BIOCHEMISTRY AND GENETICS OF HYPERTENSION

总的目标是确定基因座， 大鼠的血压差异。 因为高血压在 动物和人类是一种复杂的多基因疾病， 在可以控制繁殖的动物中遗传学上的理解是可能的。 我们把遗传学研究的重点放在近交系达尔的候选基因上 盐高敏感型（S）和近交系达尔盐高型 抗性（R）大鼠。在DNA水平上寻找遗传多态性， 或接近遗传位点的思想（根据其已知的生化/ 生理作用）与血压调节相关。 它 确定是否血压和基因型的成分， 候选基因座共分离的群体来自S和 R或S和其他对照“对照”菌株。 如果是这样的话， 候选基因座（或未知的紧密连锁基因座）作为导致 血压的遗传差异 DNA序列分析 然后需要涉及的候选等位基因来找到结构上的 可能对以下方面产生功能影响的差异 血压. 如果共分离是负的，则候选基因座可以是 实验结果表明， 有足够的统计能力，几个不同的人群， 研究了 对于与血压共分离的候选基因座，结果将 通过同类菌株的生产得到证实。 低血 来自对照菌株的压力等位基因被转移到S基因 背景通过重复回交的标准遗传技术， 对低血压等位基因进行反向选择。 同类的 S品系的血压应低于亲本S品系， 事实上，转移的等位基因降低了血压。 “双同源” 菌株将通过杂交两个单一的同类产生， 在S基因的不同位点携带低血压基因 背景 双床与单床血压比较 与亲本S菌株的同源性将允许定义 相关基因座之间的相互作用。 初步研究表明， 相互作用是非常高水平的基因调控所必需的， 血压要达到。 很可能，理解这样的 复杂性需要动物繁殖技术，最初不能 在与人类的合作中被解开。

The overall objective is to identify-the loci which cause genetic differences in blood pressure in the rat. Because hypertension in animals and humans is a complex polygenic disease it can best be understood genetically in animals where controlled breeding is possible. We have focused our genetic studies on candidate genes in the inbred Dahl salt-hypertension sensitive (S) and inbred Dahl salt-hypertension resistant (R) rats. Genetic polymorphisms are sought at the DNA level in or near genetic loci thought (on the basis of their known biochemical/ physiological actions) to be relevant to blood pressure regulation. It is determined if a component of blood pressure and genotypes at the candidate locus cosegregate in populations derived from crosses of S and R, or S and other contrasting "control" strains. If so, this establishes the candidate locus (or an unknown closely linked locus) as a cause for genetic differences in blood pressure. DNA sequence analysis of the candidate alleles involved is then required to find a structural difference that is likely to have functional consequences with regard to blood pressure. If cosegregation is negative the candidate locus can be rejected as causing blood pressure differences provided the experiments have adequate statistical power and several different populations are studied. For candidate loci which cosegregate with blood pressure, the result will be con-firmed by the production of congenic strains. The low blood pressure allele from a control strain is transferred to the S genetic background by the standard genetic technique of repeated backcrossing to S with counter selection for the low blood pressure allele. The congenic S strain should have lower blood pressure than the parental S strain if in fact the allele transferred lowers blood pressure. "Double congenic" strains will be produced by crossing two single congenics each of which carries genes for low blood pressure at different loci on the S genetic background. Comparisons of blood pressure among double and single congenics with the parental S strain will allow definition of interactions between the loci involved. Initial studies show that such interactions are required for really high levels of genetically regulated blood pressure to be achieved. It is likely that understanding such complexity requires animal breeding techniques, and cannot be initially unraveled in work with humans.