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作者：Jacquelyn K. Beals, PhD  
出處：WebMD醫學新聞

　　October 6, 2009 — 研究者檢視了影響腰椎和股骨頸之骨質密度(BMD)的20個基因區域，其中13個在之前未曾發現與BMD有關聯。這篇新研究是對於有北歐血統者之5個基因圖關聯研究(GWASs)的統合分析；特別有趣的是，在這20個區域中有7個發現有骨骼區位特定性。
　　
　　這篇研究線上發表於10月4日的Nature Genetics期刊，第一作者是荷蘭健康老化聯合會(Netherlands Consortium for Healthy Aging，NCHA)、荷蘭鹿特丹Erasmus醫學中心內科與流行病學系的Fernando Rivadeneira博士，另有多位荷蘭與國際的合作夥伴。
　　
　　骨質疏鬆包括骨質減少與骨質惡化，降低了骨骼強度與增加骨折風險，一般而言，骨質疏鬆的發生率隨著年紀增加。BMD是診斷骨質疏鬆與預測骨折風險的臨床指標。在各個骨骼部位中，BMD評估的是腰椎和股骨頸。本研究將有關這兩個骨骼部位的5篇GWASs，共19,195名18至96歲研究對象的資料納入進行統合分析。
　　
　　將alpha值(有第1型錯誤或偽陽性的可能性) = 5× 10–8 定為這些GWAS有無顯著的切點。在20個位置中有超過400個單核苷酸多型性(SNPs)符合GWAS顯著：10個位置與股骨頸BMD有關，15個與腰椎BMD有關，5個與這兩個部位都有關。這20個區域中，有13個位置未曾在GWAS研究中發現與BMD有關(4個曾經在之前發表的研究中認為「疑似有關」，其他9個未曾被發表過)。有7個區域的BMD關聯已經被確認。
　　
　　以下為新發現位置的例子：
　　* 第1染色體的短臂上的一個區域，包括了與腰椎和股骨頸之BMD有高度相關的2個SNPs (P 值從2.63× 10–13 -1.8× 10–12)。兩個SNPs位於「高度演化保存之Wnt訊息傳遞途徑」上的一個基因內，影響骨骼細胞的分化與發展。
　　* 第7染色體的短臂上的一個區域，包括了與腰椎之BMD強烈有關的1個SNP (P= 1.1× 10–9)，但是與股骨頸的BMD沒有顯著關聯(P= 8.9× 10–4)。附近的一個基因影響內小體膽固醇運輸，亞洲的一項研究發現，此區域的另一個SNP與腳後跟、脛骨、橈骨的BMD有關。
　　* 作者們提出，歐洲人和亞洲人共通的一個基本訊息仍是由這些SNPs擷取，考量的是各種基因不平衡在不同族群之間所造成的差異。
　　* 第11染色體的短臂上的一個區域，包括了一個有強烈部位特定性的SNP，與股骨頸的BMD有基因圖關聯(P= 6.4× 10–10)，但是與腰椎的BMD無關(P= .004)。附近的一個基因在骨骼肌有高度表現，敲昏缺乏此一基因活性的老鼠顯示，輕微骨骼異常與發展中骨骼的大小及軟骨內元素的礦物質沉積有關。
　　
　　該研究也檢視了這20個區域與骨折風險的共同效應。整體而言，與腰椎BMD有關的前15名SNPs可解釋大約2.9%的測量差異；同樣地，整合與股骨頸BMD有關的前10名SNPs，可解釋大約1.9%的特徵差異。作者們表示，這些位置僅解釋BMD差異中的一小部份，因此，骨折風險的可遺傳性更小。
　　
　　不過，這些差異的相關知識指引了BMD變異的研究方向。在腰椎和股骨頸之BMD觀察到的獨立效果，可能反應出形成皮質骨或海綿骨的生物過程中的差異。作者們結論表示，這些SNPs都還沒被確認可以明確地指定為造成這些關聯的背後真因。不過，他們力主應繼續這類變異的研究，以促進風險預估且用以發展治療骨質疏鬆的新藥。
　　
　　Nat Genet. 線上發表於2009年10月4日。

Meta-Analysis Identifies 13 New Genetic Regions Associated With Bone Mineral Density

By Jacquelyn K. Beals, PhD
Medscape Medical News

October 6, 2009 — Investigators have identified 20 genetic regions that influence bone mineral density (BMD) of the lumbar spine and femoral neck; 13 were not previously associated with BMD. The new study was a meta-analysis of 5 genomewide association studies (GWASs) in people of Northern European heritage. Of particular interest was the finding of skeletal site-specificity for 7 of the 20 regions.

The work, published online October 4 in Nature Genetics, was carried out by first author Fernando Rivadeneira, MD, PhD, from the Departments of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands, and the Netherlands Consortium for Healthy Aging (NCHA), numerous colleagues in the Netherlands, and international collaborators.

Osteoporosis involves decreased bone mass along with bone deterioration, reducing bone strength and increasing the fracture risk. Typically, the incidence of osteoporosis rises with age. BMD serves as a clinical indicator for diagnosing osteoporosis and predicting the risk for fracture. Among skeletal sites where BMD is assessed are the lumbar spine and the femoral neck. This study combines data from 5 GWASs on BMD of these 2 sites into a meta-analysis of 19,195 subjects aged 18 to 96 years.

A threshold of alpha (probability of a type 1 error, or a false positive) = 5 × 10–8 was selected as the cutoff for GWAS significance. More than 400 single-nucleotide polymorphisms (SNPs) at 20 loci qualified for GWAS significance: 10 loci were associated with BMD of the femoral neck, 15 were associated with BMD of the lumbar spine, and 5 were associated with both sites. Thirteen of the 20 regions had never been associated with BMD at the GWAS level (4 were "suggestively associated" in previously published studies, but the remaining 9 were never reported in this context). The BMD associations of 7 regions were already recognized.

The following are examples of the newly reported loci:

A region on the short arm of chromosome 1 contains 2 SNPs highly associated with BMD of both the lumbar spine and the femoral neck (P from 2.63 × 10–13 to 1.8 × 10–12). Both SNPs lie within a gene involved in the "highly evolutionarily conserved Wnt signaling pathway" that influences differentiation and development of bone cells.
A region on the short arm of chromosome 7 contains a SNP strongly associated with BMD of lumbar spine (P = 1.1 × 10–9) but not significantly associated with BMD of the femoral neck (P = 8.9 × 10–4). A nearby gene influences endosomal cholesterol transport, and a study in Asian subjects found another SNP in this region associated with BMD in the heel, the tibia, and the radius.
The authors propose that "an underlying signal common to both Europeans and Asians might still be captured by these SNPs, considering the differences in [linkage disequilibrium] across populations."
A region on the short arm of chromosome 11 contains a SNP with strong site specificity, which is associated at the genomewide level with BMD of the femoral neck (P = 6.4 × 10–10) but not with BMD of the lumbar spine (P = .004). A nearby gene is highly expressed in skeletal muscle, and knockout mice lacking this gene activity demonstrate "mild skeletal abnormalities" related to the size of and mineral deposition in endochondral elements of the developing skeleton.
The study also examined the combined effect of the 20 loci on fracture risk. Together, the top 15 SNPs associated with BMD of the lumbar spine explained approximately 2.9% of the variance in this measurement; similarly, combining the top 10 SNPs associated with BMD of the femoral neck explains about 1.9% of the variance in that characteristic. The authors acknowledge that "these loci explain only a small fraction of the variance in BMD and hence an even smaller fraction of the heritability for fracture risk."

Nevertheless, knowledge of these variants illuminates pathways that contribute to variation in BMD. The independent effects observed for BMD of lumbar spine and femoral neck might reflect differences in the biological processes that contribute to the formation of cortical versus trabecular bone. "None of the SNPs . . . identified can be unequivocally designated as the underlying 'true' variants driving the associations," conclude the authors. However, they urge that the search for such variants should continue to enhance risk prediction and to translate into the development of new pharmaceuticals for the treatment of osteoporosis.

Nat Genet. Published online October 4, 2009.