Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) single nucleotide polymorphisms are associated with acute allograft renal transplantation rejection: A multilevel modelling of meta-analysis

Besut Daryanto; Athaya Febriantyo Purnomo

doi:10.12688/f1000research.75633.1

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Systematic Review

Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) single nucleotide polymorphisms are associated with acute allograft renal transplantation rejection: A multilevel modelling of meta-analysis

[version 1; peer review: 1 approved, 1 approved with reservations]

Besut Daryanto ¹, Athaya Febriantyo Purnomo¹

PUBLISHED 05 Aug 2022

Author details Author details

¹ Department of Urology, Faculty of Medicine, Universitas Brawijaya-Saiful Anwar General Hospital, Malang, East-Java, 65145, Indonesia

Besut Daryanto
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Athaya Febriantyo Purnomo
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

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Abstract

Background: Acute renal transplant rejection is believed to be an immunological phenomenon and is one of the most serious consequences of transplantation as a treatment for end-stage renal illness. In recent decades, numerous research has been conducted to investigate the relationship between cytotoxic T-lymphocyte antigen 4 +49A/G (CTLA-4 +49A/G) single nucleotide polymorphisms (SNPs) with the likelihood of rejection; nevertheless, the results are still controversial, and inconsistency has been documented among investigations. Consequently, the purpose of the present investigation was to conduct a study on the relation between CTLA-4 +49A/G polymorphism and risk of transplant rejection.
Methods: The study was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Retrospective and prospective analytical randomized control trial (RCTs) published prints from Embase, PubMed, Cochrane, and Web of science were included to the study in accordance with the PRISMA guidelines. The search was conducted on February 2nd, 2022, using the search term (cytotoxic-T-lymphocyte-antigen-4 OR CTLA-4) AND (gene polymorphism OR single nucleotide polymorphisms OR allele OR alleles OR genotype OR genotypes) AND (renal OR kidney) AND (transplant OR transplantation) AND (acute rejection).
Results: The CTLA-4 G-allele/GG-genotype was more likely to be related to renal transplantation rejection risk. It was found with odds ratio (OR) in overall analysis of G vs. A-allele was 1.22 (95%CI 1.05-1.42; p-value=0.01) and the OR of GG vs. AG+AA-genotype was 1.47 (95%CI 1.14-1.89; p-value=0.003). However, the AA-genotype was not associated with renal transplantation rejection risk. The interesting finding in this study was the association of the SNPs and rejection of renal transplantation was especially found in Asian sub-analysis.
Conclusions: Consequently, the CTLA-4 G-allele/GG-genotype is related to the likelihood of rejection in patients underwent renal transplantation.

Keywords

gene polymorphism, renal transplant rejection, cytotoxic T-lymphocyte associated protein 4 (CTLA-4)

Corresponding author: Besut Daryanto

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2022 Daryanto B and Purnomo AF. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Daryanto B and Purnomo AF. Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) single nucleotide polymorphisms are associated with acute allograft renal transplantation rejection: A multilevel modelling of meta-analysis [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2022, 11:904 (https://doi.org/10.12688/f1000research.75633.1) First published: 05 Aug 2022, 11:904 (https://doi.org/10.12688/f1000research.75633.1) Latest published: 05 Aug 2022, 11:904 (https://doi.org/10.12688/f1000research.75633.1)

Introduction

High mortality and morbidity rates are still the main issues in end-stage renal disease (ESRD), and it increases healthcare utilization.¹ There are several options directed for renal replacement therapy as ESRD treatment, which are hemodialysis (HD), continuous-ambulatory peritoneal-dialysis (CAPD), and renal transplantation. For now, renal transplantation is the gold standard treatment for ESRD.¹^,² Renal transplantation is still the best method option for treatment for ESRD due to better quality of life, the modifiable morbidity rate, promising survival rates, and the greatest impacts in daily basis activities in spite of the rejection risks as one of the complications.³^,⁴

Presently, renal transplantation is the most effective treatment for end-stage renal illness, because it preserved individuals with ESRD’s lives.² However, the big issue of renal transplantation is acute rejection in some recipient cases, which diminishes the quality of the donated kidney.² Renal transplantation rejection can consequently decrease the renal physiological function and become a threat to a patient’s life. Therefore, it is essential to investigate factors that aggravate transplantation rejection.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), is a regulatory molecule that inhibits T-cell effector action after first costimulatory signal activation.³^,⁴ CTLA-4 has been implicated in acute renal transplantation rejection etiology, according to available dataset.³ The CTLA-4 +49A/G single nucleotide polymorphism (SNPs) involves a shift from the A to the G-allele that leads to several complicated sequences that jeopardize the next transcription-translation phase of DNA. CTLA-4 is a key CTLA variation, and current findings indicate that the CTLA-4 +49A/G SNPs increases the likelihood of rejection. Previous meta-analysis has been conducted to evaluate the association between the CTLA-4 +49A/G SNPs and the incidence of renal transplantation rejection.⁴ Nonetheless, there was no assessment of the nature of polymorphism, which included Hardy-Weinberg equilibrium in order to exclude the chance of polymorphism influenced by evolution, moreover only limited studies were included. This study was conducted to determine if the CTLA-4 +49A/G SNPs were connected with the incidence of renal transplantation rejection by compiling a large number of previously published papers.

Methods

Search strategy

The study was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.⁵ The search was conducted on February 2^nd, 2022. Retrospective and prospective analytical randomized control trials (RCTs) published prints from Embase, PubMed, Cochrane, and Web of science were included in accordance with the PRISMA guideline and thoroughly analyzed using a random or fixed effect model regarding to its heterogeneity. These datasets were populated with the retrieval approach “(cytotoxic-T-lymphocyte-antigen-4 OR CTLA-4) AND (gene polymorphism OR single nucleotide polymorphisms OR allele OR alleles OR genotype OR genotypes) AND (renal OR kidney) AND (transplant OR transplantation) AND (acute rejection).” The extra reports were discovered using the citations found in the selected papers.

Inclusion and exclusion criteria

Studies included had quantitative data of renal transplantation rejection genotype that had the cases of acute rejection and non-acute rejection comparison data; and adequate data on the distribution of the CTLA-4 +49A/G genotype was required. We also include retrospective or prospective studies, randomized trials, that provided sufficient data of odds ratio (OR) 95% confidence interval (CI). The thirteen studies that were included are shown in Figure 1. Other studies than those stated before were excluded.

Figure 1. A flowchart of the article selection in our study.

We also measured the Hardy-Weinberg Equilibrium (HWE) formula (X2>3.84 indicated as deviation from HWE) as described by Rodriguez et al. 2009.⁶ Two reviewers (BD and AFP) worked independently at first to screen each record and each report retrieved, then reviewers discussed to achieve consensus. Any disagreement toward the included studies was resolved by consensus.

Data synthesis and extraction

Two reviewers (BD and AFP) performed the literature selection and gathered the data from electronic databases that accumulated into a dataset qualified study that collected: the first author, the year of publication, the ethnicity, and patient-control proportions for CTLA-4 +49A/G genotyping into Microsoft Excel v2013. Using the distribution of the associated genotypes, the occurrence of the G-allele in CTLA-4 +49A/G were computed. The outcomes were compared, and differences were addressed via discussion.

Data analysis

Application of Review Manager version 5 (Cochrane Library, UK) was utilized to compute the available dataset from the included studies. The dataset included in the software was firstly collected in Microsoft Excel. Model of random effect was applied when p-value in heterogeneity test was <0.05. For dichotomous data, results were reported using OR, and 95% CI was also computed. Overall analysis needed p-value <0.05 to be interpreted as statistically significant. I² was utilized for heterogeneity between the included studies as well.

Results

Characteristics of the included study

This meta-analysis included 13 out of 15 papers⁷^–²¹ investigating the relationship between CTLA-4 +49A/G SNPs and renal transplantation rejection risk. The data were extracted, and the occurrence of the G-allele of CTLA-4 +49A/G in the groups was determined. Table 1 presents the characteristics of the studies. These 13 studies included 959 patients with acute rejection and 2069 controls with non-acute rejection.

Table 1. Characteristics of the included studies.

Author, reference (year)	Case genotype				Control genotype				Country	Ethnicity	Genotyping	X2 HWE (control)
Author, reference (year)	AA	AG	GG	N	AA	AG	GG	N	Country	Ethnicity	Genotyping	X2 HWE (control)
Canossi et al.¹⁸ (2013)	5	11	18	34	2	21	11	34	Italy	Caucasians	Polymerase Chain Reaction	3,6662
Dmitrienko et al.⁷ (2005)	3	29	18	50	3	24	23	50	Canada	Caucasians	Polymerase Chain Reaction	1,0204
Domanski et al.¹⁶ (2012)	13	35	22	70	32	96	51	179	Poland	Caucasians	Polymerase Chain Reaction	1,2887
Gao et al.¹⁷ (2012)	25	16	4	45	44	62	16	122	China	Asians	Polymerase Chain Reaction	0,6485
Gendzekhadze et al.¹⁰ (2006)	5	16	9	30	5	11	17	33	Venezuela	Caucasians	Polymerase Chain Reaction	1,7723
Gorgi et al.⁹ (2006)	14	10	7	31	22	15	2	39	Tunisia	Africans	Polymerase Chain Reaction	0,0745
Kim et al.¹⁵ (2010)	34	19	6	59	124	115	27	266	Korea	Asians	Polymerase Chain Reaction	0,0020
Krichen et al.¹² (2009)	4	1	0	5	6	11	1	18	Tunisia	Africans	Polymerase Chain Reaction	1,8944
Misra et al.¹⁹ (2014)	10	12	14	36	20	56	78	154	India	Asians	Polymerase Chain Reaction	3,5822
Ruhi et al.¹⁴ (2010)	5	20	24	49	4	20	23	47	Turkey	Caucasians	Polymerase Chain Reaction	0,0141
Ruhi et al.²⁰ (2015)	4	17	13	34	4	20	23	47	Turkey	Caucasians	Polymerase Chain Reaction	0,0141
Slavcheva et al.²¹ 2001	24	81	60	165	15	51	53	119	USA	Mixed	Polymerase Chain Reaction	0,2467
Wisniewski et al.⁸ (2006)	12	13	13	38	11	23	19	53	Poland	Caucasians	Polymerase Chain Reaction	0,6629
Haimila et al.¹¹ (2009)	37			37	151			151	Finland	Caucasians	Polymerase Chain Reaction	None
Kusztal et al.¹³ (2010)	22			22	48			48	Poland	Caucasians	Polymerase Chain Reaction	None

Association between acute rejection and CTLA-4 +49A/G SNPs

As shown in Figure 2 and Table 2, in the overall analysis (OR=1.22, 95% CI:1.05-1.42, P=0.001), the CTLA-4 +49A/G G-allele was shown to be related to an increased risk of acute rejection after renal transplantation in this meta-analysis. In contrast, the A-allele seemed to be related with protective effect toward acute rejection risk. For renal transplantation, the presence of the GG-genotype (OR=1.47, 95% CI:1.14-1.89, P=0.003) increased the risk of acute rejection, as shown in Figure 3 and Table 2. However, the AA-genotype did not seem to protect against the acute rejection associated with transplantations (OR=0.87, 95% CI:0.69-1.09, P=0.21). This meta-analysis found that the CTLA-4 +49A/G SNPs were not linked to an increased risk of acute rejection in African or Caucasian ethnicities, according to multilevel modelling of analyses (Table 2). However, the CTLA-4 +49A/G G-allele was related with renal transplantation rejection risk among Asian populations, as shown in Figure 4 (OR=1.55, 95% CI:1.16-2.06, P=0.003; Table 2), but not in the general population. The GG-genotype was also linked to an increased risk of acute rejection after the analysis, as shown in Figure 5 (OR=1.91, 95% CI:1.29-2.84, P=0.001) and Table 2.

Figure 2. Forest plot of G-allele vs. A-allele in the overall population.

CI: confidence interval; P: P-value; I²: heterogeneity.

Table 2. Summary of the association between cytotoxic T-lymphocyte antigen 4 +49A/G (CTLA-4 +49A/G) single nucleotide polymorphisms (SNPs) (rs231775) and increased risk of acute renal transplantation rejection.

Allele & genotype	NS	Model	Sensitivity, %	Specificity, %	OR	95%CI	pH (Tau² if random)	I²	P
*Overall analysis*
G vs. A	13	Fixed	50.64	44.56	1.22	1.05 – 1.42	0.24	20%	0.010*
A vs. G	13	Fixed	49.36	55.40	0.82	0.71 – 0.95	0.24	20%	0.010*
GG vs. AG+AA	13	Fixed	30.78	63.90	1.47	1.14 – 1.89	0.60	0%	0.003*
AG vs. AA+GG	13	Fixed	39.72	61.40	0.88	0.29 – 1.61	0.10	36%	0.22
AA vs. AG+GG	13	Fixed	29.50	74.71	0.87	0.69 – 1.09	0.28	17%	0.21
*Asian sub-group*
G vs. A	3	Fixed	66.07	43.82	1.55	1.16 – 2.06	0.62	0%	0.003*
A vs. G	3	Fixed	33.93	56.18	0.65	0.48 – 0.86	0.62	0%	0.003*
GG vs. AG+AA	3	Fixed	49.29	65.31	1.91	1.29 – 2.84	0.57	0%	0.001*
AG vs. AA+GG	3	Fixed	33.57	57.01	0.65	0.44 – 0.96	0.64	0%	0.03
AA vs. AG+GG	3	Fixed	17.14	77.68	0.72	0.43 – 1.22	0.71	0%	0.22
*Caucasian sub-group*
G vs. A	7	Fixed	48.49	42.76	1.12	0.90 – 1.39	0.74	0%	0.32
A vs. G	7	Fixed	51.51	57.24	0.90	0.72 – 1.11	0.74	0%	0.32
GG vs. AG+AA	7	Fixed	29.12	59.50	1.31	0.85 – 2.01	0.95	0%	0.22
AG vs. AA+GG	7	Fixed	38.74	66.51	0.95	0.71 – 1.28	0.10	44%	0.74
AA vs. AG+GG	7	Fixed	32.14	73.99	0.92	0.68 – 1.25	0.26	23%	0.60
*African sub-group*
G vs. A	2	Random	65.28	28.07	1.28	0.14 – 12.04	0.05 (2.04)	75%	0.83
A vs. G	2	Random	34.72	71.93	0.78	0.08 – 7.36	0.05 (2.04)	75%	0.83
GG vs. AG+AA	2	Random	50	50.88	1.76	0.15 – 20.33	0.05 (2.37)	73%	0.65
AG vs. AA+GG	2	Fixed	30.56	54.39	0.58	0.24 – 1.42	0.23	29%	0.23
AA vs. AG+GG	2	Fixed	19.44	94.74	3.99	0.99 – 16.10	0.39	0%	0.05

* P<0.05.

Figure 3. Forest plot of GG-allele vs. AG-AA-allele in the overall population.

CI: confidence interval; P: P-value; I²: heterogeneity.

Figure 4. Forest plot of G-allele vs. A-allele in the Asian population.

CI: confidence interval; P: P-value; I²: heterogeneity.

Figure 5. Forest lot of GG-allele vs. AG-AA-allele in the Asian population.

CI: confidence interval; P: P-value; I²: heterogeneity.

Discussion

This meta-analysis found a connection between the CTLA-4 +49A/G G-allele/GG-genotype and the increased prevalence of acute renal transplantation rejection, with more prominent emphasis of evolution influence exclusion in the genetic polymorphism study. Additionally, we tested for publication bias and found that the CTLA-4 +49A/G SNPs had no influence on an increased incidence of acute renal rejection in general populations. The association of CTLA-4 +49A/G SNPs and acute renal rejection risk was shown to be strong. After further investigation, we discovered no association between the CTLA-4 +49A/G SNPs and the incidence of the rejection in the African and Caucasian population. Caucasians and Africans were underrepresented in the included studies. Therefore, further research about the role of the polymorphism among different ethnicities is necessary to be done.

Intriguingly, we discovered that the G-allele and GG-genotype were both linked to risk of renal transplantation rejection in Asians. It means that the G-allele and GG-genotype seemed to be a risk factor for acute rejection in Asian populations, according to this study. However, further research is needed to examine the link between the two variables. Our findings seemed to be quite stable in certain respects. Meta-analysis studied by Duan et al.²² found that the G-allele was related with a higher risk of acute rejection after renal transplantation, but not with the GG-genotype and the AA-genotype in the general population. However, a limitation of the previous paper was not classifying cases into ethnic subgroups, also the previous publication was not validated by the Hardy-Weinberg equilibrium that explains evolution theory influences that need to be excluded in order to make sure the SNPs occurred actually came from the patient’s case itself.

According to Zhu et al.,²³ the CTLA-4 +49A/G SNPs were not related with the incidence of renal transplant rejection in general populations. In a meta-analysis of nine studies, Gao et al.²⁴ found that the G-allele and GG-genotype were related with acute renal rejection risks in Asian populations and in general populations. As a consequence of the increased number of studies included in our meta-analysis (13 included studies), our findings were more vigorously updated than those from the prior meta-analyses, also the use of HWE analysis provides more valid results in terms of polymorphism study. CTLA-4 +49A/G SNPs, particularly the G-allele/GG-genotype, were associated with acute renal rejection risk in Asian ethnicity and overall populations, according to our findings. Because of a wide range of issues including linguistic bias, a small sample size, poor statistical power and heterogeneity of recruited patients, as well as a variety of research designs and varied therapies, the findings should be taken with a grain of salt.

Conclusions

To summarize, the findings of the conducted meta-analysis indicate that the CTLA-4 +49A/G SNPs, particularly the G-allele/GG-genotype, were related with the acute rejection, increased risk in renal transplantation cases of Asian ethnicity and global populations. But in spite of that, further association research is necessary to better elucidate this.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA checklist and flow diagram for ‘Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) Single Nucleotide Polymorphisms was corresponded with acute allograft renal transplantation rejection: a multilevel modelling of meta-analysis’. https://doi.org/10.6084/m9.figshare.20124215.²⁵

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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¹ Department of Urology, Faculty of Medicine, Universitas Brawijaya-Saiful Anwar General Hospital, Malang, East-Java, 65145, Indonesia

Competing interests

No competing interests were disclosed.

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The author(s) declared that no grants were involved in supporting this work.

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© 2022 Daryanto B and Purnomo AF. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Daryanto B and Purnomo AF. Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) single nucleotide polymorphisms are associated with acute allograft renal transplantation rejection: A multilevel modelling of meta-analysis [version 1; peer review: 1 approved, 1 approved with reservations]. F1000Research 2022, 11:904 (https://doi.org/10.12688/f1000research.75633.1)

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Reviewer Report 22 Feb 2023

Nurul Cholifah Lutfiana, Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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https://doi.org/10.5256/f1000research.79527.r146722

The strength of this paper is the meta-analysis in terms of effect estimates. This paper revealed the association not only of the overall population but also based on ethnicity, therefore although it seems to give significance to overall population, the interesting part is that only Asian sub-group has significant association, not for Caucasian and African. This meta-analysis was thoroughly and systematically reviewed using the PRISMA Guideline. The research question builds a good sense of the issue, on how the inconsistency of each findings, especially in SNPs study in renal transplantation, still have a hazy conclusion. Therefore the gap of inconsistency in the literature was well overcome by the explanation of further analysis using multilevel modelling.

The search strategy was comprehensive by searching the published prints from trusted resources for the field. The authors highlight the keywords they used in the study, and all the processes were well described and illustrated in a PRISMA flow diagram. The results are well presented, because they are summarized in tables, and illustrated in forest plots as it is the basic necessity for meta-analysis. The authors described how they discovered that the G-allele and GG-genotype were both linked to risk of renal transplantation rejection in Asians. They also highlight the prior report lacked a classification of patients into ethnic categories. In addition, the previous article was not evaluated by the Hardy-Weinberg equilibrium, which describes evolution theory factors that must be ruled out to ensure that the SNPs observed originated from the patient's instance

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Medicine

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Reviewer Report 31 Aug 2022

Yuki Nakagawa, Department of Urology, Graduate School of Medicine, Juntendo University, Tokyo, Japan

Approved with Reservations

https://doi.org/10.5256/f1000research.79527.r146723

This is a meta-analysis review of the association between cytotoxic T-lymphocyte antigen 4 +49A/G (CTLA-4 +49A/G) single nucleotide polymorphisms (SNPs) and the risk of kidney transplant rejection. It was systematically analyzed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, resulting in a more accurate survey.
It is interesting to note that the Asian subanalysis and SNP associations show that the G/GG genotype was associated with the risk of rejection. However, 54% of his Asian SNPs were GG type, 39% GA type, and 7% AA type. On top of that, it is necessary to re-evaluate whether this result is effective.

The ratio of single nucleotide polymorphism events by race was posted in the background of the target cases.
Depending on the number of subjects, the credibility of whether or not Asians can say the relationship between SNP GG type and rejection will come out.
Impaired absorption and metabolism of immunosuppressants (FK) is often observed in SNP GG type. We would like you to discuss the relevance of immunosuppressive drugs in this meaningful data on rejection.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: kidney transplant sorgen , ABO incompatible kidney transplantation

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 15 May 2023

Besut Daryanto, Department of Urology, Faculty of Medicine, Universitas Brawijaya-Saiful Anwar General Hospital, Malang, 65145, Indonesia

15 May 2023

Author Response

Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an ... Continue reading Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an association related to that. In order to take the next step of validating the SNPs toward the functionality and phenotype of the patients even more in the next studies. This could be an interesting further research field in order to explore more of the reasons and flows.

The relevance of immunosuppressive drugs in the context of patients with specific genotypes, such as those carrying GG genotype single nucleotide polymorphisms (SNPs), can be crucial in understanding the incidence of rejection in kidney transplantation. Genetic variations, such as SNPs, can affect how individuals metabolize or respond to certain medications, including immunosuppressive drugs.

For example, the CYP3A5 gene, which is responsible for the production of the CYP3A5 enzyme, plays an important role in the metabolism of calcineurin inhibitors like tacrolimus, a commonly used immunosuppressive drug in kidney transplantation. There is a well-known SNP in this gene, CYP3A5*3 (rs776746), where the non-expresser allele (G) results in reduced enzyme activity. Individuals with the GG genotype exhibit lower enzyme activity, leading to higher blood levels of tacrolimus at a given dose compared to those with other genotypes (e.g., AG or AA). As a result, GG individuals may require lower doses of tacrolimus to achieve the same therapeutic effect and avoid toxic side effects.

The relevance of genotyping for SNPs, like the one mentioned above, lies in its potential to personalize immunosuppressive therapy. By identifying patients with specific genotypes that influence drug metabolism or response, clinicians can tailor dosing regimens and therapeutic strategies to minimize the risk of rejection and adverse side effects. This approach is known as pharmacogenomics and can significantly improve the outcomes of kidney transplantation.
In summary, the relevance of immunosuppressive drugs in the context of patients with GG genotype SNPs is to understand how these genetic variations can impact drug metabolism or response. By identifying such variations, personalized immunosuppressive therapy can be designed to minimize the risk of rejection and optimize transplant outcomes. As this would be beneficial and applied in this study reviewed.
Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an association related to that. In order to take the next step of validating the SNPs toward the functionality and phenotype of the patients even more in the next studies. This could be an interesting further research field in order to explore more of the reasons and flows.

The relevance of immunosuppressive drugs in the context of patients with specific genotypes, such as those carrying GG genotype single nucleotide polymorphisms (SNPs), can be crucial in understanding the incidence of rejection in kidney transplantation. Genetic variations, such as SNPs, can affect how individuals metabolize or respond to certain medications, including immunosuppressive drugs.

For example, the CYP3A5 gene, which is responsible for the production of the CYP3A5 enzyme, plays an important role in the metabolism of calcineurin inhibitors like tacrolimus, a commonly used immunosuppressive drug in kidney transplantation. There is a well-known SNP in this gene, CYP3A5*3 (rs776746), where the non-expresser allele (G) results in reduced enzyme activity. Individuals with the GG genotype exhibit lower enzyme activity, leading to higher blood levels of tacrolimus at a given dose compared to those with other genotypes (e.g., AG or AA). As a result, GG individuals may require lower doses of tacrolimus to achieve the same therapeutic effect and avoid toxic side effects.

The relevance of genotyping for SNPs, like the one mentioned above, lies in its potential to personalize immunosuppressive therapy. By identifying patients with specific genotypes that influence drug metabolism or response, clinicians can tailor dosing regimens and therapeutic strategies to minimize the risk of rejection and adverse side effects. This approach is known as pharmacogenomics and can significantly improve the outcomes of kidney transplantation.
In summary, the relevance of immunosuppressive drugs in the context of patients with GG genotype SNPs is to understand how these genetic variations can impact drug metabolism or response. By identifying such variations, personalized immunosuppressive therapy can be designed to minimize the risk of rejection and optimize transplant outcomes. As this would be beneficial and applied in this study reviewed.
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Author Response 15 May 2023

Besut Daryanto, Department of Urology, Faculty of Medicine, Universitas Brawijaya-Saiful Anwar General Hospital, Malang, 65145, Indonesia

15 May 2023

Author Response

Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an ... Continue reading Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an association related to that. In order to take the next step of validating the SNPs toward the functionality and phenotype of the patients even more in the next studies. This could be an interesting further research field in order to explore more of the reasons and flows.

The relevance of immunosuppressive drugs in the context of patients with specific genotypes, such as those carrying GG genotype single nucleotide polymorphisms (SNPs), can be crucial in understanding the incidence of rejection in kidney transplantation. Genetic variations, such as SNPs, can affect how individuals metabolize or respond to certain medications, including immunosuppressive drugs.

For example, the CYP3A5 gene, which is responsible for the production of the CYP3A5 enzyme, plays an important role in the metabolism of calcineurin inhibitors like tacrolimus, a commonly used immunosuppressive drug in kidney transplantation. There is a well-known SNP in this gene, CYP3A5*3 (rs776746), where the non-expresser allele (G) results in reduced enzyme activity. Individuals with the GG genotype exhibit lower enzyme activity, leading to higher blood levels of tacrolimus at a given dose compared to those with other genotypes (e.g., AG or AA). As a result, GG individuals may require lower doses of tacrolimus to achieve the same therapeutic effect and avoid toxic side effects.

The relevance of genotyping for SNPs, like the one mentioned above, lies in its potential to personalize immunosuppressive therapy. By identifying patients with specific genotypes that influence drug metabolism or response, clinicians can tailor dosing regimens and therapeutic strategies to minimize the risk of rejection and adverse side effects. This approach is known as pharmacogenomics and can significantly improve the outcomes of kidney transplantation.
In summary, the relevance of immunosuppressive drugs in the context of patients with GG genotype SNPs is to understand how these genetic variations can impact drug metabolism or response. By identifying such variations, personalized immunosuppressive therapy can be designed to minimize the risk of rejection and optimize transplant outcomes. As this would be beneficial and applied in this study reviewed.
Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an association related to that. In order to take the next step of validating the SNPs toward the functionality and phenotype of the patients even more in the next studies. This could be an interesting further research field in order to explore more of the reasons and flows.

The relevance of immunosuppressive drugs in the context of patients with specific genotypes, such as those carrying GG genotype single nucleotide polymorphisms (SNPs), can be crucial in understanding the incidence of rejection in kidney transplantation. Genetic variations, such as SNPs, can affect how individuals metabolize or respond to certain medications, including immunosuppressive drugs.

For example, the CYP3A5 gene, which is responsible for the production of the CYP3A5 enzyme, plays an important role in the metabolism of calcineurin inhibitors like tacrolimus, a commonly used immunosuppressive drug in kidney transplantation. There is a well-known SNP in this gene, CYP3A5*3 (rs776746), where the non-expresser allele (G) results in reduced enzyme activity. Individuals with the GG genotype exhibit lower enzyme activity, leading to higher blood levels of tacrolimus at a given dose compared to those with other genotypes (e.g., AG or AA). As a result, GG individuals may require lower doses of tacrolimus to achieve the same therapeutic effect and avoid toxic side effects.

The relevance of genotyping for SNPs, like the one mentioned above, lies in its potential to personalize immunosuppressive therapy. By identifying patients with specific genotypes that influence drug metabolism or response, clinicians can tailor dosing regimens and therapeutic strategies to minimize the risk of rejection and adverse side effects. This approach is known as pharmacogenomics and can significantly improve the outcomes of kidney transplantation.
In summary, the relevance of immunosuppressive drugs in the context of patients with GG genotype SNPs is to understand how these genetic variations can impact drug metabolism or response. By identifying such variations, personalized immunosuppressive therapy can be designed to minimize the risk of rejection and optimize transplant outcomes. As this would be beneficial and applied in this study reviewed.
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Yuki Nakagawa, Juntendo University, Tokyo, Japan
Nurul Cholifah Lutfiana, University of Groningen, Groningen, The Netherlands

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Nurul Cholifah Lutfiana, Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Approved

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Competing Interests

No competing interests were disclosed.

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Medicine

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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31 Aug 2022 | for Version 1

Yuki Nakagawa, Department of Urology, Graduate School of Medicine, Juntendo University, Tokyo, Japan

16 Views Cite this report Responses(1)

Approved With Reservations

The ratio of single nucleotide polymorphism events by race was posted in the background of the target cases.
Depending on the number of subjects, the credibility of whether or not Asians can say the relationship between SNP GG type and rejection will come out.
Impaired absorption and metabolism of immunosuppressants (FK) is often observed in SNP GG type. We would like you to discuss the relevance of immunosuppressive drugs in this meaningful data on rejection.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

kidney transplant sorgen , ABO incompatible kidney transplantation

Respond to this report

Responses (1)

Author Response

15 May 2023

Besut Daryanto, Department of Urology, Faculty of Medicine, Universitas Brawijaya-Saiful Anwar General Hospital, Malang, 65145, Indonesia

Thank you for your input Prof. Absolutely, whether that 54% of this SNPs is effective should be interrogated further. However by this study, we could actually see there was an association related to that. In order to take the next step of validating the SNPs toward the functionality and phenotype of the patients even more in the next studies. This could be an interesting further research field in order to explore more of the reasons and flows.

The relevance of immunosuppressive drugs in the context of patients with specific genotypes, such as those carrying GG genotype single nucleotide polymorphisms (SNPs), can be crucial in understanding the incidence of rejection in kidney transplantation. Genetic variations, such as SNPs, can affect how individuals metabolize or respond to certain medications, including immunosuppressive drugs.

For example, the CYP3A5 gene, which is responsible for the production of the CYP3A5 enzyme, plays an important role in the metabolism of calcineurin inhibitors like tacrolimus, a commonly used immunosuppressive drug in kidney transplantation. There is a well-known SNP in this gene, CYP3A5*3 (rs776746), where the non-expresser allele (G) results in reduced enzyme activity. Individuals with the GG genotype exhibit lower enzyme activity, leading to higher blood levels of tacrolimus at a given dose compared to those with other genotypes (e.g., AG or AA). As a result, GG individuals may require lower doses of tacrolimus to achieve the same therapeutic effect and avoid toxic side effects.

The relevance of genotyping for SNPs, like the one mentioned above, lies in its potential to personalize immunosuppressive therapy. By identifying patients with specific genotypes that influence drug metabolism or response, clinicians can tailor dosing regimens and therapeutic strategies to minimize the risk of rejection and adverse side effects. This approach is known as pharmacogenomics and can significantly improve the outcomes of kidney transplantation.
In summary, the relevance of immunosuppressive drugs in the context of patients with GG genotype SNPs is to understand how these genetic variations can impact drug metabolism or response. By identifying such variations, personalized immunosuppressive therapy can be designed to minimize the risk of rejection and optimize transplant outcomes. As this would be beneficial and applied in this study reviewed.

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Competing Interests

None of competing interest was declared.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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[25] 25. Daryanto B, Purnomo AF: Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) Single Nucleotide Polymorphisms was corresponded with acute allograft renal transplantation rejection: a multilevel modelling of meta-analysis. Figshare. [Dataset].2022.

Cytotoxic T-lymphocyte associated-protein-4 +49A/G-allele (rs231775) single nucleotide polymorphisms are associated with acute allograft renal transplantation rejection: A multilevel modelling of meta-analysis

Abstract

Keywords

Introduction

Methods

Search strategy

Inclusion and exclusion criteria

Figure 1. A flowchart of the article selection in our study.

Data synthesis and extraction

Data analysis

Results

Characteristics of the included study

Table 1. Characteristics of the included studies.

Association between acute rejection and CTLA-4 +49A/G SNPs

Figure 2. Forest plot of G-allele vs. A-allele in the overall population.

Table 2. Summary of the association between cytotoxic T-lymphocyte antigen 4 +49A/G (CTLA-4 +49A/G) single nucleotide polymorphisms (SNPs) (rs231775) and increased risk of acute renal transplantation rejection.

Figure 3. Forest plot of GG-allele vs. AG-AA-allele in the overall population.

Figure 4. Forest plot of G-allele vs. A-allele in the Asian population.

Figure 5. Forest lot of GG-allele vs. AG-AA-allele in the Asian population.

Discussion

Conclusions

Data availability

Underlying data

Reporting guidelines

References

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