Pituitary Adenoma: SSTR2 rs2236750, SSTR5 rs34037914, and AIP rs267606574 Genetic Variants, Serum Levels, and Ki-67 Labeling Index Associations
Abstract
:1. Introduction
2. Materials and Methods
2.1. DNA Extraction and Genotyping
- SSTR2 rs2236750: TaqMan® Genotyping Assay (Assay ID: C__15954985_10; Catalog # 4351379), with specific primers and fluorescently labeled probes designed for this SNP.
- SSTR5 rs34037914: TaqMan® Genotyping Assay (Assay ID: C__26059313_10; Catalog # 4351379), with specific primers and fluorescently labeled probes designed for this SNP.
- AIP rs267606574: TaqMan® Genotyping Assay (Assay ID: C_189786883_20; Catalog # 4351379), with specific primers and fluorescently labeled probes designed for this SNP.
2.2. Serum Levels’ Measurement
- Sample incubation. Test samples, along with standards of known concentrations and biotin-conjugated reagents, were added to the wells and allowed to incubate. This step facilitated the binding of the target proteins to the immobilized capture antibodies.
- Enzymatic reaction initiation. Subsequent addition of horseradish peroxidase (HRP)-conjugated reagents initiated an enzymatic reaction. This reaction generated a measurable signal directly proportional to the concentration of the target protein bound to the antibodies.
- Colorimetric detection. The enzymatic reaction catalyzed by HRP resulted in the conversion of a colorless substrate, tetramethylbenzidine (TMB), to a blue-colored product. Upon addition of an acidic stop solution, the reaction was terminated, causing the color to change to yellow. The intensity of this yellow color was directly correlated with the concentration of the target protein in the sample.
- Optical density measurement. The absorbance of the resulting yellow color was measured at 450 nm using a microplate reader. This optical density (OD) value served as the basis for precise concentration calculations, particularly within blood serum samples.
2.3. Ki-67
2.4. Study Group
- Confirmed diagnosis: only patients with a confirmed diagnosis of PA through imaging (MRI/CT) and/or histopathological examination were included.
- Age and health status: patients were included regardless of age (age of 18 years or older) and overall good health status, provided they met the diagnostic criteria for PA.
- Our study exclusively included patients whose PA was investigated and diagnosed based on clinical symptoms.
- Overall good health condition of the patient.
- Absence of other brain tumors, tumors in other locations, intracranial infections, demyelinating lesions, or cerebrovascular diseases.
- Consent: an informed consent form was obtained from all patients included in the study.
- Comprehensive data collection: we included a broad range of patients with different types of PAs (functional and non-functional) to ensure diversity and representativeness.
- Standardized diagnostic criteria: Consistent diagnostic criteria were applied to all patients to ensure uniformity in inclusion. PAs in our study were detected while investigating symptomatic patients. The diagnosis was based on clinical symptoms suggestive of PAs, such as hormonal imbalances, visual disturbances, or headaches.
- Non-confirmed diagnosis: patients without a confirmed diagnosis of pituitary adenoma (PA) through imaging (MRI/CT) and/or histopathological examination were excluded.
- Age and health status: patients younger than 18 years of age, or those with significant health issues that could impact their participation or the study results, were excluded.
- Non-clinical diagnosis: patients whose PAs were not investigated and diagnosed based on clinical symptoms were excluded.
- Poor health condition: patients in poor overall health, as determined by their clinical assessment, were excluded.
- Other brain or systemic conditions: patients with other brain tumors, tumors in other locations, intracranial infections, demyelinating lesions, or cerebrovascular diseases were excluded.
- Lack of consent: patients who did not provide informed consent were excluded from the study.
- Healthy status: individuals must be in overall good health, with no history of pituitary adenomas or other significant health issues that could affect the study’s results.
- Age: individuals must be 18 years of age or older to ensure comparability with the patient group.
- No brain or systemic disorders: individuals must have no history of brain tumors, tumors in other locations, intracranial infections, demyelinating lesions, cerebrovascular diseases, or any other major systemic disorders.
- No prior diagnosis of pituitary disorders: individuals must not have a history or diagnosis of pituitary disorders, including pituitary adenomas, as confirmed through imaging or clinical evaluation.
- Consent: informed consent must be obtained from all individuals included in the reference group.
- Presence of health issues: individuals with significant health conditions, including pituitary disorders, brain tumors, or major systemic diseases, were excluded.
- Age restrictions: individuals younger than 18 years were excluded to match the age range of the patient group.
- History of pituitary or brain disorders: individuals with a history of pituitary disorders, brain tumors, or other relevant conditions were excluded.
- Informed consent: individuals who did not provide informed consent were excluded from the reference group.
2.5. Statistical Analysis
2.6. Strengths and Limitations of the Study
3. Results
Ki-67 Labeling Index
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristics | Group | p-Value | ||
---|---|---|---|---|
PA Group | Reference Group | |||
Gender | Males, N (%) | 52 (40.6) | 86 (31.6) | 0.077 * |
Females, N (%) | 76 (59.4) | 186 (68.4) | ||
Age, Median (IQR) | 54.5 (20) | 56.0 (40) | 0.821 ** | |
Recurrence: Absent/Present | 88/39 | NA | - | |
Invasiveness: Invasive/Noninvasive | 81/46 | NA | - | |
Size: Micro/Macro | 49/78 | NA | - | |
Activity: | NA | - | ||
Active PA/Nonactive PA | 61/66 | |||
Prolactin producing PA | 48 | |||
IGF1 producing PA | 3 | |||
GF producing PA | 6 | |||
ACTH producing PA | 4 | |||
Ki-67: | NA | - | ||
<1% | 53 | |||
1% | 11 | |||
>1% | 15 |
Gene, SNP | Genotype, Allele | PA Group, n (%) | Reference Group, n (%) | p-Value |
---|---|---|---|---|
SSTR2 rs2236750 | AA | 43 (33.6) | 118 (43.4) | |
AG | 73 (57.0) | 126 (46.3) | 0.125 | |
GG | 12 (9.4) | 28 (10.3) | ||
Total | 128 (100) | 272 (100) | ||
Allele | ||||
A | 159 (62.1) | 362 (66.5) | 0.220 | |
G | 97 (37.9) | 182 (33.5) | ||
SSTR5 rs34037914 | CC | 114 (89.1) | 238 (87.5) | |
CT | 12 (9.4) | 33 (12.1) | 0.322 | |
TT | 2 (1.6) | 1 (0.4) | ||
Total | 128 (100) | 272 (100) | ||
Allele | ||||
C | 240 (93.8) | 509 (93.6) | 0.921 | |
T | 16 (6.2) | 35 (6.4) | ||
AIP rs267606574 | TAC | 128 (100) | 272 (100) | |
Total | 128 (100) | 272 (100) | 1.000 | |
Allele | ||||
T | 128 (33.3) | 272 (33.3) | ||
A | 128 (33.3) | 272 (33.3) | 1.000 | |
C | 128 (33.3) | 272 (33.3) |
Gene and SNP | Allele Frequencies | Genotype Distribution | p-Value | |
---|---|---|---|---|
SSTR2 rs2236750 | 0.67 A | 0.33 G | 28/126/118 | 0.505 |
SSTR5 rs34037914 | 0.94 C | 0.06 T | 1/33/238 | 0.899 |
AIP rs267606574 | NA | NA | 0/0/272 | NA |
Model | Genotype/Allele | OR (95% CI) | p-Value | AIC |
---|---|---|---|---|
SSTR2 rs2236750 | ||||
Co-dominant | AG vs. AA GG vs. AA | 1.602 (1.015–2.527) 1.170 (0.543–2.522) | 0.043 0.688 | 498.138 |
Dominant | AG + GG vs. AA | 1.524 (0.980–2.371) | 0.062 | 496.848 |
Recessive | AA vs. GG + AG | 0.890 (0.435–1.822) | 0.749 | 500.300 |
Over-dominant | AG vs. AA + GG | 1.550 (1.013–2.373) | 0.044 | 496.298 |
Adityve | G | 1.241 (0.892–1.725) | 0.200 | 498.760 |
SSTR5 rs34037914 | ||||
Co-dominant | CT vs. CC TT vs. CC | 0.781 (0.387–1.576) 4.348 (0.384–49.187) | 0.490 0.235 | 500.343 |
Dominant | CT + TT vs. CC | 0.887 (0.456–1.725) | 0.724 | 500.277 |
Recessive | TT vs. CC + CT | 4.447 (0.393–50.299) | 0.228 | 498.834 |
Over-dominant | CT vs. CC + TT | 0.772 (0.383–1.557) | 0.470 | 499.865 |
Adityve | T | 0.999 (0.550–1.814) | 0.997 | 500.404 |
Gene, SNP | Genotype, Allele | PA Group Females, n (%) | Reference Group Females, n (%) | p-Value |
---|---|---|---|---|
SSTR2 rs2236750 | AA | 24 (31.6) | 82 (44.1) | 0.171 |
AG | 44 (57.9) | 87 (46.8) | ||
GG | 8 (10.5) | 17 (9.1) | ||
Total | 76 (100) | 186 (100) | ||
Allele | ||||
A | 92 (60.5) | 251 (67.5) | 0.129 | |
G | 60 (39.5) | 121 (32.5) | ||
SSTR5 rs34037914 | CC | 64 (84.2) | 163 (87.6) | |
CT | 10 (13.2) | 23 (12.4) | 0.082 | |
TT | 2 (2.6) | 0 (0) | ||
Total | 76 (100) | 186 (100) | ||
Allele | ||||
C | 138 (90.8) | 349 (93.8) | 0.219 | |
T | 14 (9.2) | 23 (6.2) |
Gene, SNP | Genotype, Allele | PA Group Males, n (%) | Reference Group Males, n (%) | p-Value |
---|---|---|---|---|
SSTR2 rs2236750 | AA | 19 (36.5) | 36 (41.9) | 0.423 |
AG | 29 (55.8) | 39 (45.3) | ||
GG | 4 (7.7) | 11 (12.8) | ||
Total | 52 (100) | 86 (100) | ||
Allele | ||||
A | 67 (64.4) | 111 (64.5) | 0.984 | |
G | 37 (35.6) | 61 (35.5) | ||
SSTR5 rs34037914 | CC | 50 (96.2) | 75 (87.2) | 0.207 |
CT | 2 (3.8) | 10 (11.6) | ||
TT | 0 (0) | 1 (1.2) | ||
Total | 52 (100) | 86 (100) | ||
Allele | ||||
C | 102 (98.1) | 160 (93) | 0.063 | |
T | 2 (1.9) | 12 (7) |
Model | Genotype/Allele | OR (95% CI) | p-Value | AIC |
---|---|---|---|---|
SSTR2 rs2236750 | ||||
Co-dominant | AG vs. AA GG vs. AA | 1.722 (0.962–3.083) 1.600 (0.615–4.164) | 0.067 0.335 | 315.898 |
Dominant | AG + GG vs. AA | 1.702 (0.968–2.993) | 0.065 | 313.923 |
Recessive | AA vs. GG + AG | 1.165 (0.480–2.828) | 0.735 | 317.324 |
Over-dominant | AG vs. AA + GG | 1.560 (0.910–2.675) | 0.106 | 314.796 |
Adityve | G | 1.402 (0.923–2.131) | 0.114 | 314.927 |
SSTR5 rs34037914 | ||||
Co-dominant | CT vs. CC TT vs. CC | 1.117 (0.502–2.486) - | 0.786 0.999 | 314.452 |
Dominant | CT + TT vs. CC | 1.345 (0.630–2.869) | 0.444 | 316.864 |
Recessive | TT vs. CC + CT | - | 0.999 | 312.525 |
Over-dominant | CT vs. CC + TT | 1.088 (0.490–2.420) | 0.835 | 317.394 |
Adityve | T | 1.526 (0.771–3.023) | 0.225 | 316.008 |
Model | Genotype/Allele | OR (95% CI) | p-Value | AIC |
---|---|---|---|---|
SSTR2 rs2236750 | ||||
Co-dominant | AG vs. AA GG vs. AA | 1.449 (0.690–3.044) 0.736 (0.202–2.685) | 0.327 0.643 | 184.776 |
Dominant | AG + GG vs. AA | 1.305 (0.635–2.682) | 0.468 | 183.976 |
Recessive | AA vs. GG + AG | 0.591 (0.176–1.990) | 0.396 | 183.743 |
Over-dominant | AG vs. AA + GG | 1.544 (0.770–3.096) | 0.221 | 182.996 |
Adityve | G | 1.039 (0.605–1.786) | 0.889 | 184.486 |
SSTR5 rs34037914 | ||||
Co-dominant | CT vs. CC TT vs. CC | 0.295 (0.062–1.408) - | 0.126 1 | 182.751 |
Dominant | CT + TT vs. CC | 0.271 (0.058–1.278) | 0.099 | 181.054 |
Recessive | TT vs. CC + CT | - | 1 | 183.649 |
Over-dominant | CT vs. CC + TT | 0.298 (0.062–1.422) | 0.129 | 181.656 |
Adityve | T | 0.279 (0.062–1.267) | 0.098 | 180.844 |
Gene, SNP | Genotype, Allele | Reference Group, n (%) | Micro-PA Group, n (%) | Macro-PA Group, n (%) | p-Value |
---|---|---|---|---|---|
SSTR2 rs2236750 | AA | 118 (43.4) | 18 (38.3) | 25 (30.9) | 0.423 * |
AG | 126 (46.3) | 25 (53.2) | 48 (59.3) | 0.103 ** | |
GG | 28 (10.3) | 4 (8.5) | 8 (9.9) | 0.691 *** | |
Total | 272 (100) | 47 (100) | 81 (100) | ||
Allele | 0.754 * | ||||
A | 362 (66.5) | 61 (64.9) | 98 (60.5) | 0.156 ** | |
G | 182 (33.5) | 33 (35.1) | 64 (39.5) | 0.484 *** | |
SSTR5 rs34037914 | CC | 238 (87.5) | 42 (89.4) | 72 (88.9) | 0.022 * |
CT | 33 (12.1) | 3 (6.4) | 9 (11.1) | 0.833 ** | |
TT | 1 (0.4) | 2 (4.3) | 0 (0.0) | 0.125 *** | |
Total | 272 (100) | 47 (100) | 81 (100) | ||
Allele | 0.715 * | ||||
C | 509 (93.6) | 87 (92.6) | 153 (94.4) | 0.685 ** | |
T | 35 (6.4) | 7 (7.4) | 9 (5.6) | 0.547 *** |
Model | Genotype/Allele | OR (95% CI) | p-Value | AIC |
---|---|---|---|---|
Micro-PA | ||||
SSTR2 rs2236750 | ||||
Co-dominant | AG vs. AA GG vs. AA | 1.301 (0.675–2.506) 0.937 (0.294–2.985) | 0.432 0.912 | 269.952 |
Dominant | AG + GG vs. AA | 1.234 (0.654–2.330) | 0.516 | 268.295 |
Recessive | AA vs. GG + AG | 0.811 (0.271–2.427) | 0.708 | 268.575 |
Over-dominant | AG vs. AA + GG | 1.317 (0708–2.449) | 0.385 | 267.965 |
Adityve | G | 1.081 (0.673–1.737) | 0.747 | 268.618 |
SSTR5 rs34037914 | ||||
Co-dominant | CT vs. CC TT vs. CC | 0.515 (0.151–1.756) 11.333 (1.005–127.806) | 0.289 0.050 | 265.188 |
Dominant | CT + TT vs. CC | 0.833 (0.308–2.253) | 0.719 | 268.588 |
Recessive | TT vs. CC + CT | 12.044 (1.070–135.599) | 0.044 | 264.500 |
Over-dominant | CT vs. CC + TT | 0.494 (0.145–1.681) | 0.259 | 267.217 |
Adityve | T | 1.156 (0.515–2.593) | 0.726 | 268.602 |
Macro-PA | ||||
SSTR2 rs2236750 | ||||
Co-dominant | AG vs. AA GG vs. AA | 1.798 (1.043–3.100) 1.349 (0.550–3.305) | 0.035 0.513 | 379.660 |
Dominant | AG + GG vs. AA | 1.716 (1.011–2.913) | 0.045 | 378.113 |
Recessive | AA vs. GG + AG | 0.955 (0.417–2.186) | 0.913 | 282.257 |
Over-dominant | AG vs. AA + GG | 1.685 (1.019–2.788) | 0.042 | 378.074 |
Adityve | G | 1.333 (0.911–0.952) | 0.139 | 380.090 |
SSTR5 rs34037914 | ||||
Co-dominant | CT vs. CC TT vs. CC | 0.902 (0.412–1.972) - | 0.795 - | 383.679 |
Dominant | CT + TT vs. CC | 0.875 (0.401–1.910) | 0.737 | 382.155 |
Recessive | TT vs. CC + CT | - | - | - |
Over-dominant | CT vs. CC + TT | 0.905 (0.414–1.980) | 0.803 | 382.206 |
Adityve | T | 0.853 (0.399–1.826) | 0.682 | 382.097 |
Gender | Serum Level (pg/mL) | p-Value | |
---|---|---|---|
PA Group Mean (Std. Deviation) | Reference Group Mean (Std. Deviation) | ||
SSTR2 | |||
Male | 9643.05 (3797.57) | 8004.66 (3660.49) | 0.122 |
Female | 9159.36 (4819.88) | 9501.08 (3581.27) | 0.778 |
Gender | Serum Level (pg/mL) | p-Value | |
---|---|---|---|
PA Group Median (IQR) | Reference Group Median (IQR) | ||
SSTR5 | |||
Male | 190.75 (209.98) | 247.74 (201.46) | 0.490 |
Female | 197.56 (396.82) | 255.09 (746.07) | 0.675 |
Gender | Serum Level (ng/mL) | p-Value | |
---|---|---|---|
PA Group Mean (Std. Deviation) | Reference Group Mean (Std. Deviation) | ||
AIP | |||
Male | 0.242 (0.055) | 0.303 (0.130) | 0.149 |
Female | 0.250 (0.121) ng/mL | 0.246 (0.056) | 0.943 |
Invasiveness | Ki-67 LI | p-Value | ||
---|---|---|---|---|
<1% | 1% | >1% | ||
Noninvasive PA n = 22 (27.8%) | 16 (72.7%) | 2 (9.1%) | 4 (18.2%) | 0.717 |
Invasive PA n = 57 (72.2%) | 37 (64.9%) | 9 (15.8%) | 11 (19.3%) |
Recurrence | Ki-67 LI | p-Value | ||
---|---|---|---|---|
<1% | 1% | >1% | ||
Absent n = 56 (70.9%) | 38 (67.9%) | 7 (12.5%) | 11 (19.6%) | 0.843 |
Present n = 23 (29.1%) | 15 (62.2%) | 4 (17.4%) | 4 (17.4%) |
Activity | Ki-67 LI | p-Value | ||
---|---|---|---|---|
<1% | 1% | >1% | ||
Active PA n = 44 (55.7%) | 31 (70.5%) | 4 (9.1%) | 9 (20.5%) | 0.378 |
Nonactive PA n = 35 (44.3%) | 122 (62.9%) | 7 (20.0%) | 6 (17.1%) |
Size | Ki-67 LI | p-Value | ||
---|---|---|---|---|
<1% | 1% | >1% | ||
Micro-PA n = 31 (39.2%) | 23 (74.2%) | 4 (12.9%) | 4 (19.9%) | 0.492 |
Macro-PA n = 48 (60.8%) | 30 (62.2%) | 7 (14.6%) | 11 (22.9%) |
Gene, SNP | Genotype/Allele | Ki-67 LI | p-Value | ||
---|---|---|---|---|---|
<1% | 1% | >1% | |||
SSTR2 rs2236750 | Genotype | 20 (37.7) | 5 (45.5) | 4 (26.7) | 0.636 |
AA | 27 (50.9) | 4 (36.4) | 10 (66.7) | ||
AG | 6 (11.3) | 2 (18.2) | 1 (6.7) | ||
GG | 53 (100) | 11 (100) | 15 (100) | ||
Total | |||||
Allele | |||||
A | 67 (63.2) | 14 (62.6) | 18 (60.0) | ||
G | 39 (36.8) | 8 (36.4) | 12 (40.0) | 0.945 | |
SSTR5 rs34037914 | Genotype | 47 (88.7) | 9 (81.8) | 15 (100) | 0.087 |
CC | 6 (11.3) | 1 (9.1) | 0 (0.0) | ||
CT | 0 (0.0) | 1 (9.1) | 0 (0.0) | ||
TT | 53 (100) | 11 (100) | 15 (100) | ||
Total | |||||
Allele | |||||
C | 100 (93.6) | 19 (86.4) | 30 (100) | ||
T | 6 (6.4) | 3 (13.6) | 0 (0) | 0.275 |
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Gedvilaite-Vaicechauskiene, G.; Kriauciuniene, L.; Tamasauskas, A.; Rovite, V.; Mandrika, I.; Wu, S.-N.; Huang, C.-W.; Poskiene, L.; Liutkeviciene, R. Pituitary Adenoma: SSTR2 rs2236750, SSTR5 rs34037914, and AIP rs267606574 Genetic Variants, Serum Levels, and Ki-67 Labeling Index Associations. Medicina 2024, 60, 1252. https://doi.org/10.3390/medicina60081252
Gedvilaite-Vaicechauskiene G, Kriauciuniene L, Tamasauskas A, Rovite V, Mandrika I, Wu S-N, Huang C-W, Poskiene L, Liutkeviciene R. Pituitary Adenoma: SSTR2 rs2236750, SSTR5 rs34037914, and AIP rs267606574 Genetic Variants, Serum Levels, and Ki-67 Labeling Index Associations. Medicina. 2024; 60(8):1252. https://doi.org/10.3390/medicina60081252
Chicago/Turabian StyleGedvilaite-Vaicechauskiene, Greta, Loresa Kriauciuniene, Arimantas Tamasauskas, Vita Rovite, Ilona Mandrika, Sheng-Nan Wu, Chin-Wei Huang, Lina Poskiene, and Rasa Liutkeviciene. 2024. "Pituitary Adenoma: SSTR2 rs2236750, SSTR5 rs34037914, and AIP rs267606574 Genetic Variants, Serum Levels, and Ki-67 Labeling Index Associations" Medicina 60, no. 8: 1252. https://doi.org/10.3390/medicina60081252
APA StyleGedvilaite-Vaicechauskiene, G., Kriauciuniene, L., Tamasauskas, A., Rovite, V., Mandrika, I., Wu, S. -N., Huang, C. -W., Poskiene, L., & Liutkeviciene, R. (2024). Pituitary Adenoma: SSTR2 rs2236750, SSTR5 rs34037914, and AIP rs267606574 Genetic Variants, Serum Levels, and Ki-67 Labeling Index Associations. Medicina, 60(8), 1252. https://doi.org/10.3390/medicina60081252