Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene SLC1A3 Associated with Reduced Migraine Risk
Abstract
:1. Introduction
2. Materials and Methods
2.1. Sample Populations
2.2. Candidate Gene SNP Selection and Genotyping
2.3. Statistical Analysis
3. Results
3.1. Characteristics of Study Cohorts
3.2. Genotyping of 26 SNPs across SLC4A4, SLC1A3, and CHRNA4 in Migraine Samples versus Controls
3.3. Linkage Disequilibrium Analysis
3.4. Replication Analysis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cohort 1 | ||
Migraine N = 182 | Control N = 179 | |
Female N, (%) | 144 (79.1) | 121 (67.6) |
Male N, (%) | 38 (20.9) | 58 (32.4) |
Age (years), mean ± SD | 44 ± 16 | 44 ± 14 |
Migraine with aura | 104 (57.1) | - |
Migraine without aura | 78 (42.9) | - |
Cohort 2 | ||
Migraine N = 258 | Control N = 290 | |
Female N, (%) | 221 (85.6) | 250 (86.2) |
Male N, (%) | 37 (14.4) | 40 (13.8) |
Age (years), mean ± SD | 54 ± 13 | 54 ± 14 |
Migraine with aura | 213 (82.5) | - |
Migraine without aura | 45 (17.5) | - |
SNP | Chromosome Position * | Allele | Wildtype Homozygotes, AA (%) | Heterozygotes, AB (%) | Mutant Homozygotes, BB (%) | ||||
---|---|---|---|---|---|---|---|---|---|
A | B | Migraine | Control | Migraine | Controls | Migraine | Controls | ||
SLC4A4 | Chr 4: | ||||||||
rs2602070 | 71,250,885 | C | A | 180 (98.9) | 173 (96.6) | 2 (1.1) | 6 (3.4) | 0 (0.0) | 0 (0.0) |
rs2602072 | 71,256,316 | G | T | 179 (98.4) | 172 (96.1) | 3 (1.6) | 7 (3.9) | 0 (0.0) | 0 (0.0) |
rs4353873 | 71,428,816 | A | G | 123 (67.6) | 123 (69.5) | 54 (29.7) | 49 (27.7) | 5 (2.7) | 5 (2.8) |
rs4458426 | 71,475,673 | T | A | 116 (63.7) | 124 (69.3) | 59 (32.4) | 51 (28.5) | 7 (3.8) | 4 (2.2) |
rs10938142 | 71,496,462 | G | A | 154 (84.6) | 147 (82.1) | 28 (15.4) | 29 (16.2) | 0 (0.0) | 3 (1.7) |
rs1031452 | 71,519,326 | C | T | 95 (52.2) | 90 (50.6) | 74 (40.7) | 78 (43.8) | 13 (7.1) | 10 (5.6) |
rs1453450 | 71,533,996 | C | A | 140 (76.9) | 133 (74.3) | 38 (20.9) | 41 (22.9) | 4 (2.2) | 5 (2.8) |
rs12504851 | 71,545,167 | A | G | 112 (61.5) | 103 (57.9) | 60 (33.0) | 61 (34.3) | 10 (5.5) | 14 (7.9) |
rs16846575 | 71,555,992 | T | C | 118 (64.8) | 116 (64.8) | 56 (30.8) | 60 (33.5) | 8 (4.4) | 3 (7.7) |
rs4254735 | 71,564,768 | T | C | 179 (98.9) | 175 (97.8) | 2 (1.1) | 4 (2.2) | 0 (0.0) | 0 (0.0) |
rs9997127 | 71,570,781 | A | G | 180 (98.9) | 175 (97.8) | 2 (1.1) | 4 (2.2) | 0 (0.0) | 0 (0.0) |
SLC1A3 | Chr 5: | ||||||||
rs7728680 | 36,612,951 | A | G | 88 (48.4) | 80 (44.7) | 78 (42.8) | 72 (40.2) | 16 (8.8) | 27 (15.1) |
rs7729389 | 36,613,099 | A | G | 117 (64.3) | 116 (64.8) | 58 (31.9) | 57 (31.8) | 7 (3.8) | 6 (3.4) |
rs3776565 | 36,631,551 | T | C | 123 (67.6) | 129 (72.1) | 54 (29.7) | 44 (24.6) | 5 (2.7) | 6 (3.3) |
rs3776567 | 36,632,373 | A | C | 124 (84.3) | 137 (91.3) | 22 (15.0) | 13 (8.7) | 1 (0.7) | 0 (0.0) |
rs1428968 | 36,646,844 | C | T | 133 (73.5) | 127 (71.3) | 45 (24.9) | 43 (24.2) | 3 (1.6) | 8 (4.5) |
rs3776578 | 36,651,884 | T | C | 173 (95.1) | 159 (88.8) | 9 (4.9) | 20 (11.2) | 0 (0.0) | 0 (0.0) |
rs16903247 | 36,653,353 | T | C | 173 (95.1) | 160 (89.4) | 9 (4.9) | 19 (10.6) | 0 (0.0) | 0 (0.0) |
rs10491374 | 36,667,477 | C | G | 48 (26.4) | 45 (25.3) | 93 (51.1) | 90 (50.6) | 41 (22.5) | 43 (24.2) |
rs2269272 | 36,687,754 | C | T | 112 (61.9) | 120 (67.0) | 65 (35.9) | 49 (27.4) | 4 (2.2) | 10 (5.6) |
rs1529461 | 36,689,261 | G | A | 104 (57.1) | 116 (64.8) | 72 (39.6) | 55 (30.7) | 6 (3.3) | 8 (4.5) |
CHRNA4 | Chr 20: | ||||||||
rs4809538 | 63,338,824 | G | A | 102 (56.4) | 100 (56.8) | 73 (40.3) | 69 (39.2) | 6 (3.3) | 7 (4.0) |
rs4522666 | 63,343,128 | A | G | 71 (39.0) | 64 (35.7) | 93 (51.1) | 90 (50.3) | 18 (9.9) | 25 (14.0) |
rs2273504 | 63,356,709 | G | A | 128 (70.3) | 120 (67.4) | 52 (28.6) | 52 (29.2) | 2 (1.1) | 6 (3.4) |
rs6010918 | 63,358,149 | G | A | 116 (95.1) | 103 (88.8) | 6 (4.9) | 13 (11.2) | 0 (0.0) | 0 (0.0) |
rs6122429 | 63,361,854 | C | T | 134 (73.6) | 133 (74.3) | 45 (24.7) | 44 (24.6) | 3 (1.6) | 2 (1.1) |
SNP | Allele | F_A | F_U | X2 | p-Value | OR | L95 | U95 | |
---|---|---|---|---|---|---|---|---|---|
A | B | ||||||||
SLC4A4 | |||||||||
rs2602070 | C | A | 0.0054 | 0.0167 | 2.0900 | 0.1482 | 0.3241 | 0.064 | 1.617 |
rs2602072 | G | T | 0.0082 | 0.0195 | 1.6910 | 0.1935 | 0.4167 | 0.106 | 1.624 |
rs4353873 | A | G | 0.1758 | 0.1667 | 0.1060 | 0.7447 | 1.0670 | 0.723 | 1.573 |
rs4458426 | T | A | 0.2005 | 0.1648 | 1.5440 | 0.2141 | 1.2710 | 0.870 | 1.857 |
rs10938142 | G | A | 0.0769 | 0.0977 | 0.9844 | 0.3211 | 0.7690 | 0.457 | 1.293 |
rs1031452 | C | T | 0.2747 | 0.2753 | 0.0002 | 0.9867 | 0.9972 | 0.718 | 1.383 |
rs1453450 | C | A | 0.1264 | 0.1425 | 0.4015 | 0.5263 | 0.8708 | 0.567 | 1.336 |
rs12504851 | A | G | 0.2198 | 0.2500 | 0.9150 | 0.3388 | 0.8451 | 0.598 | 1.193 |
rs16846575 | T | C | 0.1978 | 0.1844 | 0.2110 | 0.6460 | 1.0910 | 0.752 | 1.581 |
rs4254735 | T | C | 0.0055 | 0.0111 | 0.6949 | 0.4045 | 0.4917 | 0.089 | 2.701 |
rs9997127 | A | G | 0.0054 | 0.0111 | 0.7062 | 0.4007 | 0.4890 | 0.088 | 2.686 |
SLC1A3 | |||||||||
rs7728680 | A | G | 0.3022 | 0.3520 | 2.0310 | 0.1541 | 0.7974 | 0.583 | 1.089 |
rs7729389 | A | G | 0.1978 | 0.1927 | 0.0294 | 0.8637 | 1.0330 | 0.714 | 1.492 |
rs3776565 | T | C | 0.1758 | 0.1564 | 0.4902 | 0.4839 | 1.1500 | 0.776 | 1.704 |
rs3776567 | A | C | 0.0816 | 0.0433 | 3.7290 | 0.0534 | 1.9620 | 0.979 | 3.932 |
rs1428968 | C | T | 0.1409 | 0.1657 | 0.8541 | 0.3554 | 0.8255 | 0.549 | 1.24 |
rs3776578 | T | C | 0.0247 | 0.0558 | 4.5400 | 0.0331 * | 0.4285 | 0.192 | 0.954 |
rs16903247 | T | C | 0.0247 | 0.0530 | 3.8910 | 0.0485 * | 0.4523 | 0.201 | 1.014 |
rs10491374 | C | G | 0.4808 | 0.4944 | 0.1335 | 0.7148 | 0.9470 | 0.684 | 1.279 |
rs2269272 | C | T | 0.2017 | 0.1927 | 0.0904 | 0.7636 | 1.0580 | 0.706 | 1.268 |
rs1529461 | G | A | 0.2308 | 0.1983 | 1.1270 | 0.2884 | 1.2130 | 0.732 | 1.527 |
CHRNA4 | |||||||||
rs4809538 | G | A | 0.2348 | 0.2358 | 0.0009 | 0.9752 | 0.9945 | 0.849 | 1.732 |
rs4522666 | A | G | 0.3544 | 0.3911 | 1.0380 | 0.3083 | 0.8548 | 0.703 | 1.405 |
rs2273504 | G | A | 0.1538 | 0.1798 | 0.8712 | 0.3506 | 0.8295 | 0.632 | 1.156 |
rs6010918 | G | A | 0.0245 | 0.0537 | 2.7440 | 0.0976 | 0.4441 | 0.560 | 1.229 |
rs6122429 | C | T | 0.1401 | 0.1341 | 0.0555 | 0.8138 | 1.0520 | 0.166 | 1.188 |
rs6122429 | C | T | 0.1401 | 0.1341 | 0.0555 | 0.8138 | 1.0520 | 0.688 | 1.608 |
TEST | OR | SE | L95 | U95 | STAT | p-Value |
---|---|---|---|---|---|---|
SLC1A3 rs16903247 | ||||||
Logistic Regression (Unadjusted) | 0.4381 | 0.4193 | 0.1926 | 0.996 | −1.969 | 0.0490 * |
Adjusted by Sex and Age | 0.447 | 0.4229 | 0.1951 | 1.024 | −1.904 | 0.0569 |
Sex Association with Disease | 1.812 | 0.2443 | 1.1220 | 2.924 | 2.433 | 0.01497 * |
Age Association with Disease | 1.006 | 0.0078 | 0.9908 | 1.022 | 0.787 | 0.4310 |
SLC1A3 rs3776578 | ||||||
Logistic Regression (Unadjusted) | 0.4136 | 0.4161 | 0.1830 | 0.935 | −2.122 | 0.03387 * |
Adjusted by Sex and Age | 0.4282 | 0.4198 | 0.1881 | 0.975 | −2.020 | 0.04336 * |
Sex Association with Disease | 1.797 | 0.2445 | 1.1130 | 2.902 | 2.397 | 0.01654 * |
Age Association with Disease | 1.006 | 0.0078 | 0.9908 | 1.022 | 0.778 | 0.4360 |
SNP | Allele | F_A | F_U | X2 | p-Value | OR | L95 | U95 | |
---|---|---|---|---|---|---|---|---|---|
A | B | ||||||||
SLC1A3 | |||||||||
rs3776578 | T | C | 0.0119 | 0.0404 | 8.232 | 0.0041 * | 0.2866 | 0.1158 | 0.7907 |
rs16903247 | T | C | 0.0116 | 0.0347 | 6.197 | 0.0127 * | 0.3283 | 0.1308 | 0.8241 |
SNPs | Haplotype | F_A | F_U | X2 | DF | p-Value |
---|---|---|---|---|---|---|
rs16903247/rs3776578 | H1-CC | 0.018 | 0.042 | 8.866 | 1 | 0.002 * |
H2-TT | 0.982 | 0.958 | 8.866 | 1 | 0.002 * | |
H3-TC | 0.000 | 0.000 | - | - | - | |
H4-CT | 0.000 | 0.000 | - | - | - |
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Albury, C.L.; Sutherland, H.G.; Lam, A.W.Y.; Tran, N.K.; Lea, R.A.; Haupt, L.M.; Griffiths, L.R. Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene SLC1A3 Associated with Reduced Migraine Risk. Genes 2024, 15, 797. https://doi.org/10.3390/genes15060797
Albury CL, Sutherland HG, Lam AWY, Tran NK, Lea RA, Haupt LM, Griffiths LR. Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene SLC1A3 Associated with Reduced Migraine Risk. Genes. 2024; 15(6):797. https://doi.org/10.3390/genes15060797
Chicago/Turabian StyleAlbury, Cassie L., Heidi G. Sutherland, Alexis W. Y. Lam, Ngan K. Tran, Rod A. Lea, Larisa M. Haupt, and Lyn R. Griffiths. 2024. "Identification of Polymorphisms in EAAT1 Glutamate Transporter Gene SLC1A3 Associated with Reduced Migraine Risk" Genes 15, no. 6: 797. https://doi.org/10.3390/genes15060797