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MRPL28: A New Candidate Gene for Aerobic Capacity

Han, Jianhua
Master thesis
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http://hdl.handle.net/11250/2373958
Date
2015
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  • Institutt for klinisk og molekylær medisin [3829]
Abstract
Large-scale epidemiological studies demonstrate that aerobic capacity, measured as maximal oxygen uptake (VO2max), is the single best predictor for future cardiovascular mortality in both healthy individuals and patients with cardiovascular diseases. However, limited progress has been observed in the identification of the genetic basis of aerobic capacity. Recently, our group was able to identify a new and uncharacterized aerobic capacity locus (rs540 on TMEM8A gene) on chromosome 16p13.3 in the general population from The Nord-Trøndelag Health (HUNT) Study. Therefore, this Master thesis aimed to dissect this locus and search for other candidate genes associated with aerobic capacity, as well as their clinical relevance. The reanalyzes of genetic variants located in the vicinity of chromosome 16p13.3 locus reveled the existence of another variant (rs3830160 on MRPL28 gene) significantly associated with VO2max. We have also checked for association of several other MRPL28 variants in myocardial infarction (MI) patients from the HUNT MI Study but none of then reached significant levels. In experimental models, MRPL28 was found ubiquitously expressed in mice, especially in kidney, brain, testis and ovary. Transient transfection of HEK-293 cells with siRNA against MRPL28 was performed and proteins involved in the oxidative phosphorylation were evaluated, but we fail to knocked down MRPL28. Regarding pathological conditions, we did not find MRPL28 differently expressed in two different cancer cachexia models (Wistar rats injected with Walker 256 tumor and B16 melanoma). In contrast, MRPL28 protein levels were 1.78 fold increased in the left ventricle of HCR compared to LCR. Regarding MRPL28 post-transcriptional regulation, we found that hsa-miR-18a-5p, hsa-miR-130b-3p, hsa-miR-326 and hsa-miR-328-3p are predicted to target MRPL28. Taken together, we have described that MRPL28 is a promising candidate target for aerobic capacity. The identification and validation of new aerobic capacity genetic variants will bring forward a potential to establish original and novel diagnostic and therapeutic tools and strategies for cardiovascular disease (CVD) management, thus contributing to reduce the burden of cardiovascular and life-style related diseases.
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NTNU

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