Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 24 annotations for this variant. Register or sign in to see them.
There are 6 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in SLC19A1
Note: The SLC19A1 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations may differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
The most extensively studied variant of SLC19A1 gene is 80G>A (rs1051266), a common non-synonymous polymorphism in exon 2 that results in substitution of a histidine for an arginine at residue 27 in the protein sequence. The estimated genotype frequencies among Caucasians were found to be: GG=0.29, GA=0.473, AA=0.237 [Article:11461197]. The frequency of allele A was 0.473 in Caucasians, 0.564 in African Americans, and 0.472 in Hispanics. This variant has been widely studied for its function in transport uptake as well as its association with risk to diseases and drug response and toxicity. Below we summarize examples of these associations with this important SLC19A1 variant, Arg27His.
Association with plasma folate levels. This common nonsynonymous variant of SLC19A1 80G>A was associated with plasma folate levels in which individuals who were homozygous AA had higher plasma folate levels in comparison to individuals who carried the G allele [Article:10993718]. This association was not observed in other studies [Articles:16522921, 19650776]. One study observed an association of SLC19A1 80G>A and folate levels in red blood cells, and this association is greater in women than in men [Article:19650776].
Association with risk of common birth defects. Since folic acid and vitamin B12 are very important in reducing the occurrences of common birth defects such as neural tube defects, or NTD, the genetic variants in SLC19A1 and other folate pathway genes have been investigated for their roles in common birth defects. One study showed that in Italians, the G allele of variant G80A was observed at higher frequencies in affected children with neural tube defects (NTD), their mothers, and their fathers [Article:11813127]. Another study investigated the interaction between use of periconceptional folate supplementation in mothers and the risk of spina bifida in their infants as a function of the genotype at nucleotide position 80 of SLC19A1 in the infants [Article:11857541]. It was found that infants born from mothers who did not take folate during periconception were at higher risk of having spina bifida if they carried the GG genotype (OR=2.4) compared to infants with the AA genotype. On the other hand, infants whose mothers took folate during periconception had a decreased risk of spina bifida if they carried the GG genotype compared to infants with the AA genotype. Although the findings did not reach statistical significance, this study reveals a potentially interesting gene-nutrient interaction involving folate use in mothers and SLC19A1 genotype at nucleotide position 80 in infants and risk of spina bifida. The G80A variant has also been studied in congenital defects, such as congenital heart disease (CHD) and cleft palate. One study showed that infants born from mothers who did not use folate supplementation were at significantly higher risk of CHD (OR=2.94) compared to infants whose mothers took folate during periconception. In addition, the CHD risk was significantly higher in infants with the GG (OR=4.03) and GA (OR=4.14) genotypes compared to infants with the AA genotype, if their mothers did not use folate supplementation. No significant association was found between SLC19A1 G80 genotype or maternal folic acid supplementation and the risks of cleft palate [Article:16019224].
Association with other risks affected by folate levels. There are several biosynthetic pathways in humans that require folate. As a result, any changes to the folate bioavailability could influence human health. A study involving 156 patients showed that the A allele had a significant protective effect against thrombosis (OR = 0.56) [Article:15964598].
Association with methotrexate transport. The functional effect of the G80A polymorphism was assessed in transport-impaired K562 cells transfected with the reference Arg27 or variant His27-RFC1 proteins [Article:11705857]. The variant protein, Arg27His, transported methotrexate and 5-formyl tetrahydrofolate similarly compared to reference RFC1. Although the kinetics of methotrexate transport by Arg27-RFC1 protein were not significantly different compared to K562 cells transfected with His27-RFC1, minor differences (~ 2-fold) were detected between the Arg27-RFC1 and His27-RFC1 proteins in the interaction affinity (Ki) of other anti-folates, including Tomudex, 5,10-dideazatetrahydrofolate, GW1843U89, 10-ethyl-10-deazaaminopterin, and 5-formyl tetrahydrofolate. The Ki for these other anti-folates in His27-RFC1 were ~ 2-fold lower although there were no significant differences between the K562 cells transfected with Arg27-RFC1 and His27-RFC1 with their sensitivities to growth inhibition by methotrexate and other anti-folates. The results suggested that there were at most minor functional differences between Arg27- and His27-RFC1 in terms of substrate affinities and/or transport efficiencies.
Association with methotrexate plasma levels and response. Altered cellular uptake of methotrexate may have an effect on methotrexate plasma level and thus hamper the efficacy and toxicities of methotrexate. A clinical study assessed whether there was an association of this variant Arg27His with methotrexate plasma level and clinical outcome in childhood acute lymophoblastic leukemias [Article:12411325]. The result showed that children with the AA genotype had more adverse events and worse overall prognosis than patients with the GG genotype. In addition, it was determined that patients carrying the AA genotype had higher methotrexate plasma levels (P =0.004) than patients with either the GG or GA genotypes. Another clinical study was conducted in patients treated with weekly low-dose methotrexate for rheumatoid arthritis [Article:15564880]. The result showed that the AA genotype was associated with 3.4-fold higher level of methotrexate polyglutamates (the active metabolites of methotrexate) compared to those with the 80GG and 80GA (OR 95% CI 1.4- 8.4; p=0.007). This result is supported by another study, where they showed that patients with AA genotype have a 3.32-fold higher probability of remission of rheumatoid arthritis symptoms [Article:17325736]. Genetic variants in the candidate genes of the folate pathway have also been examined for their role in drug response. One of the studies describes the association of polymorphisms in folate pathway with the response of methotrexate and sulfasalazine combination regimens in early rheumatoid arthritis patients [Article:18322994]. In this study (n=98 Caucasians), a gene-gene interaction between SLC19A1 80A allele and MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) 2756A (rs1805087) is observed with response to the therapy. The result showed that the allele combinations associated with responders are MTR2756A allele in combination with SLC19A1 80A allele (multivariate analysis, p=0.0002). Recently, Gregers et al. reported the influence of this variant G80A on the risk of methotrexate relapse and toxicity [Article:20335220]. This study consisting of 500 children with ALL found that the AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants.
Association with methotrexate toxicities. Given the importance of SLC19A1 G80A in methotrexate plasma level and response as discussed above, additional studies have been carried out to assess the effect of this variant with methotrexate toxicities in ALL patients who are treated with high-dose methotrexate. A large retrospective candidate gene study involving 240 ALL patients, this variant G80A is associated with methotrexate gastrointestinal toxicity [Article:17264302]. In addition, a recent study by Gregers et al. reported that children with ALL (a total of 182 children with toxicity phenotype information) who have AA variant has higher degree of bone marrow toxicity and a higher degree of liver toxicity [Article:20335220].
Association with risk of cancer. Genes involved with folate uptake and distribution have been investigated for different types of cancer risk including breast, prostate, colorectal and lymphoma [Articles:17891500, 17311260, 19706844, 20037791]. Most of them have found no significant association of this variant with the cancer risk. However, a recent case-control study involving Chinese population revealed significant association of 80AA with increased risk of esophageal cancer (n=216) and gastric cancer (n=633) with adjusted odds ratio (OR) of 1.80 (95% confidence interval = 1.29-2.51) and 1.59 (95% confidence interval = 1.25-2.02) respectively [Article:16962770]. In addition, a case-control study involving 245 pediatric acute lymphobastoid leukemia patients and 500 controls has found a gene-gene interaction between SLC19A1 and nicotinamide N-methyltransferase (NNMT) [Article:19020309], where subjects with SLC19A1 80AA/NNMT IVS 151CT + TT genotype had a 4.2 fold increase in ALL risk (p=0.001).
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (2)
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| Diseases | Heart Defects, Congenital 6 Precursor Cell Lymphoblastic Leukemia-Lymphoma 7 Thrombosis 8 |
| Phenotype |
MTX plasma levels
9
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| Phenotype Datasets |
Homocysteine concentrations in leukemia patients Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia |
Appendix
1. SLC19A1:Arg27His; 80G>A (rs1051266)
| Genomic Variant & GenBank ID: | 2,275,130 G>A on NT_011515 |
|---|---|
| mRNA Variant & GenBank ID: | 199 G>A on NM_194255 |
| Protein Variant & GenBank ID: | 27 Arg>His on NP_919231 |
| GoldenPath Position: | Chr21:45,782,222 (hg18) |
Connected Drugs
Connected Diseases
Publications related to rs1051266 at chr21:46957794: 28
Cross-References
- UCSC Golden Path:
- chr21:46957794
- dbSNP:
- rs1051266
- ALFRED:
- SI003688Z
- HapMap:
- rs1051266
Platform Availability
- Illumina