Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Effect Size of Homocysteine in Sickle Cell Disease
2.2. Effect Size of Homocysteine in Adult Sickle Cell Disease
2.3. Effect Size of Homocysteine in Childhood Sickle Cell Disease
2.4. Effect Size of Homocysteine on Vaso-Occlusive Crisis
2.5. Effect Size of Methylenetetrahydrofolate Reductase in Sickle Cell Disease
2.6. Effect Size of Cystathionine Beta Synthase in Sickle Cell Disease
2.7. Effect Size of Methylenetetrahydrofolate Reductase in Vaso-Occlusive Crisis
2.8. Effect Size of Methylenetetrahydrofolate Reductase in Ischaemic Stroke
2.9. Effect Size of Methylenetetrahydrofolate Reductase in Avascular Necrosis
2.10. Age at Presentation of Vaso-Occlusive Crisis
3. Discussion
4. Methods
4.1. Search Strategy
4.2. Inclusion Criteria
4.3. Exclusion Criteria
4.4. Data Extraction
4.5. Evaluation of the Quality of the Studies
4.6. Outcome Measures
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Ref. | Author/Year | Ethnicity | CTR | F/M | Age | HC | SCD | F/M | Age | HC | HC | FA | B12 | VOC | IS | HU | NOS | |
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SS | SC/βthal | |||||||||||||||||
No. | No. | Years | μmol/L | No. | No. | No. | Years | μmol/L | Method | |||||||||
x ± SD | x ± SD | x ± SD | x ± SD | |||||||||||||||
Case control studies | ||||||||||||||||||
[11] | van der Dijs 1998 | Dutch Antilles | 20 | 10/10 | 9 ± 4 | 10.9 ± 3.5 | 27 | 15/12 | 8 ± 4 | 12.5 ± 5 | HPLC | nor | nor | 7 | ||||
[12] | Balasa 1999 | USA | 198 | 8.3 ± 4.9 | 6 ± 3.1 | 40 | 12.8 ± 6.2 | 6.5 ± 3 | HPLC | nor | nor | y | y | 6 | ||||
[13] | Rodriguez-Cortes 1999 | USA | 73 | 6.1 ± 2.7 | 120 | 51/69 | 10.5 ± 5 | 5.2 ± 2.5 | HPLC | nor | na | y | 6 | |||||
[14] | Lowenthal 2000 | USA | 16 | 36 ± 12 | 9.7 ± 3.7 | 37 | 12 | 30/19 | 30.5 ± 9 | 16.8 ± 7.9 | HPLC | high | nor | 5 | ||||
[15] | Balasa 2002 | USA | 110 | 63/47 | 10.8 ± 4.29 | 7.5 ± 2.1 | 77 | 43/34 | 11.1 ± 5.2 | 8.25 ± 3.4 | HPLC | nor | B6 | y | 5 | |||
[16] | VanderJagt 2002 | USA | 77 | 40/37 | 13.3 ± 3.0 | 9.9 ± 5.6 | 77 | 37/40 | 13.4 ± 3.6 | 9.5 ± 3.35 | FPIA | na | na | 4 | ||||
[17] | Dhar 2004 | USA | 75 | 50/25 | 42 ± 13 | 8.5 ± 3.1 | 63 | 8/9 | 63/27 | 37 ± 12 | 9.7 ± 4.2 | ELISA | high | nor | y | 7 | ||
[18] | Segal 2004 | USA | 11 | 8/3 | 8.3 ± 3.7 | 4.3 ± 1.03 | 17 | 9/8 | 9.8 ± 3.9 | 5.4 ± 0.96 | HPLC | nor | nor | exc | 6 | |||
[19] | Abbas 2011 | Iraq | 25 | 13/12 | 14.4 ± 7.69 | 18.65 ± 4.56 | 6 | 0/20 | 10/16 | 14.3 ± 7.6 | 44.52 ± 23 | HPLC | nor | nor | 5 | |||
[20] | Ajayi 2012 | USA | 57 | 33/24 | 464 ± 14 | 9.12 ± 0.9 | 20 | 7/2 | 9/20 | 34 ± 10 | 8.35 ± 2 | na | high | na | y | 8 | ||
[21] | Pandey 2012 | India | 60 | 23/37 | 11.2 ± 5.3 | 8.7 ± 4.25 | 40 | 16/24 | 11.2 ± 5.3 | 25.7 ± 8.24 | ELISA | na | na | 5 | ||||
[22] | Al-Nuzaily 2014 | Yemen | 20 | 8/12 | 8.6 ± 4.6 | 8.9 ± 1.8 | 5 | 1/4 | 6.9 ± 3.0 | 20.8 ± 6.9 | ELISA | na | na | 5 | ||||
[23] | Olaniyi 2014 | Nigeria | 30 | 16/14 | 26 ± 4.8 | 9.13 ± 0.75 | 60 | 28/32 | 26 ± 5 | 5.79 ± 0.65 | HPLC | low | low | y | 6 | |||
[24] | Nnodim 2015 | Nigeria | 100 | 13.6 ± 4.8 | 100 | 5–30 | 24.2 ± 6.2 | Spectro | na | na | y | 4 | ||||||
[25] | Abdelsalam 2016 | Sudan | 200 | 26.25 ± 5.25 | 4.92 ± 1.77 | 200 | 29.5 ± 5.5 | 6.47 ± 2.08 | ELISA | na | na | 4 | ||||||
[26] | Knox-Macaulay 2018 | Oman | 151 | 27/114 | 26.6 ± 10.7 | 11.55 ± 5.9 | 32 | 0/101 | 73/60 | 21 ± 5.7 | 8.05 ± 2.4 | FPIA | nor | nor | y | exc | 6 | |
[27] | Raouf 2017 | Egypt | 30 | 13/17 | 6.03 ± 2.64 | 18.8 ± 3.7 | 18 | 0/32 | 17/33 | 6.2 ± 2.5 | 44.6 ± 9 | HPLC | low | nor | y | 5 | ||
[53] | Ali 2019 | Nigeria | 26 | 12/14 | 27.6 ± 6.6 | 9.9 ± 2.5 | 55 | 28/27 | 24.8 ± 5.5 | 11.1 ± 3.4 | ELISA | nor | nor | y | 6 | |||
[28] | Higuera 2019 | Venezuela | 23 | 13/10 | 33 ± 7 | 9.43 ± 1.8 | 15 | 10/5 | 31 ± 7.6 | 6.97 ± 2.2 | FPIA | na | na | 5 | ||||
[29] | Meher 2019 | India | 50 | 32/18 | 21 ± 4 | 13.2 ± 4.4 | 120 | 61/59 | 24 ± 8 | 22.41 ± 7.78 | Spectro | na | na | y | exc | 7 | ||
[30] | Uche 2019 | Nigeria | 96 | 51/45 | 30 ± 11 | 9.16 ± 4.29 | 96 | 51/45 | 29 ± 12 | 19.8 ± 19.7 | ELISA | na | na | y | 5 | |||
[31] | Ayoola 2020 | Nigeria | 33 | 16/17 | 24 ± 3 | 10.2 ± 4.1 | 44 | 3/0 | 21/23 | 25 ± 3.7 | 17.95 ± 5.3 | ELISA | na | na | 6 | |||
Cohort studies | ||||||||||||||||||
[32] | Houston 1997 | USA | 99 | 53/46 | 19 | 11.1 ± 4 | HPLC | nor | na | y | 6 | |||||||
[33] | Al-Saqladi 2010 | Yemen | 102 | 46/56 | 7.2 | 2.8 ± 1.7 | EIA | nor | nor | 5 |
Ref. | Author/Year | Ethnicity | CTR | F/M | Age | M-TT | SCD | F/M | Age | M-TT | VOC | NOS | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SS | SC/βthal | ||||||||||||
No. | No. | Years | No. | No. | No. | No. | Years | No. | |||||
x ± SD | x ± SD | ||||||||||||
[34] | Andrade 1998 | Brazil | 137 | 2 | 73 | 53/20 | 40/33 | 35 ± 13 | 0 | 4 | |||
[35] | Romana 2002 | Guadalupe | 203 | 6 | 314 | 314 | 7 | y | 5 | ||||
[36] | Fawaz 2004 | Saudi Arabia | 105 | 40/65 | 32.2 ± 15 | 4 | 87 | 87 | 49/38 | 23.1 ± 14.1 | 8 | 5 | |
[37] | Al-Absi 2006 | Bahrain | 156 | 76/80 | 27.8 ± 15.1 | 10 | 106 | 106 | 38/68 | 15.8 ± 9.8 | 5 | 4 | |
[38] | Nishank 2013 | India | 150 | 17 ± 6.8 | 0 | 150 | 150 | 16 ± 6 | 22 | 5 | |||
[39] | Kangne 2013 | India | 130 | 16.5 ± 11 | 4 | 180 | 126/54 | 78/102 | 16.5 ± 11 | 1 | y | 5 | |
[40] | Sedki 2015 | Egypt | 40 | 1 | 40 | 3 | y | 4 | |||||
[54] | Saad 2017 | Egypt | 40 | 3 | 40 | 13/27 | 2 | y | NE | ||||
[41] | Nefissi 2018 | Tunisia | 100 | 1 | 64 | 35/29 | 38/26 | 3–27 | 1 | 6 | |||
[42] | Adelekan 2019 | Nigeria | 96 | 51/45 | 29.3 ± 10.3 | 0 | 96 | 96 | 51/45 | 29.3 ± 10.3 | 1 | 7 | |
CBSin68 | CBSin68 | ||||||||||||
[35] | Romana 2002 | Guadalupe | 203 | 2.2 | 2 | 317 | 7 | 4 | 4 | ||||
[43] | El-Gawhary 2017 | Egypt | 42 | 0 | 1 | 53 | 0 | NE |
Ref. | Author/Year | Ethnicity | SCD | F/M | Age | M-TT + ve | IS + ve | AVN + ve | VOC + ve | NOS | |
---|---|---|---|---|---|---|---|---|---|---|---|
SS | SC/βthal | ||||||||||
No. | No. | No. | Years | No. | No. | No. | No. | ||||
x ± SD | |||||||||||
[44] | Zimmerman 1998 | USA | 76 | 9/1 | 32/54 | 23 ± 15 | 0 | 16 | 14 | 5 | |
[45] | Cumming 1999 | Jamaica | 96 | 26/22 | 7–36 | 1 | 48 | 5 | |||
[46] | Driscoll 1999 | USA | 53 | 14/39 | 2–17 | 1 | 18 | 5 | |||
[47] | Kutlar 2001 | USA | 107 | 66/41 | 31.9 | 1 | 45 | 4 | |||
[48] | Adekile 2001 | Kuwait | 33 | 8 | 12.8 ± 8.6 | 1 | 7 | 6 | |||
[49] | Filho 2011 | Brazil | 94 | 46/48 | 6.6 | 4 | 24 | 7 | |||
[50] | Jacob 2011 * | Brazil | 48 | 20/23 | 19–59 | 2 | 1 | 59 | 4 | ||
[51] | Italia 2014 @ | India | 80 | 30 | 20 ± 8 | 1 | 6 | 21 | 6 | ||
[52] | Merghani 2015 | Sudan | 96 | 60/36 | 11 ± 9.2 | 1 | 34 | 5 |
(A) Sensitivity Analysis by Meta-Regression | ||||
Studies No. | CC | 95% CI | p Value | |
Year of publication | 12 | −0.0006 | −0.108, 0109 | 0.99 |
Sample size | 12 | 0.101 | −0.003, 0.024 | 0.13 |
Mean age of SCD participants | 12 | 0.014 | −0.124, 0.163 | 0.80 |
Female/male ratio | 10 | 0.032 | −0.343, 0.279 | 0.83 |
NOQAS | 12 | −0.136 | −0.365, 0.092 | 0.24 |
(B) Sensitivity Analysis by Subgroups | ||||
Subgroup | Studies No. | Heterogeneity | Effect Size | |
No. | % | p Value | p Value | |
By ethnicity | ||||
USA | 3 | 87.8 | 0.0001 | 0.55 |
Africa | 6 | 97.8 | 0.0001 | 0.74 |
Other | 3 | 97.5 | 0.0001 | 0.83 |
by HC assay | ||||
HPLC | 2 | 99.1 | 0.0001 | 0.5 |
ELISA | 5 | 78.5 | 0.001 | 0.0001 |
Spectrometry | 2 | 81.9 | 0.01 | 0.0001 |
FPIA | 2 | 61.1 | 0.19 | 0.005 |
by vitamin B12 | ||||
Normal | 4 | 91.0 | 0.0001 | 0.47 |
Low | 2 | 98.6 | 0.0001 | 0.20 |
Not reported | 6 | 93.9 | 0.0001 | 0.002 |
by folate | ||||
Normal | 5 | 89.1 | 0.0001 | 0.79 |
Low | 1 | |||
Not reported | 6 | 93.9 | 0.0001 | 0.002 |
by vaso-occlusive crisis | ||||
Yes | 6 | 98.3 | 0.0001 | 0.81 |
No | 6 | 92.8 | 0.0001 | 0.29 |
(A) Sensitivity Analysis by Meta-Regression | ||||
Studies No. | CC | 95% CI | p Value | |
Year of publication | 10 | 0.185 | 0.133, 0231 | <0.0001 |
Sample size | 10 | −0.022 | −0.041, 0.024 | 0.027 |
Mean age of SCD participants | 10 | −0.286 | −0.566, −0.006 | 0.045 |
Female/male ratio | 9 | −1.939 | −3.671, −0.206 | 0.028 |
NOQAS | 12 | −0.136 | −0.365, 0.092 | 0.24 |
(B) Sensitivity Analysis by Subgroups | ||||
Subgroup | Studies No. | Heterogeneity | Effect Size | |
No. | % | p Value | p Value | |
By HC Assay | ||||
HPLC | 7 | 94.3 | 0.0001 | 0.01 |
ELISA | 2 | 15.3 | 0.27 | 0.0001 |
FPIA | 1 | na | na | na |
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Ames, P.R.J.; Arcaro, A.; Caruso, M.; Graf, M.; Marottoli, V.; Gentile, F. Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2022, 23, 14641. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314641
Ames PRJ, Arcaro A, Caruso M, Graf M, Marottoli V, Gentile F. Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences. 2022; 23(23):14641. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314641
Chicago/Turabian StyleAmes, Paul R. J., Alessia Arcaro, Matilde Caruso, Maria Graf, Vincenzo Marottoli, and Fabrizio Gentile. 2022. "Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis" International Journal of Molecular Sciences 23, no. 23: 14641. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314641