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Pleiotropic relationships among measures of bone mineral density, bone geometry, lean muscle mass and fat mass.

机译：骨矿物质密度，骨骼几何形状，瘦肌肉质量和脂肪质量之间的多亲关系。

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摘要

Osteoporosis, sarcopenia and changes in fat distribution with age increase risk of fractures, affect quality of life, and are of major public health significance. Investigations into the genetic architecture of endophenotypes of these conditions could lead to better prediction of who is at greatest risk as well as revealing targets for therapies to delay disease onset or diminish their effects on afflicted individuals. Covariation among these conditions may be due to pleiotropy, although little is known about the specific genes involved. I explored relationships among twenty-two measures of arm and leg bone mineral density and geometry, arm and leg lean mass and arm and leg fat mass using data from two populations of Afro-Caribbeans from the island of Tobago: a sample of 1,937 unrelated men aged ≥ 40 years and a set of 470 men and women aged ≥ 18 years in seven extended pedigrees (mean family size = 67). I also performed genomewide association (GWA) studies of lumber spine and femoral neck bone mineral density (BMD) and fractures in an older (aged ≥ 70 years) population of European and African Americans ( n = 1,663 and 1,139 respectively). Hierarchical and principal component (PC) analysis revealed three clusters: (1) a "geometry group" that comprises mostly bone geometry traits and leanmass (PC1); (2) a "density group" that comprises mostly BMD traits (PC2); and (3) a "fat mass group" that comprises measures of fat mass (PC3). Estimates of residual heritability ranged from 0.206 to 0.763 (p 0.007 for all traits). Linkage analysis revealed significant evidence (LOD > 3.3) for quantitative trait loci (QTLs) on two chromosomes: 10q for PC1 and tibial periosteal circumference and 21q for PC3 and arm fat mass. GWA analyses of BMD and fractures in European and African Americans revealed several dozen potential candidate loci with suggestive levels of significance ( p ≤ 5 x 10-6), the most promising of which is SLC4A7 on 3q24.1, a sodium bicarbonate cotransporter expressed in osteoclasts. Thus, I present evidence for specific QTLs with pleiotropic effects on multiple body composition traits, as well as loci associated with arealBMDand fracture risk. Additional analyses of these regions could reveal genes that jointly influence susceptibility to osteoporosis, sarcopenia and obesity.
机译：骨质疏松症，肌肉减少症和脂肪分布随年龄的变化会增加骨折的风险，影响生活质量，并且对公共卫生具有重要意义。对这些情况的内表型遗传结构的研究可以更好地预测谁最有风险，并揭示治疗靶点以延缓疾病发作或减轻其对患病个体的影响。这些条件之间的协变可能是由于多效性所致，尽管对所涉及的特定基因知之甚少。我使用来自多巴哥岛的两个非洲加勒比海种群的数据，探索了22种测量手臂和腿部骨骼的矿物质密度和几何形状，手臂和腿部瘦体重以及手臂和腿部脂肪质量之间的关系：1,937名无关男性的样本年龄≥40岁，有470名年龄在18岁以上的男女，分布在七个扩展谱系中（平均家庭人数= 67）。我还对欧洲和非洲裔美国人（年龄分别≥70岁）的老年人（年龄≥70岁）的腰椎和股骨颈骨矿物质密度（BMD）和骨折进行了全基因组关联（GWA）研究。层次和主成分（PC）分析显示了三个簇：（1）“几何组”，主要包含骨骼几何特征和瘦肉（PC1）； （2）主要由BMD特征（PC2）组成的“密度群”； （3）包括脂肪量度（PC3）的“脂肪量组”。剩余遗传力的估计值介于0.206至0.763之间（所有性状的p <0.007）。连锁分析显示两个染色体上的数量性状基因座（QTL）的重要证据（LOD> 3.3）：PC1和胫骨骨膜周长为10q，PC3和臂脂肪量为21q。对欧洲和非裔美国人的BMD和骨折进行的GWA分析显示，有数十个潜在候选基因位点具有显着性意义（p≤5 x 10-6），其中最有希望的是3q24.1上的SLC4A7，这是一种碳酸氢钠共转运蛋白，表达于破骨细胞。因此，我为特定QTL提供了证据，这些QTL对多种身体成分性状具有多效性作用，以及与arealBMD和骨折风险相关的基因座。对这些区域的进一步分析可以揭示共同影响对骨质疏松症，少肌症和肥胖症易感性的基因。

著录项

  • 作者

    Minster, Ryan L.;

  • 作者单位

    University of Pittsburgh.;

  • 授予单位 University of Pittsburgh.;
  • 学科 Biology Genetics.;Health Sciences Epidemiology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 222 p.
  • 总页数 222
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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