Study for genetic determinants in height growth and body proportion

身高的增长是由基因决定的，大约60%的这个过程是通过长骨的软骨内骨形成来实现的。PTH/PTHrP受体（PTHR1）介导甲状旁腺激素相关肽（PTHrP）信号，PTHrP是软骨内骨形成的重要调节因子。在功能研究中，PTHR1基因P3启动子AAAG6多态性在正常日本人和白种人的3、5、6、7、8倍重复数中启动子活性最低。在青壮年和初中生女性受试者中，具有AAAG6多态性的群体比其他群体高，PTHR1水平可能较低。这种启动子多态性是决定身高生长个体差异的因素之一。以脊髓踝距（SMD）评价的上/下节段长度比（U/L比）的体比例在不同AAAG重复次数组间无显著差异。Gsα蛋白介导PTHR1的胞内信号。Gsα蛋白的突变导致假甲状旁腺功能减退症Ia型伴身材矮小。由于该基因调控区域的DNA甲基化可能影响Gsα的量，我们研究了假性甲状旁腺功能减退症Ia型和Ib型患者Gsα基因5'调控区域的甲基化模式，但DNA甲基化异常仅在Ib型患者中发现，且不伴有身材矮小。在本研究中，我们建立了新的U/L比标准。这个标准在评估生长障碍儿童时是有用的。我们检测了峰值骨量受试者PTHR1多态性与骨密度没有关系，但AAAG6组骨吸收标志物较低。这可能与衰老导致的骨矿物质流失率有关，值得进一步研究。

Height growth is genetically determined and approximately 60 % of this process is achieved by endochondral bone formation of long bones. The PTH/PTHrP receptor (PTHR1) mediates the signal of parathyroid hormone-related peptide (PTHrP) which is an important regulator of endochondral bone formation. In functional study AAAG6 polymorphism in P3 promoter of PTHR1 gene have the lowest promoter activity among 3, 5, 6, 7 and 8 times repeat numbers which are found in normal Japanese and Caucasian population. In the female subjects of young adults and junior high school students, the group having AAAG6 polymorphism, which might have low PTHR1 level, was taller than other groups. This promoter polymorphism is one of the factors specifying the individual difference of height growth. The body proportion assessed by the upper / lower segment length ratio (U/L ratio) by means of spina malleolar distance (SMD) was not different between groups with various repeat number of AAAG. Gsα protein mediates the intracellular signal of PTHR1. The mutations in Gsα protein causes pseudohypoparathyroidism type Ia accompanied by short stature. Since the DNA methylation in the regulatory region of the gene may influence the amount of Gsα, we studied the methylation pattern in the 5' regulatory region of Gsα gene in pseudohypoparathyroidism type Ia and type Ib. However, the abnormality in DNA methylation was found only in type Ib, which does not accompany by short stature. In this study, we established the new standard for U/L ratio. This standard is useful when evaluating the children with growth disorders. We examined PTHR1 polymorphism and bone mineral density in the subjects with peak bone mass and found no relationship, however, bone resorption markers were low in AAAG6 group. This may relate the rate of bone mineral loss by aging and warrants further investigation.