Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation.
Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation.
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DOI：
10.1016/j.atherosclerosis.2017.09.031
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发表时间：
2017-11
期刊：
影响因子：
5.3
通讯作者：
IMPROVE study group
中科院分区：
文献类型：
--
作者：
Strawbridge RJ;Silveira A;Hoed MD;Gustafsson S;Luan J;Rybin D;Dupuis J;Li-Gao R;Kavousi M;Dehghan A;Haljas K;Lahti J;Gådin JR;Bäcklund A;de Faire U;Gertow K;Giral P;Goel A;Humphries SE;Kurl S;Langenberg C;Lannfelt LL;Lind L;Lindgren CCM;Mannarino E;Mook-Kanamori DO;Morris AP;de Mutsert R;Rauramaa R;Saliba-Gustafsson P;Sennblad B;Smit AJ;Syvänen AC;Tremoli E;Veglia F;Zethelius B;Björck HM;Eriksson JG;Hofman A;Franco OH;Watkins H;Jukema JW;Florez JC;Wareham NJ;Meigs JB;Ingelsson E;Baldassarre D;Hamsten A;IMPROVE study group
胰岛素原相对于胰岛素水平的升高与亚临床动脉粥样硬化（通过颈动脉内膜中层厚度（cIMT）测量）相关，并且可以预测未来的心血管疾病（CVD），独立于既定的风险因素。胰岛素原与动脉粥样硬化和心血管疾病的联系机制尚不清楚。一项全基因组荟萃分析确定了9个与循环胰岛素原水平相关的基因座。使用胰岛素原相关的SNP，我们开始使用孟德尔随机化方法来检验胰岛素原在亚临床血管重塑中起因果作用的假设。我们研究了高CVD风险IMPROVE队列（n = 3345），该队列具有详细的生化表型和重复的、最先进的、高分辨率的颈动脉超声检查。使用Illumina Metabo和Immuno阵列进行基因分型，其中包括报告的胰岛素原相关基因座。2型糖尿病患者（n = 904）被排除在分析之外。线性回归用于识别胰岛素原相关的遗传变异。我们在15号染色体（rs 8029765）上发现了一个胰岛素原基因座，并在另外20,003名个体的数据中复制了该基因座。11-SNP评分，包括先前确定的和染色体15胰岛素原相关位点，与基线IMT平均值和IMT最大值（主要cIMT表型）显著负相关，但与进展指标无关。然而，MR-Eggers反驳了胰岛素原相关的11-SNP评分的任何显著影响，并且三种变体（包括rs 8029765）的非多效性SNP评分对基线或进展cIMT测量没有影响。我们发现了一个新的胰岛素原相关位点，并证明了虽然胰岛素原水平与cIMT指标相关，但胰岛素原本身不太可能对cIMT产生致病作用。15号染色体上一个新的胰岛素原相关位点的鉴定。引导染色体15 SNP rs 8029765影响肝脏中UNC 45 A的表达。胰岛素原对颈动脉内膜中层厚度的影响具有节段特异性。胰岛素原增加SNP评分对颈动脉内膜中层厚度的影响有限。胰岛素原不太可能对内膜中层厚度产生因果影响。
Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. Identification of a novel proinsulin-associated locus on chromosome 15. Lead chromosome 15 SNP rs8029765 influences expression of UNC45A in liver. Proinsulin effects on carotid intima-media thickness are segment-specific. Proinsulin-increasing SNP scores had limited effects on carotid intima-media thickness. Proinsulin is unlikely to have causal effects on intima-media thickness.
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影响因子：
5.4
作者：
Persson J;Strawbridge RJ;McLeod O;Gertow K;Silveira A;Baldassarre D;Van Zuydam N;Shah S;Fava C;Gustafsson S;Veglia F;Sennblad B;Larsson M;Sabater-Lleal M;Leander K;Gigante B;Tabak A;Kivimaki M;Kauhanen J;Rauramaa R;Smit AJ;Mannarino E;Giral P;Humphries SE;Tremoli E;de Faire U;Lind L;Ingelsson E;Hedblad B;Melander O;Kumari M;Hingorani A;Morris AD;Palmer CN;Lundman P;Öhrvik J;Söderberg S;Hamsten A;IMPROVE Study Group
通讯作者：
IMPROVE Study Group
影响因子：
--
作者：
Folkersen, Lasse;van't Hooft, Ferdinand;Eriksson, Per
通讯作者：
Eriksson, Per
影响因子：
37.8
作者：
Boquist, S;Ruotolo, G;Hamsten, A
通讯作者：
Hamsten, A
影响因子：
7.1
作者：
Eriksson, Johan G.
通讯作者：
Eriksson, Johan G.
影响因子：
7.7
作者：
Strawbridge, Rona J.;Dupuis, Josee;Florez, Jose C.
通讯作者：
Florez, Jose C.