PMC:4951402 / 10779-16501 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4951402","sourcedb":"PMC","sourceid":"4951402","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4951402","text":"Discussion\nWe identified five SNPs and three genomic regions, associated with BMD. Four of these SNPs (rs17124500, rs34594869, rs17124504, and rs140155614) were linked with LS-BMD and dispersed between two loci (14q31.1 and 15q25.1). One SNP (rs111822233) found in 4q31.1 was exclusively associated with FT-BMD. We also re-evaluated three previously established genetic relationships. First, we confirmed the connection between LS-BMD and the following loci: rs61382873 in LRP5, rs9567003 in TNFSF11, and rs9935828 in FOXL1. Next, we linked rs33997547 in ZBTB40 and rs1664496 in MEF2C with FT-BMD and analyzed rs61769193 expression patterns in FN-BMD.\nThree of our significant markers—rs17124500, rs34594869, and rs17124504—were located on the KCNK10 gene. This channel protein, embedded in the cellular membrane, consists of two pore-forming P domains and regulates K+ concentration. The role of potassium ions in maintaining the acid-base homeostasis of most organs and tissues, including bones, has been well established in the literature [25]. Additionally, KCNK10 is located on 14q31, a locus previously associated with LS-BMD in linkage analyses [26]. Although the relationship between the gene and osseous metabolism is not clear, it is highly possible that its translational mechanisms influence bone biological parameters.\nrs140155614 was prominent in the AGPHD1 domain. Alternatively known as hydroxylysine kinase (HYKK), this protein-coding gene and its associated pathway, catalyze the GTP-dependent phosphorylation of 5-hydroxy-L-lysine. Located on 15q25.1, it has a well-known connection to the development of lung cancer. CHRNA3-CHRNA5-CHRNB4, a gene complex near AGPHD1, has been linked to nicotine dependence in several genetic studies [27]. Current scientific evidence is insufficient in determining the role of this locus in BMD development 's replication patterns is needed to validate or dispute a relationship with BMD.\nrs111822233 was the only genetic marker with a direct relationship to FT-BMD levels. Located on 4q31.1, it is near NR3C2, a nuclear receptor involved in steroid signaling and regulation. Mineralocorticoid and various sex hormones, such as testosterone and estradiol, alternatively bind to the protein, which influences their secretion via a feedback loop [28]. Bone resorption has been reported to increase with the withdrawal of these sex hormones. Although estrogen is the major steroid in regulating ossein metabolism, testosterone is also important in the resorption mechanism [29]. Moreover, prevalence of osteoporosis in the hipbone has been shown to increase in men whose testosterone levels are lower than the reference range [30].\nAs established in our introduction, research conducted with Korean participants tends to be inconclusive owing to extensive focus on replication of results obtained by the original GWASs. Thus, we attempted to bridge this gap in information by validating previously established genetic linkages in Caucasian populations, whose significance has been confirmed in Korean men by replication studies [1314]. LRP5, MEF2C, and ZBTB40 belong to the Wnt signaling pathway, which is largely related to cellular development and growth. Several studies have observed a link between this cascade and BMD [31]. We utilized a series of SNP markers from various Wnt-associated genes and were able to prove as association between rs61382873 in LRP5 and LS-BMD, between rs33997547 in ZBTB40 and rs1664496 in MEF2C and FT-BMD, and between rs61769193 in ZBTB40 and FN-BMD. TNFSF11, also known as receptor activator of nuclear factor kappa-B ligand (RANKL) plays a critical role in adequate bone metabolism via activation of osteoclast cells to regulate resorption [31]. We identified a significant SNP marker in TNFSF11, rs9567003, which was related to LS-BMD. Our results were consistent with those of a previous genetic research, which has established a connection between TNFSF11 and BMD of the lumbar spinal cord [31]. FOXL1 was originally identified by Genetic Factors for Osteoporosis (GEFOS) and has been associated with LS-BMD in European sample groups; this result has been replicated with high significance in Korean populations [13]. Our marker in FOXL1, rs9935828, was also correlated with LS-BMD levels. In conclusion, we described a series of new loci and confirmed GWAS results in Korean male populations by working with skeletal-specific BMD and gene associations.\nThere were several limitations to our study. First, no replications were performed to validate our results. Because indicators for measuring BMD in men tend to be narrow, recruiting a sufficient replication sample proved challenging. Thus, we aimed to use previously identified genetic markers, which have been established as valid in our selected ethnicity and gender. Despite our efforts, BMD is a less meaningful factor of osteoporosis in men than in women. Additionally, we could not consider all factors, including sex, age, weight, and menopausal status, owing to using only young men as our test subjects. Finally, we needed a very large sample because phenotypic variations are hard to detect in homogenous populations. However, our sample size was too small to employ a Bonferroni correction, and we were forced to set the significant threshold as p \u003c 1 × 10-6, thus increasing the chance of false-positives. To minimize statistical error, we thoroughly analyzed gene functions and mechanisms. Nevertheless, further research is necessary to validate our findings.\nIn conclusion, our study identified novel loci correlated with BMD at 14q31.3, 15q25.1, and 4q31.1 in Korean men. Future studies should investigate these associations and the underlying genetic mechanisms.","divisions":[{"label":"Title","span":{"begin":0,"end":10}}],"tracks":[{"project":"2_test","denotations":[{"id":"27445649-8202051-44837784","span":{"begin":1043,"end":1045},"obj":"8202051"},{"id":"27445649-15746152-44837785","span":{"begin":1153,"end":1155},"obj":"15746152"},{"id":"27445649-18385676-44837786","span":{"begin":1754,"end":1756},"obj":"18385676"},{"id":"27445649-17105867-44837787","span":{"begin":2298,"end":2300},"obj":"17105867"},{"id":"27445649-11120762-44837788","span":{"begin":2524,"end":2526},"obj":"11120762"},{"id":"27445649-16849417-44837789","span":{"begin":2677,"end":2679},"obj":"16849417"},{"id":"27445649-23575750-44837790","span":{"begin":3079,"end":3081},"obj":"23575750"},{"id":"27445649-25132170-44837791","span":{"begin":3079,"end":3083},"obj":"25132170"},{"id":"27445649-23575750-44837792","span":{"begin":4203,"end":4205},"obj":"23575750"}],"attributes":[{"subj":"27445649-8202051-44837784","pred":"source","obj":"2_test"},{"subj":"27445649-15746152-44837785","pred":"source","obj":"2_test"},{"subj":"27445649-18385676-44837786","pred":"source","obj":"2_test"},{"subj":"27445649-17105867-44837787","pred":"source","obj":"2_test"},{"subj":"27445649-11120762-44837788","pred":"source","obj":"2_test"},{"subj":"27445649-16849417-44837789","pred":"source","obj":"2_test"},{"subj":"27445649-23575750-44837790","pred":"source","obj":"2_test"},{"subj":"27445649-25132170-44837791","pred":"source","obj":"2_test"},{"subj":"27445649-23575750-44837792","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93a1ec","default":true}]}]}}