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Shagufta Khaliq
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0576-3969
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Background: Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population.
Methods: A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis.
Results: Three SPP1 promoter polymorphisms, rs2853744:G>T, rs11730582:T>C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744:G>T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed.
Conclusions: In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G>T polymorphism after meta-analysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease.
Keywords
Candidate Gene Association Study, Meta-analysis, Pakistan, Renal Calculi, SPP1, SNP
Figure 1
Figure 2
This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1.pdf
Additional file 1 (.docx): Oligonucleotide sequences, PCR conditions and restriction enzyme used for the genotyping of SPP1 gene polymorphisms.
- Additionalfile2.docx
Additional file 2 (.docx): Basic characteristics of the study participants in the case-control part of the study.
- Additionalfile3.docx
Additional file 3 (.docx): Basic information and HWE analysis for SPP1 gene polymorphisms analyzed in this study.
- Additionalfile4.docx
Additional file 4 (.docx): Representative electropherograms for each genotype of three SPP1 polymorphisms. (A) rs11730582:T>C, (B) rs2853744:G>T and (C) rs11439060:delG>G.
- Additionalfile5.docx
Additional file 5 (.docx): Pairwise linkage disequilibrium (LD) map, based on D´ values, of SPP1 polymorphic markers analyzed in the present study. No significant LD was apparent in any of the SPP1 polymorphic pairs analyzed.
- Additionalfile6.docx
Additional file 6A (.docx): Association of SPP1 rs2853744:G>T with different clinical characteristics of urolithiasis. Additional file 6B (.docx): Association of SPP1 rs11730582:T>C with different clinical characteristics of urolithiasis. Additional file 6C (.docx): Association of SPP1 rs11439060:delG>G with different clinical characteristics of urolithiasis.
- Additionalfile7.docx
Additional file 7 (.docx): Meta-analysis of SPP1 rs11730582:T>C polymorphism with risk of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11730582 polymorphism using dominant and recessive model, respectively. c) and d) Funnel plots of rs11730582 polymorphism assuming dominant and recessive inheritance, respectively, using fixed effect model.
- Additionalfile8.docx
Additional file 8 (.docx): Meta-analysis of SPP1 rs11439060:delG>G polymorphism with susceptibility of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11439060 polymorphism following dominant and recessive model, respectively. c) and d) Funnel plots of rs11439060 polymorphism using dominant and recessive inheritance, respectively, by random effect model.
- Additionalfile9.xlsx
Additional file 9 (.xlsx): Raw dataset with details of genotypes and phenotypes of every study subject analyzed for SPP1 polymorphisms in this study.
- Additionalfile9030820.xlsx
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See the published version of this preprint at BMC Medical Genetics.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Shagufta Khaliq
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0576-3969
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Medical Genetics.
Version 7
Posted 10 Aug, 2020
No community comments so far
Submission checks complete
On 04 Aug, 2020
Editorial decision: Accept
On 04 Aug, 2020
No comments provided
Editor assigned
On 20 Jul, 2020
Submission checks complete
On 19 Jul, 2020
Editor invited
On 19 Jul, 2020
No comments provided
Submission checks complete
On 15 Jul, 2020
Editorial decision: Minor revision
On 15 Jul, 2020
No comments provided
Submission checks complete
On 19 May, 2020
Editorial decision: Minor revision
On 19 May, 2020
No comments provided
Editorial decision: Minor revision
On 22 Apr, 2020
Editor assigned
On 20 Apr, 2020
Submission checks complete
On 19 Apr, 2020
Editor invited
On 19 Apr, 2020
No comments provided
Editorial decision: Minor revision
On 16 Apr, 2020
Review #1 received
Received 15 Apr, 2020
Reviewer #2 agreed
On 15 Apr, 2020
Review #2 received
Received 15 Apr, 2020
Editor assigned
On 13 Apr, 2020
Reviewers invited
Invitations sent on 13 Apr, 2020
Reviewer #1 agreed
On 13 Apr, 2020
Submission checks complete
On 12 Apr, 2020
Editor invited
On 12 Apr, 2020
No comments provided
Review #2 received
Received 25 Mar, 2020
Editorial decision: Minor revision
On 25 Mar, 2020
Review #1 received
Received 24 Mar, 2020
Reviewer #2 agreed
On 04 Mar, 2020
Reviewer #1 agreed
On 02 Mar, 2020
Reviewers invited
Invitations sent on 01 Mar, 2020
Editor assigned
On 24 Feb, 2020
Submission checks complete
On 21 Feb, 2020
Editor invited
On 20 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at BMC Medical Genetics.
Background: Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population.
Methods: A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis.
Results: Three SPP1 promoter polymorphisms, rs2853744:G>T, rs11730582:T>C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744:G>T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed.
Conclusions: In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G>T polymorphism after meta-analysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease.
Figure 1
Figure 2
This is a list of supplementary files associated with this preprint. Click to download.
- Additionalfile1.pdf
Additional file 1 (.docx): Oligonucleotide sequences, PCR conditions and restriction enzyme used for the genotyping of SPP1 gene polymorphisms.
- Additionalfile2.docx
Additional file 2 (.docx): Basic characteristics of the study participants in the case-control part of the study.
- Additionalfile3.docx
Additional file 3 (.docx): Basic information and HWE analysis for SPP1 gene polymorphisms analyzed in this study.
- Additionalfile4.docx
Additional file 4 (.docx): Representative electropherograms for each genotype of three SPP1 polymorphisms. (A) rs11730582:T>C, (B) rs2853744:G>T and (C) rs11439060:delG>G.
- Additionalfile5.docx
Additional file 5 (.docx): Pairwise linkage disequilibrium (LD) map, based on D´ values, of SPP1 polymorphic markers analyzed in the present study. No significant LD was apparent in any of the SPP1 polymorphic pairs analyzed.
- Additionalfile6.docx
Additional file 6A (.docx): Association of SPP1 rs2853744:G>T with different clinical characteristics of urolithiasis. Additional file 6B (.docx): Association of SPP1 rs11730582:T>C with different clinical characteristics of urolithiasis. Additional file 6C (.docx): Association of SPP1 rs11439060:delG>G with different clinical characteristics of urolithiasis.
- Additionalfile7.docx
Additional file 7 (.docx): Meta-analysis of SPP1 rs11730582:T>C polymorphism with risk of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11730582 polymorphism using dominant and recessive model, respectively. c) and d) Funnel plots of rs11730582 polymorphism assuming dominant and recessive inheritance, respectively, using fixed effect model.
- Additionalfile8.docx
Additional file 8 (.docx): Meta-analysis of SPP1 rs11439060:delG>G polymorphism with susceptibility of urolithiasis. a) and b) Forest plots of urolithiasis association with rs11439060 polymorphism following dominant and recessive model, respectively. c) and d) Funnel plots of rs11439060 polymorphism using dominant and recessive inheritance, respectively, by random effect model.
- Additionalfile9.xlsx
Additional file 9 (.xlsx): Raw dataset with details of genotypes and phenotypes of every study subject analyzed for SPP1 polymorphisms in this study.
- Additionalfile9030820.xlsx
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