Introduction
Materials and methods
Literature search
Inclusion and exclusion criteria
Data extraction
Quality assessment
Statistical analysis
Ethical approval
Results
Study selection and characteristics
Author | Year | Region | Ethnicity | PCOS Diagnostic criteria | Inclusion criteria for the control group | Control source | Genotyping method | SNP | NOS |
---|---|---|---|---|---|---|---|---|---|
Almawi [20] | 2016 | Bahrain | Caucasian | Rotterdam | age-and ethnically-matched; testosterone levels were within range (0.4–3.5 nmol/L) in the menstrual cycle follicular phase; no metabolic or endocrine diseases; BMI were between 18 and 45 kg/m2;without recent illness; without treatment may affect carbohydrate metabolism or hormonal levels within 3 months; without using anti-hypertensive, oral contraceptive, anti-inflammatory and lipid-lowering drugs | PB | RT-PCR | rs2010963 rs833061 rs3025039 rs699947 rs1570360 | 8 |
Bao [21] | 2019 | India | Asian | Rotterdam | age-and ethnically-matched; testosterone levels were within range (0.4–3.5 nmol/L) in the menstrual cycle follicular phase; no metabolic or endocrine diseases; BMI were between 18 and 45 kg/m2;without recent illness; without using anti-hypertensive, oral contraceptive, anti-inflammatory and lipid-lowering drugs | PB | RT-PCR | rs2010963 rs833061 rs3025039 rs699947 rs1570360 | 6 |
Ben Salem [22] | 2016 | Tunisia | Caucasian | Rotterdam | women with regular menstrual cycles and no evidence of hirsutism, acne, alopecia, or endocrinopathies; without treatment may affect carbohydrate metabolism or hormonal levels within 3 months | PB | RT-PCR | rs833061 rs3025039 rs699947 rs1570360 | 7 |
Ding [28] | 2009 | China | Asian | Rotterdam | women with regular menstrual cycles; with normal ovarian morphology; without treatment may affect carbohydrate metabolism or hormonal levels within 3 months; no metabolic or endocrine diseases; | HB | PCR | rs3025039 | 6 |
Gomes [23] | 2019 | Brazil | Caucasian | Rotterdam | age- matched; fertile women with no history of hyperandrogenism, menstrual dysfunction, infertility, or sonographic signal of PCOS; without using contraceptives, antiandrogens, statins, glucocorticoids or infertility medications within 6 months | PB | PCR-RFLP (rs699947) RT-PCR (rs1570360) | rs699947 rs1570360 | 6 |
Guruvaiah [24] | 2014 | India | Asian | Rotterdam | fertile women with regular menstrual cycles and had a successful pregnancy record; with normal ovarian morphology confirmed by ultrasound | PB | PCR | rs2010963 rs833061 | 7 |
Huang [25] | 2019 | China | Asian | Rotterdam | women with normal menstrual cycles and had at least one successful pregnancy history; without endocrine disorders, family history of diabetes or sonographic signs of PCOS | HB | PCR-LDR | rs2010963 rs833061 | 7 |
Lee [26] | 2008 | Korea | Asian | Rotterdam | BMI-matched; with regular menstrual cycles; with normal ovarian morphology confirmed by ultrasound | PB | PCR | rs2010963 rs3025039 | 6 |
Li [29] | 2014 | China | Asian | Rotterdam | fertile women with regular menstrual cycles | HB | PCR-RFLP | rs1570360 | 6 |
Vural [27] | 2009 | Turkey | Caucasian | Rotterdam | fertile women without hyperandrogenism, history of menstrual dysfunction, infertility or sonographic signs of PCOS. | PB | PCR | rs2010963 rs833061 rs699947 | 6 |
SNP | Author | Sample size | Case Genotype | Control genotype | HWE | |||||
---|---|---|---|---|---|---|---|---|---|---|
Case | Control | GG | GC | CC | GG | GC | CC | Y/N(p) | ||
rs2010963 | Almawi | 382 | 393 | 183 | 142 | 57 | 161 | 190 | 42 | 0.45 |
Bao | 55 | 52 | 28 | 11 | 16 | 26 | 12 | 14 | 0.47 | |
Guruvaiah | 126 | 130 | 70 | 46 | 10 | 52 | 59 | 19 | 0.73 | |
Huang | 118 | 130 | 60 | 45 | 13 | 47 | 64 | 19 | 0.71 | |
Lee | 134 | 100 | 46 | 60 | 26 | 34 | 45 | 20 | 0.47 | |
Vural | 137 | 155 | 90 | 44 | 3 | 112 | 39 | 4 | 0.78 | |
SNP | Author | Sample size | Case Genotype | Control genotype | HWE | |||||
Case | Control | TT | TC | CC | TT | TC | CC | Y/N(p) | ||
rs833061 | Almawi | 382 | 393 | 130 | 174 | 78 | 132 | 190 | 71 | 0.91 |
Bao | 55 | 52 | 32 | 9 | 14 | 24 | 11 | 17 | 0.06 | |
Ben Salem | 118 | 150 | 33 | 55 | 30 | 42 | 76 | 32 | 0.82 | |
Guruvaiah | 126 | 130 | 40 | 59 | 27 | 33 | 72 | 25 | 0.20 | |
Huang | 118 | 130 | 63 | 45 | 10 | 80 | 42 | 8 | 0.44 | |
Vural | 137 | 155 | 55 | 64 | 18 | 52 | 74 | 29 | 0.77 | |
SNP | Author | Sample size | Case Genotype | Control genotype | HWE | |||||
Case | Control | CC | CT | TT | CC | CT | TT | Y/N(p) | ||
rs3025039 | Almawi | 382 | 393 | 296 | 81 | 5 | 318 | 68 | 7 | 0.78 |
Bao | 55 | 52 | 31 | 9 | 15 | 24 | 11 | 17 | 0.10 | |
Ben Salem | 118 | 150 | 89 | 27 | 2 | 127 | 19 | 4 | 0.005 | |
Ding | 80 | 84 | 45 | 35 | 0 | 54 | 30 | 0 | 0.04 | |
Lee | 134 | 100 | 89 | 35 | 4 | 59 | 31 | 10 | 0.06 | |
SNP | Author | Sample size | Case Genotype | Control genotype | HWE | |||||
Case | Control | AA | AC | CC | AA | AC | CC | Y/N(p) | ||
rs699947 | Almawi | 382 | 393 | 135 | 183 | 64 | 165 | 178 | 50 | 0.48 |
Bao | 55 | 52 | 34 | 5 | 16 | 26 | 09 | 17 | 0.17 | |
Ben Salem | 118 | 150 | 35 | 63 | 20 | 45 | 77 | 28 | 0.62 | |
Gomes | 87 | 84 | 27 | 38 | 22 | 18 | 41 | 25 | 0.70 | |
Vural | 137 | 155 | 52 | 63 | 22 | 52 | 78 | 25 | 0.64 | |
SNP | Author | Sample size | Case Genotype | Control genotype | HWE | |||||
Case | Control | AA | AG | GG | AA | AG | GG | Y/N(p) | ||
rs1570360 | Almawi | 382 | 393 | 197 | 140 | 45 | 218 | 131 | 44 | 0.09 |
Bao | 55 | 52 | 24 | 13 | 18 | 30 | 9 | 13 | 0.03 | |
Ben Salem | 118 | 150 | 57 | 42 | 19 | 75 | 57 | 18 | 0.17 | |
Gomes | 87 | 84 | 56 | 24 | 7 | 52 | 31 | 1 | 0.12 | |
Li | 110 | 100 | 78 | 29 | 3 | 65 | 30 | 5 | 0.53 |
Study | Adequacy of Case Definition | Representativeness of the Cases | Selection of Controls | Definition of Controls | Compara- bility | Ascertainment of exposure | Same method of ascertainment | Non-Response rate | score |
---|---|---|---|---|---|---|---|---|---|
Almawi 2016 [20] | * | * | * | * | * | * | * | * | 8 |
Bao 2019 [21] | * | * | * | * | * | * | 6 | ||
Ben Salem 2016 [22] | * | * | * | * | * | * | * | 7 | |
Ding 2009 [28] | * | * | * | * | * | * | 6 | ||
Gomes 2019 [23] | * | * | * | * | * | * | 6 | ||
Guruvaiah 2014 [24] | * | * | * | * | * | * | * | 7 | |
Huang 2019 [25] | * | * | * | * | * | * | * | 7 | |
Lee 2008 [26] | * | * | * | * | * | * | 6 | ||
Li 2014 [29] | * | * | * | * | * | * | 6 | ||
Vural 2009 [27] | * | * | * | * | * | * | 6 |
Meta-analysis results
Meta-analysis of association between VEGF gene rs2010963 polymorphism and PCOS susceptibility
Group/ Subgroup | Sample size (Case/Control) | Allele model | Dominant model | Heterozygote model | Recessive model | Homozygote model | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OR (95%CI) | p | I2 | OR (95%CI) | p | I2 | OR (95%CI) | p | I2 | OR (95%CI) | p | I2 | OR (95%CI) | p | I2 | ||
rs2010963 | ||||||||||||||||
Total | 952/960 | 0.88 [0.76,1.01] | 0.06 | 48% | 0.78 [0.65, 0.94] | 0.008 | 49% | 0.75 [0.61, 0.91] | 0.004 | 48% | 1.03 [0.79, 1.36] | 0.82 | 24% | 0.88 [0.65, 1.17] | 0.38 | 28% |
Caucasian | 519/548 | 0.99 [0.82, 1.20] | 0.94 | 24% | 0.98 [0.55, 1.73] | 0.93 | 75% | 0.93 [0.44, 1.96] | 0.85 | 84% | 1.41 [0.93, 2.12] | 0.10 | 0% | 1.17 [0.76, 1.80] | 0.48 | 0% |
Asian | 433/412 | 0.76 [0.63, 0.93] | 0.008 | 39% | 0.69 [0.50, 0.95] | 0.02 | 26% | 0.68 [0.50, 0.92] | 0.01 | 0% | 0.80 [0.55, 1.16] | 0.24 | 0% | 0.68 [0.46, 1.02] | 0.06 | 21% |
PB | 834/830 | 0.92 [0.79, 1.06] | 0.24 | 45% | 0.82 [0.68, 1.00] | 0.29 | 48% | 0.83 [0.59, 1.16] | 0.27 | 51% | 1.09 [0.81, 1.47] | 0.56 | 29% | 0.95 [0.69, 1.30] | 0.73 | 24% |
rs833061 | ||||||||||||||||
Total | 936/1010 | 0.98 [0.86, 1.12] | 0.80 | 25% | 0.93 [0.77,1.12] | 0.45 | 6% | 0.91 [0.74,1.11] | 0.35 | 0% | 1.06 [0.84,1.33] | 0.63 | 0% | 0.97 [0.75,1.26] | 0.83 | 0% |
Caucasian | 637/698 | 0.99 [0.84, 1.15] | 0.85 | 22% | 0.93 [0.74,1.16] | 0.51 | 0% | 0.90 [0.71,1.15] | 0.4 | 0% | 1.06 [0.81,1.40] | 0.66 | 27% | 1.00 [0.73,1.35] | 0.98 | 28% |
Asian | 299/312 | 0.96 [0.68, 1.37] | 0.83 | 51% | 0.90 [0.54,1.49] | 0.67 | 54% | 0.93 [0.64,1.33] | 0.68 | 47% | 1.05 [0.68,1.62] | 0.84 | 0% | 0.92 [0.57,1.48] | 0.73 | 0% |
PB | 818/880 | 0.95 [0.83, 1.09] | 0.48 | 10% | 0.87 [0.71,1.07] | 0.18 | 0% | 0.85 [0.68,1.06] | 0.14 | 0% | 1.04 [0.82,1.32] | 0.74 | 0% | 0.94 [0.72,1.23] | 0.63 | 0% |
rs3025039 | ||||||||||||||||
Total | 779/834 | 0.97 [0.68, 1.39] | 0.88 | 65% | 1.07 [0.73, 1.57] | 0.73 | 58% | 1.21 [0.95, 1.55] | 0.12 | 42% | 0.59 [0.34, 1.02] | 0.06 | 0% | 0.56 [0.32, 0.99] | 0.05 | 0% |
Caucasian | 500/543 | 1.22 [0.93, 1.60] | 0.16 | 0% | 1.35 [1.00, 1.83] | 0.05 | 10% | 1.43 [1.04, 1.95] | 0.03 | 33% | 0.70 [0.27, 1.82] | 0.46 | 0% | 0.76 [0.29, 1.97] | 0.57 | 0% |
Asian | 269/236 | 0.79 [0.48, 1.29] | 0.35 | 63% | 0.83 [0.49, 1.41] | 0.49 | 52% | 0.94 [0.63, 1.39] | 0.75 | 26% | 0.54 [0.28, 1.05] | 0.07 | 48% | 0.48 [0.24, 0.97] | 0.04 | 36% |
PB | 689/695 | 0.91 [0.60, 1.39] | 0.68 | 71% | 1.00 [0.63, 1.60] | 0.99 | 66% | 1.13 [0.72, 1.76] | 0.60 | 55% | 0.59 [0.34, 1.02] | 0.06 | 0% | 0.56 [0.32, 0.99] | 0.05 | 0% |
HWE (yes) | 571/545 | 0.79 [0.50,1.25] | 0.32 | 70% | 0.84 [0.51,1.40] | 0.51 | 63% | 1.06 [0.79,1.41] | 0.71 | 41% | 0.58 [0.33,1.04] | 0.07 | 4% | 0.55 [0.30,0.99] | 0.05 | 0% |
rs699947 | ||||||||||||||||
Total | 779/834 | 1.03 [0.90, 1.19] | 0.65 | 49% | 1.03 [0.84, 1.26] | 0.78 | 48% | 1.01 [0.81, 1.26] | 0.91 | 37% | 1.07 [0.82, 1.38] | 0.62 | 0% | 1.06 [0.80, 1.41] | 0.69 | 36% |
Caucasian | 724/782 | 1.00 [0.80, 1.25] | 0.99 | 51% | 1.07 [0.87, 1.32] | 0.53 | 49% | 1.05 [0.83, 1.31] | 0.70 | 30% | 1.09 [0.83, 1.43] | 0.52 | 0% | 1.11 [0.82, 1.51] | 0.49 | 44% |
rs1570360 | ||||||||||||||||
Total | 752/779 | 1.11 [0.95, 1.30] | 0.20 | 0% | 1.15 [0.94, 1.41] | 0.17 | 11% | 0.69 [0.37, 1.27] | 0.23 | 82% | 1.23 [0.89, 1.70] | 0.21 | 15% | 1.29 [0.92, 1.80] | 0.14 | 13% |
Caucasian | 587/627 | 1.12 [0.94, 1.34] | 0.19 | 0% | 1.18 [0.94, 1.49] | 0.14 | 0% | 0.58 [0.24, 1.37] | 0.21 | 88% | 1.26 [0.88, 1.81] | 0.21 | 40% | 1.31 [0.90, 1.90] | 0.16 | 23% |
Asian | 165/152 | 1.08 [0.53, 2.23] | 0.83 | 73% | 1.11 [0.49, 2.53] | 0.79 | 66% | 0.95 [0.24, 3.81] | 0.95 | 82% | 1.12 [0.55, 2.30] | 0.75 | 27% | 1.22 [0.58, 2.57] | 0.60 | 50% |
PB | 642/679 | 1.16 [0.98, 1.37] | 0.08 | 0% | 1.22 [0.98, 1.52] | 0.07 | 0% | 0.75 [0.35, 1.58] | 0.44 | 84% | 1.29 [0.92, 1.79] | 0.14 | 13% | 1.36 [0.96, 1.93] | 0.08 | 0% |
HWE (yes) | 697/727 | 1.08 [0.91,1.27] | 0.39 | 0% | 1.12 [0.90,1.38] | 0.30 | 8% | 0.56 [0.29,1.09] | 0.09 | 84% | 1.19 [0.84,1.69] | 0.32 | 33% | 1.23 [0.85,1.76] | 0.27 | 25% |
Meta-analysis of association between VEGF gene rs833061 polymorphism and PCOS susceptibility
Meta-analysis of association between VEGF gene rs3025039 polymorphism and PCOS susceptibility
Meta-analysis of association between VEGF gene rs699947 polymorphism and PCOS susceptibility
Meta-analysis of association between VEGF gene rs1570360polymorphism and PCOS susceptibility
Publication bias
SNP | Comparison model type | begg’s text | egger’s text | ||
---|---|---|---|---|---|
z | p value | t | p value | ||
rs2010963 | Allele model | −0.19 | 0.851 | 0.04 | 0.969 |
Dominant model | 0.56 | 0.573 | 0.48 | 0.655 | |
Heterozygote model | 0.56 | 0.576 | 1.31 | 0.261 | |
Recessive model | −0.56 | 0.573 | −2.01 | 0.115 | |
Homozygote model | −0.94 | 0.348 | −1.31 | 0.260 | |
rs833061 | Allele model | 0.19 | 0.851 | −0.50 | 0.641 |
Dominant model | −0.94 | 0.348 | 3.15 | 0.035 | |
Heterozygote model | −1.32 | 0.188 | −0.45 | 0.679 | |
Recessive model | −0.19 | 0.851 | −0.55 | 0.608 | |
Homozygote model | −0.19 | 0.851 | −0.33 | 0.760 | |
rs3025039 | Allele model | 0.49 | 0.624 | −0.01 | 0.993 |
Dominant model | 0.00 | 1.000 | −0.22 | 0.837 | |
Heterozygote model | 0.49 | 0.624 | −0.23 | 0.835 | |
Recessive model | −1.36 | 0.174 | −0.66 | 0.576 | |
Homozygote model | −0.68 | 0.497 | 1.17 | 0.362 | |
rs699947 | Allele model | −1.47 | 0.142 | −5.82 | 0.010 |
Dominant model | −1.47 | 0.142 | −5.19 | 0.014 | |
Heterozygote model | −0.98 | 0.327 | −3.59 | 0.037 | |
Recessive model | −1.47 | 0.142 | −5.07 | 0.015 | |
Homozygote model | −1.47 | 0.142 | −10.90 | 0.002 | |
rs1570360 | Allele model | 0.98 | 0.327 | 0.24 | 0.828 |
Dominant model | 0.00 | 1.000 | −0.43 | 0.696 | |
Heterozygote model | −0.49 | 0.624 | −0.50 | 0.651 | |
Recessive model | 1.47 | 0.142 | 1.49 | 0.233 | |
Homozygote model | 1.47 | 0.142 | 1.43 | 0.249 |