Use of Mendelian randomisation to examine the role of abnormal hip shape in the development of hip osteoarthritis

背景：骨关节炎（OA）是一种导致疼痛和功能丧失的关节变性。由于OA随着年龄的增长而更常见，随着社会老龄化，越来越多的人受到影响。我的研究重点是髋关节OA，关节置换术是髋关节OA的主要治疗方法。在英国，2016年有8万例髋关节置换术，花费了NHS 5亿英镑。在少数情况下，髋关节骨关节炎是由早期髋关节发育缺陷引起的，导致髋关节形状异常，引起异常的生物力学力，加速关节破坏。在更广泛的人群中，髋骨形状更细微的变化（用标准x光片更难识别）可能导致髋骨关节炎的发生。然而，由于早期骨关节炎本身可能影响髋关节形状，因此尚不清楚与骨关节炎相关的髋关节形状改变是致病因素还是仅仅是早期疾病的表现。孟德尔随机化（MR）是一种统计方法，其中遗传因素被用来估计任何给定因素的因果效应，而不受混杂因素的影响，它代表了解决这个问题的理想方法。尽管MR需要大量的数据集来确保足够的统计能力，但英国生物银行（UK Biobank）的髋关节DXA扫描（一种低辐射x射线）的可用性意味着这种方法现在是可行的。目的：我的目的是确定髋关节形状的改变是否与髋关节OA相关，包括我在初步研究中发现的新特征，是髋关节OA发展的因果因素，而不是疾病过程的结果。这将通过对来自英国生物银行（UK Biobank）的10万人进行MR分析来实现，并将髋关节DXA扫描与遗传数据和髋关节OA信息联系起来。1)我将扩展自动髋关节形状测量，包括新的髋关节形状角度和模型，使用英国生物银行的100,000次DXA扫描。2)同样的DXA扫描将对髋关节OA进行分级，使用进一步的自动化过程，这也是我的研究的一部分。3)我将描述(1)中特征的髋关节形状与(2)中特征的髋关节OA之间的关联。以及其他与OA相关的表型，包括自我报告的髋关节疼痛和后续髋关节置换术的风险。4)MR方法将用于确定(3)中描述的髋关节形状与髋关节OA之间的关联是否代表因果关系。在我的申请将利用的惠康资助的AUGMENT拨款下，一种自动在髋关节（大腿骨和骨盆）轮廓周围放置点的方法将被开发并应用于英国生物银行髋关节DXA扫描。我将在我的研究中使用这些标记点，使用不同的子集和组合来生成髋关节形状的一系列方面，并根据骨赘（骨突起）和关节间隙狭窄的存在对OA的髋关节扫描进行分类。一些被认为与髋关节骨关节炎相关的形状参数将被推导出来，包括相对于大腿骨的高度的宽度，股骨头中部（大腿骨）与髋臼边缘（骨盆）之间的角度，以及小转子的大小（大腿骨内侧的一个骨突起）。潜在益处：在更广泛的人群中，识别引起髋关节骨关节炎的髋关节形状改变将有助于我们理解骨关节炎的原因，特别是改变的生物力学力的作用。这些知识将为髋关节骨关节炎更有效的预防策略提供基础，包括定制运动、物理治疗和矫形器的作用，旨在纠正特定形状变化导致的异常关节负荷。通过研究髋关节DXA评估的髋关节形态与髋关节置换术风险之间的关系，我的研究也将有助于DXA扫描的发展，DXA扫描广泛用于筛查骨质疏松症，并筛查髋关节OA。

Context: Osteoarthritis (OA) is a type of joint degeneration that leads to pain and loss of function. Since OA is more common with increasing age, more people are becoming affected as society ages. My research focuses on hip OA, for which joint replacement surgery is the main treatment. In the UK in 2016, there were 80,000 hip replacements for OA costing the NHS £500 million. In a small minority, hip OA results from defective hip development in early life, leading to abnormal hip shape causing aberrant biomechanical forces that accelerate joint destruction. More subtle alterations in hip shape, harder to recognise using standard X-rays, have been suggested to contribute to hip OA development in the wider population. However, since early OA may itself affect hip shape, it's unclear whether hip shape changes reported in association with hip OA are causative factors or simply manifestations of early disease. Mendelian randomisation (MR), a statistical method where genetic factors are used to estimate the causal effect of any given factor independently of confounding, represents an ideal method to address this question. Although MR requires large datasets to ensure sufficient statistical power, the availability of hip DXA scans (a low radiation X-ray) in UK Biobank means that such an approach is now feasible. Aims: I aim to establish whether alterations in hip shape reported to be associated with hip OA, including novel characteristics identified in my preliminary studies, are causal factors in hip OA development, as opposed to a consequence of the disease process. This will be achieved by performing MR analyses in 100,000 individuals from UK Biobank, with hip DXA scans linked to genetic data and information about hip OA. 1) I will extend automatic hip shape measurement to include new hip shape angles and models, using 100,000 DXA scans with UK Biobank2) The same DXA scans will be graded for hip OA, using a further automated process also developed as part of my fellowship 3) I will describe associations between hip shape as characterised in (1), and hip OA as characterised in (2), as well as with other OA-related phenotypes including self-reported hip pain and risk of subsequent hip replacement 4) MR methods will be applied to establish whether associations between hip shape and hip OA described in (3) represent causal relationships Methods: Under the separate Wellcome funded AUGMENT grant which my application will exploit, a method for automating placement of points around the outline of the hip joint (thigh bone and pelvis) will be developed and applied to UK Biobank hip DXA scans. I will use these marked up points in my fellowship, using different subsets and combinations to generate a range of aspects of hip shape, and to classify hip scans for OA according to the presence of osteophytes (bony protuberances) and joint space narrowing. A number of shape parameters thought to be associated with hip OA will be derived, including width relative to height of the upper thigh bone, the angle between the middle of the femoral head (thigh bone) and the edge of the acetabulum (pelvis), and the size of the lesser trochanter (a boney protusion on the inner aspect of the thigh bone).Potential benefits: Identification of alterations in hip shape causing hip OA in the wider population will contribute to our understanding of the causes of OA, particularly the role of altered biomechanical forces. This knowledge will provide the basis for more effective preventative strategies for hip OA, including the role of bespoke exercises, physiotherapy and orthotics, designed to correct the abnormal joint loading predicted to follow from specific shape changes. By studying associations between hip morphology as evaluated by hip DXA and subsequent risk of hip replacement, my fellowship will also contribute to development of use of DXA scans, widely used to screen for osteoporosis, to additionally screen for hip OA.