Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Physiol Genomics. 2023 Oct 1;55(10):440-451. doi: 10.1152/physiolgenomics.00026.2023. Epub 2023 Aug 14.
Low cardiorespiratory fitness, measured as maximal oxygen uptake (V̇o), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured V̇o and disease. We believe that identifying the mechanisms explaining how low V̇o is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study approach to test for shared genetics. A total of 64,479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants previously linked to V̇o were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, and cancer as well as clinical measurements and biomarkers from HUNT. In the total population, three single-nucleotide polymorphisms (SNPs) in and near the follicle-stimulating hormone receptor gene () were found to be associated (false discovery rate < 0.05) with serum creatinine levels and one intronic SNP in the Rap-associating DIL domain gene () with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in the PBX/knotted homeobox 2 gene () were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance; the associations with the lowest values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between V̇o and disease. However, further effort should be put into investigating the potential shared genetics between inborn V̇o and disease in larger cohorts to increase statistical power. To our knowledge, this is the first genetic association study exploring how genes linked to cardiorespiratory fitness (CRF) relate to disease risk. By investigating shared genetics, we found indications that genetic variants linked to directly measured CRF also affect the level of blood creatinine, risk of diabetes, and endocarditis. Less certain findings showed that genetic variants of high CRF might cause lower body mass index, healthier HDL cholesterol, and lower resting heart rate.
低心肺适能，以最大摄氧量（V̇o）衡量，与全因死亡率和疾病特异性发病率和死亡率相关，据估计具有很大的遗传成分（约 60%）。然而，解释这些关联的潜在机制尚不清楚，也没有关联研究评估过直接测量的 V̇o 与疾病之间的共同遗传。我们相信，确定解释低 V̇o 与增加疾病风险之间关系的机制可以为预防和治疗做出贡献。我们使用表型全基因组关联研究方法来测试共同遗传。总共纳入了来自特隆赫姆健康研究（HUNT）的 64479 名参与者。先前与 V̇o 相关的遗传变异被测试与心血管系统、糖尿病、痴呆、精神障碍和癌症相关的疾病以及来自 HUNT 的临床测量和生物标志物的关联。在总人群中，发现卵泡刺激素受体基因（）中的三个单核苷酸多态性（SNP）和附近的与血清肌酐水平相关（错误发现率 < 0.05），而 Rap 相关 DIL 结构域基因（）中的一个内含子 SNP 与有神经表现的 1 型糖尿病相关。在男性中，发现 PBX/knotted homeobox 2 基因（）中的四个内含子 SNP 与心内膜炎相关。女性群体中的任何关联测试均未达到总体统计学意义； 值最低的关联包括其他心脏传导障碍、硬膜下血肿和心肌炎。结果可能表明 V̇o 和疾病之间存在共同遗传。然而，应该投入更多努力在更大的队列中研究与先天性 V̇o 和疾病相关的潜在共同遗传，以提高统计能力。据我们所知，这是第一项探索与心肺适能（CRF）相关的基因如何与疾病风险相关的遗传关联研究。通过研究共同遗传，我们发现有迹象表明与直接测量的 CRF 相关的遗传变异也会影响血液肌酐水平、糖尿病风险和心内膜炎。不太确定的发现表明，高 CRF 的遗传变异可能导致较低的体重指数、更健康的高密度脂蛋白胆固醇和较低的静息心率。
