般转录因子2 H1（GTF 2 H1）、赫-普综合征5（HPS 5）、乳酸脱氢酶A（LDHA）和乳酸脱氢酶C（LDHC）。 该区域解释了我们数据中A-SAA水平总变异的10.84%，占总估计遗传力的18.37%。第二个区域在1 p31（rs 12753193; p = 1.22×10−11）处包含瘦素受体（LEPR）基因，并且在先前的研究中发现与CRP和纤维蛋白原相关。 我们的研究结果表明11p15.5-p13区域在调节基线A-SAA水平中的关键作用，并为1 p31区域在炎症过程中的重要性以及A-SAA、瘦素和其他急性期蛋白之间的密切相互作用提供了确凿的证据。急性期血清淀粉样蛋白A（A-SAA）水平升高，急性炎症状态的敏感标志物，具有高遗传性估计，导致淀粉样变性，是动脉粥样硬化及其临床并发症，2型糖尿病，以及各种恶性肿瘤的危险因素。这项研究描述了第一个关于基线A-SAA浓度的全基因组关联研究。在对总计4，212名欧洲血统参与者的四次全基因组扫描的荟萃分析中，我们在11号和1号染色体上发现了两个与基线A-SAA浓度相关的新的遗传易感区域。11号染色体区域包含血清淀粉样蛋白A1基因和邻近基因，并解释了总估计遗传率的高百分比。1号染色体区域是已知的炎症遗传易感性区域。总之，我们确定了一个区域，这似乎是在A-SAA水平的调节中的关键重要性，并代表了一个新的潜在目标，为相关的临床实体的调查。此外，我们的研究结果表明A-SAA和其他炎症蛋白之间存在密切的相互作用，以及已知的遗传易感性区域在炎症过程中的作用更大，因为它在过去一直被认为是。
Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20×10−111) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22×10−11) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins. An elevated level of acute-phase serum amyloid A (A-SAA), a sensitive marker of the acute inflammatory state with high heritability estimates, causes amyloidosis and is a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. This study describes the first genome-wide association study on baseline A-SAA concentrations. In a meta-analysis of four genome-wide scans totalling 4,212 participants of European descent, we identified two novel genetic susceptibility regions on chromosomes 11 and 1 to be associated with baseline A-SAA concentrations. The chromosome 11 region contains the serum amyloid A1 gene and the adjacent genes and explains a high percentage of the total estimated heritability. The chromosome 1 region is a known genetic susceptibility region for inflammation. Taken together, we identified one region, which seems to be of key importance in the regulation of A-SAA levels and represents a novel potential target for the investigation of related clinical entities. In addition, our findings indicate a close interplay between A-SAA and other inflammatory proteins, as well as a larger role of a known genetic susceptibility region for inflammatory processes as it has been assumed in the past.
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