Analysis of common and coding variants with cardiovascular disease in the Diabetes Heart Study.
Analysis of common and coding variants with cardiovascular disease in the Diabetes Heart Study.
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DOI：
10.1186/1475-2840-13-77
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发表时间：
2014-04-12
影响因子：
9.3
通讯作者：
Bowden DW
中科院分区：
文献类型：
--
作者：
Adams JN;Raffield LM;Freedman BI;Langefeld CD;Ng MC;Carr JJ;Cox AJ;Bowden DW
2型糖尿病（T2 DM）是一种主要的心血管疾病（CVD）危险因素。识别CVD的遗传风险因素对于了解疾病风险非常重要。两项最近的全基因组关联研究（GWAS）荟萃分析在基因组流行病学（CHARGE）联盟的心脏和衰老研究队列中检测到CVD相关基因座。在糖尿病心脏研究（DHS）中测试了CHARGE中识别的变体与CVD表型（包括血管钙化）和传统CVD风险因素的相关性（n = 1208; >80%的T2 DM受影响）。这包括来自DHS GWAS数据的36个基因分型或估算的单核苷酸多态性（SNP）。还从外显子组测序资源中鉴定了来自14个顶级CHARGE基因的28个编码SNP并进行了基因分型，还测试了来自DHS中Illumina HumanExome BeadChip基因型数据的沿着209个编码变体。计算遗传风险评分（GRS），以评估变异组合与CVD指标的相关性。多重比较校正后，没有一个CHARGE SNP与血管钙化相关（p < 0.0014）。多个SNP显示出与钙化的标称显著性，包括rs 599839（PSRC 1，p = 0.008）、rs646776（CELSR 2，p = 0.01）和rs 17398575（PIK 3CG，p = 0.009）。另外的COL 4A 2和CXCL 12 SNPs名义上与全因或心血管疾病引起的死亡率相关。三个SNP与血脂显著或名义上相关：rs3135506（Ser 19 Trp，APOA 5）与甘油三酯（TG）（p = 5×10−5），LDL（p = 0.00070），名义上与高密度脂蛋白（HDL）（p = 0.0054）; rs651821（5′UTR，APOA 5）与TG升高相关（p = 0.0008）; rs 13832449（剪接供体，APOC 3）与TG降低相关（p = 0.0015）。Rs 45456595（CDKN 2A，Gly 63 Arg）、rs 5128（APOC 3，3′UTR）和rs72650673（SH 2B 3，Glu 400 Lys）与CVD病史、亚临床CVD或CVD危险因素名义上相关（p < 0.010）。从外显子组芯片，rs3750103（CHN 2，His 204 Arg/His 68 Arg）与颈动脉内膜中层厚度（IMT）（p = 3.9×10−5），rs61937878（HAL，Val 549 Met）与肾下腹主动脉CP（AACP）（p = 7.1×10−5）。未加权GRS包含冠状动脉钙化斑块（CAC）SNP与既往CVD病史名义上相关（p = 0.033; OR = 1.09）。加权GRS包含SNPs与CAC相关，心肌梗死（MI）与MI病史相关（p = 0.026; OR = 1.15）。一般人群中亚临床CVD的遗传风险因素（CHARGE）与DHS中的T2 DM相关风险因素和CVD结局中度相关。
Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci. Variants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures. After correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5×10−5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5′UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3′UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9×10−5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1×10−5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15). Genetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.
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影响因子：
16.2
作者：
Agarwal S;Cox AJ;Herrington DM;Jorgensen NW;Xu J;Freedman BI;Carr JJ;Bowden DW
通讯作者：
Bowden DW
影响因子：
3.5
作者：
Pennacchio, LA;Olivier, M;Cohen, JC
通讯作者：
Cohen, JC
影响因子：
5.3
作者：
Cox AJ;Ng MC;Xu J;Langefeld CD;Koch KL;Dawson PA;Carr JJ;Freedman BI;Hsu FC;Bowden DW
通讯作者：
Bowden DW
DOI：
10.1073/pnas.84.2.512
发表时间：
1987-01-01
影响因子：
11.1
作者：
GRIFFIN, CA;EMANUEL, BS;MYERS, JC
通讯作者：
MYERS, JC
影响因子：
5
作者：
Carr, JJ;Crouse, JR;Burke, GL
通讯作者：
Burke, GL