GENETICS OF BONE LOSS AND BONE STRENGTH IN MEN AND WOMEN

骨质疏松性骨折是由于年龄相关的骨强度降低所致。骨强度包括骨密度、结构、质量和转换率，所有这些都具有高度的遗传性。最严重的骨质疏松性骨折发生在髋部。髋骨强度的降低是由于峰值骨量低和与年龄相关的骨丢失所致。髋部骨量的遗传力很高，但髋部骨丢失的遗传力尚未被研究。女性的骨骼强度比男性低，髋部骨折的发生率比男性高。在男性中，骨强度的遗传性还没有得到牢固的确立。对760对姐妹的骨强度遗传力进行了测量，10 cM的基因组筛查发现了几个影响骨强度的染色体位点。现在将检验两个假设：1.女性髋部骨质丢失的速度是由基因决定的。在我们目前的研究中，将通过重新测量500对姐妹的髋部骨量来测试这一点，如果是可遗传的，使用已经产生的基因类型进行连锁分析。2.男性对骨强度的遗传效应与女性相似，但某些基因座具有性别特异性。这将通过测量700对兄弟的骨骼强度，比较我们760对姐妹的遗传性，并进行基因组筛查来确定影响男性骨骼强度的基因来进行测试。了解骨强度的遗传基础将实现三个主要目标：1)确定女性髋部骨丢失率是否有遗传成分，如果有，定位导致丢失的基因；2)建立男性骨强度的遗传力，并将其与女性的遗传性进行比较；3)丰富我们的数据库，用于精细定位骨强度基因，并确定某些基因座是否具有性别特异性。这些信息将使人们更好地了解骨质疏松性髋部骨折的原因以及男女发病率的差异，并最终找到新的治疗和预防方法。

Osteoporotic fracture is due to age-related reduction in bone strength. Bone strength comprises bone mineral density, structure, quality and turnover, all of which are highly heritable. The most serious osteoporotic fracture occurs at the hip. Reduction in hip bone strength is due to a combination of low peak bone mass and age-related bone loss. Heritability of bone mass at the hip is high, but heritability of bone loss at the hip has not been studied. Women have lower bone strength and higher incidence of hip fracture than men. In men, heritability of bone strength has not been firmly established. Heritability of bone strength has been measured in 760 pairs of sisters, and a 10 cM genome screen has identified several chromosomal loci influencing bone strength. Two hypotheses will now be tested: 1. The rate of bone loss at the hip in women is genetically determined. This will be tested by remeasuring hip bone mass in 500 pairs of sisters in our current study and, if heritable, perform linkage analysis using genotypic already generated. 2. The genetic effect on bone strength in men is similar to that in women, but certain loci are sex specific. This will be tested by measuring bone strength in 700 pairs of brothers, comparing heritabilities to those in our 760 of sisters, and performing a genome screen to identify loci influencing bone strength in men. Three major goals in understanding the genetic basis of bone strength will be achieved: 1) establish if the rate of bone loss at the hip in women has a genetic component, and if so, localize the genes that underlie the loss; 2) establish heritabilities of bone strength in men and compare these with those established in women; 3) enrich our database for fine mapping bone-strength genes and establish if certain loci are sex specific. This information will lead to a much better understanding of the causes of osteoporotic hip fracture and of the difference in incidence between men and women and, ultimately, to new therapeutic and preventative treatments.