Using genetics to test the disease consequences of higher adiposity uncoupled from its adverse metabolic effects

除了2型糖尿病和心脏病外，肥胖还与许多疾病有关。体重过重的人患关节疾病(如骨关节炎)、肠道和肠道疾病(如胃食道反流病、憩室病)、精神健康疾病(如抑郁症)和某些癌症(如绝经后乳腺癌)的风险也更大。对于这些情况中的许多，我们不知道超重是一个原因，还是仅仅是因为共同的因素，如老龄化和一般健康状况不佳。即使我们确实知道超重是一个直接原因，我们也不知道多余脂肪质量的哪个方面是重要的。例如，对于关节疾病，如骨关节炎，超重本身可能更重要，或者通常伴随超重的炎症可能更重要，导致疾病。在这项提案中，我们的目标是了解超重的两个不同方面对常见疾病的因果影响--过量脂肪，以及通常伴随过度脂肪的不良后果。这些不良后果包括对胰岛素有益影响的敏感性降低，血液中脂肪和胆固醇水平升高，以及炎症。我们将使用一种新的遗传学方法来描述两组基因变异--与“正常脂肪”相关的基因变异和与“有益脂肪”相关的基因变异。“正常脂肪”基因变异与更多的脂肪和更高的代谢性疾病(如2型糖尿病)风险有关。“有益脂肪”的变种与更多的脂肪有关，但患代谢性疾病的风险更低。然后，我们将使用非常大的数据集，如英国生物库和其他10,000名患有和没有疾病的人的大型集合，比较这两组基因变异对非代谢性疾病的影响。如果正常和有利的脂肪基因变异都与骨关节炎等疾病的风险有关，这将表明超重是重要的。相反，如果只有“正常脂肪”的遗传变异与之相关，这将表明不利的新陈代谢后果更为重要。我们将研究的疾病包括骨关节炎、胃食道反流、抑郁症、骨质疏松症、乳腺癌和牛皮癣。了解超重导致骨关节炎和反流病等疾病的机制对于开发有效的干预和治疗方法至关重要。例如，如果超重纯粹是通过不利的代谢影响导致的，这就增加了改变代谢影响的治疗方法的可能性，如炎症或胰岛素敏感性。如果影响纯粹是由超重本身驱动的，这些方法将是徒劳的。

Obesity is associated with many diseases in addition to type 2 diabetes and heart disease. People who are carrying too much weight are also at greater risk of diseases of the joints (e.g. osteoarthritis) , gut and intestinal tract (e.g. gastro-oesophageal reflux disease, diverticular disease), diseases of mental health (e.g. depression) and some cancers (e.g. post-menopausal breast cancer). For many of these conditions, we do not know if being overweight is a cause or is simply correlated due to shared factors such as ageing and poor general health. Even if we do know that being overweight is a direct cause, we do not know which aspect of the excess fat mass is important. For example, for a disease of the joints, such as osteoarthritis, the excess weight itself could be more important or the inflammation that normally accompanies excess weight could be more important, in causing the disease. In this proposal, we aim to understand the causal effects of two separate aspects of being overweight on common diseases - the excess fat, and the adverse consequences that normally accompany excess fat. These adverse consequences include reduced sensitivity to the beneficial effects of insulin, higher levels of fat and cholesterol in the blood, and inflammation. We will use a novel genetic approach where we characterise two sets of genetic variants - those associated with "normal fat" and those associated with "favourable fat". The "normal fat" genetic variants are associated with more fat and higher risk of metabolic diseases such as type 2 diabetes. The "favourable fat" variants are associated with more fat but lower risk of metabolic diseases. We will then compare the effects of these two sets of genetic variants on non-metabolic diseases using very large datasets such as the UK Biobank and other large collections of 10,000s of people with and without diseases. If both the normal and favourable fat genetic variants are associated with risk of a disease such as osteoarthritis, it will indicate the excess weight is important. In contrast, if only the "normal fat" genetic variants are associated, it will indicate the adverse metabolic consequences are more important. Diseases we will study include osteoarthritis, gastro-oesophageal reflux, depression, osteoporosis, breast cancer and psoriasis.Understanding the mechanism by which excess weight causes conditions such as osteoarthritis and reflux disease is of fundamental importance to developing effective interventions and treatments. For example if excess weight is shown to cause a condition purely through the adverse metabolic effects, this raises the possibility of treatments that modify the metabolic effects, such as inflammation or insulin sensitivity. If effects are purely driven by the excess weight itself, these approaches will be futile.