Scientific Applications International Corporation-Frederick, Inc., Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD, USA.
Semin Nephrol. 2010 Mar;30(2):111-25. doi: 10.1016/j.semnephrol.2010.01.003.
Until recently, knowledge of genetic causes of glomerular disease was limited to certain rare or uncommon inherited diseases, and to genes, either rare or with small effect, identified in candidate gene studies. These genetic factors accounted for only a very small fraction of kidney disease. However, the striking differences in frequency of many forms of kidney disease between African Americans and European Americans, which could not be explained completely by cultural or economic factors, pointed to a large unidentified genetic influence. Because focal segmental glomerulosclerosis (FSGS) and human immunodeficiency virus-associated collapsing glomerulopathy have striking racial disparities, we performed an admixture mapping study to identify contributing genetic factors. Admixture mapping identified genetic variants in the nonmuscle myosin heavy chain 9 gene (MYH9) as having a major influence on both FSGS and human immunodeficiency virus-associated collapsing glomerulopathy, with odds ratios from 4 to 8 and attributable fractions of 70% to 100%. Previously identified, rare, inherited MYH9 disorders point to a mechanism by which MYH9 variation disrupts the actin-myosin filaments responsible for maintaining the structure of podocytes, the cells that provide one of three filtration barriers in the glomeruli. MYH9 variation has a smaller but still highly significant effect on nondiabetic kidney disease, and a weaker but significant effect on diabetic kidney disease; it is unclear whether underlying cryptic FSGS is responsible for the MYH9 association with these diseases. The strong predicted power of MYH9 variation for disease indicates a clear role for genetic testing for these variants in personalized medicine, for assessment of genetic risk, and potentially for diagnosis.
直到最近，肾小球疾病遗传原因的知识仅限于某些罕见或不常见的遗传性疾病，以及在候选基因研究中发现的稀有或影响较小的基因。这些遗传因素仅占肾脏疾病的很小一部分。然而，非裔美国人和欧洲裔美国人之间许多形式的肾脏疾病频率存在显著差异，这些差异不能完全用文化或经济因素来解释，这表明存在很大的未被识别的遗传影响。由于局灶节段性肾小球硬化症（FSGS）和人类免疫缺陷病毒相关性塌陷性肾小球病存在明显的种族差异，我们进行了混合映射研究以确定相关的遗传因素。混合映射确定了非肌肉肌球蛋白重链 9 基因（MYH9）中的遗传变异对 FSGS 和人类免疫缺陷病毒相关性塌陷性肾小球病有重大影响，比值比为 4 到 8，归因分数为 70%到 100%。先前已确定的罕见遗传性 MYH9 疾病表明，MYH9 变异破坏了肌动球蛋白丝，肌动球蛋白丝负责维持足细胞的结构，足细胞是肾小球中三个滤过屏障之一的细胞。MYH9 变异对非糖尿病肾病有较小但仍具有高度显著影响，对糖尿病肾病有较弱但显著影响；尚不清楚隐匿性 FSGS 是否是 MYH9 与这些疾病相关的原因。MYH9 变异对疾病的强预测能力表明，这些变体的基因检测在个性化医学、遗传风险评估以及潜在的诊断中具有明确的作用。
