Ma Man Chun John, Pettus Janette M, Jakoubek Jessica A, Traxler Matthew G, Clark Karen C, Mennie Amanda K, Kwitek Anne E
Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
Iowa Institute of Human Genetics, University of Iowa, Iowa City, Iowa, United States of America.
PLoS One. 2017 Aug 8;12(8):e0182650. doi: 10.1371/journal.pone.0182650. eCollection 2017.
Hypertension is a major risk factor for cardiovascular disease, Type 2 diabetes, and end organ failure, and is often found concomitant with disorders characteristic of the Metabolic Syndrome (MetS), including obesity, dyslipidemia, and insulin resistance. While the associated features often occur together, the pathway(s) or mechanism(s) linking hypertension in MetS are not well understood. Previous work determined that genetic variation on rat chromosome 17 (RNO17) contributes to several MetS-defining traits (including hypertension, obesity, and dyslipidemia) in the Lyon Hypertensive (LH) rat, a genetically determined MetS model. We hypothesized that at least some of the traits on RNO17 are controlled by a single gene with pleiotropic effects. To address this hypothesis, consomic and congenic strains were developed, whereby a defined fragment of RNO17 from the LH rat was substituted with the control Lyon Normotensive (LN) rat, and MetS phenotypes were measured in the resultant progeny. Compared to LH rats, LH-17LN consomic rats have significantly reduced body weight, blood pressure, and lipid profiles. A congenic strain (LH-17LNc), with a substituted fragment at the distal end of RNO17 (17q12.3; 74-97 Mb; rn4 assembly), showed differences from the LH rat in blood pressure and serum total cholesterol and triglycerides. Interestingly, there was no difference in body weight between the LH-17LNc and the parental LH rat. These data indicate that blood pressure and serum lipids are regulated by a gene(s) in the distal congenic interval, and could be due to pleiotropy. The data also indicate that body weight is not determined by the same gene(s) at this locus. Interestingly, only two small haplotypes spanning a total of approximately 0.5 Mb differ between the LH and LN genomes in the congenic interval. Genes in these haplotypes are strong candidate genes for causing dyslipidemia in the LH rat. Overall, MetS, even in a simplified genetic model such as the LH-17LN rat, is likely due to both independent and pleiotropic gene effects.
高血压是心血管疾病、2型糖尿病和终末器官衰竭的主要危险因素，且常与代谢综合征（MetS）的特征性病症同时出现，这些病症包括肥胖、血脂异常和胰岛素抵抗。虽然这些相关特征常常共同出现，但连接MetS中高血压的途径或机制尚未完全明确。先前的研究确定，大鼠17号染色体（RNO17）上的基因变异导致了Lyon高血压（LH）大鼠出现多种MetS定义特征（包括高血压、肥胖和血脂异常），LH大鼠是一种基因决定的MetS模型。我们推测，RNO17上的至少某些特征由具有多效性的单个基因控制。为了验证这一假设，我们培育了代换系和近交系，即将LH大鼠RNO17的一个特定片段替换为对照Lyon正常血压（LN）大鼠的相应片段，并对所得后代的MetS表型进行测量。与LH大鼠相比，LH-17LN代换系大鼠的体重、血压和血脂水平显著降低。一个近交系（LH-17LNc），其RNO17远端（17q12.3；74-97 Mb；rn4组装）的片段被替换，该近交系大鼠在血压、血清总胆固醇和甘油三酯方面与LH大鼠存在差异。有趣的是，LH-17LNc与亲代LH大鼠的体重没有差异。这些数据表明，血压和血脂由近交系区间远端的一个或多个基因调控，这可能是由于基因的多效性。数据还表明，该位点的相同基因并不决定体重。有趣的是，在近交系区间，LH和LN基因组之间仅存在两个总共约0.5 Mb的小单倍型差异。这些单倍型中的基因是导致LH大鼠血脂异常的有力候选基因。总体而言，即使在像LH-17LN大鼠这样的简化遗传模型中，MetS可能是由独立基因效应和多效性基因效应共同导致的。
