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退行性疾病。由于OA随着年龄的增长而更加常见，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，关节置换手术是主要的治疗方法。在英国，2016年有8万例OA髋关节置换术，花费了NHS 5亿英镑。在一小部分人中，髋关节OA是由于早期髋关节发育缺陷导致的，导致髋关节形状异常，导致生物力学力异常，加速关节破坏。髋关节形状的更微妙的改变，使用标准X线难以识别，已被认为有助于更广泛人群中髋关节OA的发展。然而，由于早期OA本身可能影响髋关节形状，目前还不清楚髋关节OA相关的髋关节形状变化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关系，独立于混杂因素，代表了解决这个问题的理想方法。虽然MR需要大数据集来确保足够的统计功效，但英国生物库中髋关节DXA扫描（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骨性关节炎相关的髋关节形状改变，包括我的初步研究中发现的新特征，是否是髋关节骨性关节炎发展的因果因素，而不是疾病过程的结果。这将通过对来自英国生物库的10万人进行MR分析来实现，髋关节DXA扫描与遗传数据和髋关节OA相关信息相关联。1)我将使用UK Biobank的100，000次DXA扫描扩展自动髋关节形状测量，以包括新的髋关节形状角度和模型2）使用也作为我的奖学金的一部分开发的进一步自动化过程，将对髋关节OA进行相同的DXA扫描分级3）我将描述（1）中描述的髋关节形状与（2）中描述的髋关节OA之间的关联，以及与其他OA相关的表型，包括自我报告的髋关节疼痛和随后髋关节置换的风险。4）MR方法将用于确定（3）中描述的髋关节形状和髋关节OA之间的关联是否代表因果关系。根据我的申请将利用的单独的惠康基金会资助的增加赠款，将开发一种用于在髋关节（大腿骨和骨盆）轮廓周围自动放置点的方法，并将其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髋关节扫描进行分类。一些被认为与髋关节OA相关的形状参数将被推导出来，包括大腿骨上部的宽度相对于高度，股骨头中部与股骨头之间的角度，（大腿骨）和髋臼（骨盆）的边缘，以及小转子的大小（大腿骨内侧骨质突出）。潜在的好处：在更广泛的人群中识别导致髋关节OA的髋关节形状改变将有助于我们理解OA的原因，特别是生物力学力改变的作用。这些知识将为髋关节OA的更有效预防策略提供基础，包括定制练习，物理治疗和矫形器的作用，旨在纠正预测特定形状变化引起的异常关节负荷。通过研究髋关节DXA评估的髋关节形态与髋关节置换术的后续风险之间的关联，我的奖学金也将有助于开发DXA扫描的使用，广泛用于筛查骨质疏松症，以额外筛查髋关节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.