QTL mapping of rat blood pressure loci on RNO1 within a homologous region linked to human hypertension on HSA15

Fine-mapping of regions linked to the inheritance of hypertension is accomplished by genetic dissection of blood pressure quantitative trait loci (BP QTLs) in rats. The goal of the current study was to further fine-map two genomic regions on rat chromosome 1 with opposing blood pressure effects (BP QTL1b1 and BP QTL1b1a), the homologous region of which on human chromosome 15 harbors BP QTLs. Two new substrains were constructed and studied from the previously reported BP QTL1b1, one having significantly lower systolic BP by 17 mmHg than that of the salt-sensitive (S) rat (P = 0.007). The new limits of BP QTL1b1 were between 134.09 Mb and 135.40 Mb with a 43% improvement from the previous 2.31 Mb to the current 1.31 Mb interval containing 4 protein-coding genes (Rgma, Chd2, Fam174b, and St8sia2), 2 predicted miRNAs, and 4 lncRNAs. One new substrain was constructed and studied from the previously reported BPQTL1b1a having a significantly higher systolic BP by 22 mmHg (P = 0.006) than that of the S rat. The new limits of BPQTL1b1a were between 133.53 Mb and 134.52 Mb with a 32% improvement from the previous1.45 Mb to the current 990.21 Kb interval containing 1 protein-coding gene, Mctp2, and a lncRNA. The congenic segments of these two BP QTLs overlapped between 134.09 Mb and 134.52 Mb. No exonic variants were detected in any of the genes. These findings reiterate complexity of genetic regulation of BP within QTL regions, where elements beyond protein-coding sequences could be factors in controlling BP.

本研究通过对大鼠体内的血压数量性状基因座（blood pressure quantitative trait loci, BP QTLs）进行遗传解析，完成了高血压遗传相关区域的精细定位工作。本次研究的目标是进一步精细定位大鼠1号染色体上两个具有相反血压调控效应的基因组区域（BP QTL1b1与BP QTL1b1a），这两个区域在人类15号染色体上的同源区域同样存在血压QTL。
研究人员从已有报道的BP QTL1b1区域构建并验证了两个新的亚系，其中一个亚系的收缩压较盐敏感（S）大鼠低17 mmHg，差异具有统计学意义（P=0.007）。修正后的BP QTL1b1定位区间为134.09 Mb至135.40 Mb，相较此前2.31 Mb的区间，本次定位精度提升了43%，最终区间缩小至1.31 Mb，其中包含4个蛋白编码基因（Rgma、Chd2、Fam174b与St8sia2）、2个预测性微小RNA（miRNAs）以及4个长链非编码RNA（long non-coding RNAs, lncRNAs）。
研究人员还从已有报道的BP QTL1b1a区域构建并验证了一个新的亚系，该亚系的收缩压较盐敏感（S）大鼠高22 mmHg，差异具有统计学意义（P=0.006）。修正后的BP QTL1b1a定位区间为133.53 Mb至134.52 Mb，相较此前1.45 Mb的区间，本次定位精度提升了32%，最终区间缩小至990.21 Kb，其中包含1个蛋白编码基因Mctp2以及1个长链非编码RNA。
这两个血压QTL的同源导入片段的重叠区域为134.09 Mb至134.52 Mb。所有检测基因均未发现外显子变异。本研究结果再次印证了QTL区域内血压遗传调控的复杂性，提示除蛋白编码序列外的其他遗传元件同样可能参与血压的调控过程。