King Faisal Heart Institute, MBC-16, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
Hum Genomics. 2013 Jun 5;7(1):15. doi: 10.1186/1479-7364-7-15.
The muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System.
Among the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03-1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02-1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01-1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02-1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01-1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (χ2 = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (χ2 = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (χ2 = 3.79; p = 0.052) and CCT (χ2 = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level.
Our results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events.
肌 Ras（MRAS）基因位于 3q22.3 染色体上，编码膜相关 Ras 小 GTP 酶蛋白家族的成员，该蛋白家族在包括细胞生长和分化在内的多种过程中充当信号转导物。它在心血管疾病中的作用尚未完全了解。在杂合家族性高胆固醇血症的初步研究中，我们确定了一个与冠状动脉疾病（CAD）早发相关的基因座位于 3q22.3 染色体上，并选择使用 MegaBACE DNA 分析系统对 MRAS 基因进行测序。在本研究中，我们使用 TaqMan 分析方法，通过 Applied Biosystems real-time Prism 7900HT Sequence Detection System，在 4650 名沙特裔接受血管造影的个体中，研究了该基因座上的七个单核苷酸多态性（SNP）与 CAD 及其与脂质代谢相关的风险特征之间的关联。
在所研究的 SNP 中，rs6782181（p=0.017）和 rs9818870T（p=0.009）在调整性别、年龄和其他混杂风险因素后与 CAD 相关。rs6782181_GG 还与肥胖（1764 例 vs. 2586 例）相关[1.16（1.03-1.30）；p=0.017]，高胆固醇血症（1686 例 vs. 2744 例）[1.23（1.02-1.47）；p=0.019]，高甘油三酯血症（1155 例 vs. 3496 例）[1.29（1.01-1.45）；p=0.043]和低高密度脂蛋白胆固醇（lHDL-chol）水平（1935 例 vs. 2401 例）[1.15（1.02-1.30）；p=0.023]相关，调整后。此外，rs253662_CT+TT[1.16（1.01-1.32）；p=0.030]与 lHDL-chol 水平相关。有趣的是，rs253662（p=0.014）和 rs6782181（p=0.019）对获得高 LDL 胆固醇（hLDL-chol）水平具有保护作用（p=0.014），而 rs1720819 对 CAD 具有类似的影响（p<0.0001）。更重要的是，从研究的 SNP 构建的 7 个碱基对的单倍型 ACCTGAC（χ2=7.66；p=0.0056）、其 6 个碱基对的衍生物 CCTGAC（χ2=6.90；p=0.0086）和几个其他较短的衍生物与肥胖相关。hLDL-chol 与 CTAA（χ2=3.79；p=0.052）和 CCT（χ2=4.32；p=0.038）较弱相关，而其他几个单倍型对肥胖和 hLDL-chol 水平都有保护作用。
我们的研究结果表明，MRAS 基因的基因组座赋予了 CAD、肥胖和脂质代谢异常的风险，并指出了该基因座可能涉及其他基因或调节元件，而不是 M-Ras 蛋白功能的改变，导致了这些事件的发生。
