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      Deep sequencing analysis to identify novel and rare variants in pain-related genes in patients with acute postoperative pain and high morphine use

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          Most of the genetic variants that are reported to be associated with common pain phenotypes and analgesic use are common polymorphisms. The objective of our study was to identify new variants and investigate less common genetic variants that are usually not included in either small single-gene studies or high-throughput genotyping arrays.

          Patients and methods

          From a cohort of 1075 patients who underwent a scheduled total abdominal hysterectomy, 92 who had higher self-rated pain scores and used more morphine were selected for the re-sequencing of 105 genes.


          We identified over 2400 variants in 104 genes. Most were intronic with frequencies >5%. There were 181 novel variants, of which 30 were located in exons: 17 nonsynonymous, 10 synonymous, 2 non-coding RNA, and 1 stop-gain. For known variants that are rare (population frequency <1%), the frequencies of 54 exonic variants and eight intronic variants for the sequenced samples were higher than the weighted frequencies in the Genome Aggregation Database for East and South Asians ( P-values ranging from 0.000 to 0.046). Overall, patients who had novel and/or rare variants used more morphine than those who only had common variants.


          Our study uncovered novel variants in patients who reported higher pain and used more morphine. Compared with the general population, rare variants were more common in this group.

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          Most cited references 39

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          Accounting for human polymorphisms predicted to affect protein function.

          A major interest in human genetics is to determine whether a nonsynonymous single-base nucleotide polymorphism (nsSNP) in a gene affects its protein product and, consequently, impacts the carrier's health. We used the SIFT (Sorting Intolerant From Tolerant) program to predict that 25% of 3084 nsSNPs from dbSNP, a public SNP database, would affect protein function. Some of the nsSNPs predicted to affect function were variants known to be associated with disease. Others were artifacts of SNP discovery. Two reports have indicated that there are thousands of damaging nsSNPs in an individual's human genome; we find the number is likely to be much lower.
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            Exposing synonymous mutations.

            Synonymous codon changes, which do not alter protein sequence, were previously thought to have no functional consequence. Although this concept has been overturned in recent years, there is no unique mechanism by which these changes exert biological effects. A large repertoire of both experimental and bioinformatic methods has been developed to understand the effects of synonymous variants. Results from this body of work have provided global insights into how biological systems exploit the degeneracy of the genetic code to control gene expression, protein folding efficiency, and the coordinated expression of functionally related gene families. Although it is now clear that synonymous variants are important in a variety of contexts, from human disease to the safety and efficacy of therapeutic proteins, there is no clear consensus on the approaches to identify and validate these changes. Here, we review the diverse methods to understand the effects of synonymous mutations. Published by Elsevier Ltd.
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              Is Open Access

              The impact of rare and low-frequency genetic variants in common disease

              Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focused explorations on the contribution of low-frequency and rare variants to human traits. Here we review experimental approaches and current knowledge on the contribution of these genetic variants in complex disease and discuss challenges and opportunities for personalised medicine. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1212-4) contains supplementary material, which is available to authorized users.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                19 September 2019
                : 12
                : 2755-2770
                [1 ]Research Laboratory, KK Women’s & Children’s Hospital , Singapore, Singapore
                [2 ]Duke-NUS Medical School , Singapore, Singapore
                [3 ]Department of Women’s Anaesthesia, KK Women’s & Children’s Hospital , Singapore, Singapore
                Author notes
                Correspondence: Ene-Choo TanKK Research Centre, KK Women’s and Children’s Hospital , Singapore229899, SingaporeTel +65 6 394 3792Fax +65 6 394 1618Email tan.ene.choo@kkh.com.sg
                © 2019 Loke et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Tables: 6, References: 51, Pages: 16
                Original Research


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