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1998 Doyle et al [ 1 ] first detected in breast cancer cell lines MCF-7/AdrVp to a transmembrane transporter protein , known as breast cancer resistance protein (breast cancer resistance protein, BCRP), phylogenetic analysis of the gene for the ABC transporter superfamily (ATP-binding cassette transporter superfamily, ABC transporter superfamily) G 2 subfamily members, named as ABCG2. ABCG2 located in the cell membrane , are widely distributed in normal tissues , mainly in the secretion and excretion functions with organizations such as the placental syncytiotrophoblast , small intestine and colon epithelium , liver tubule membranes , bile duct membrane , lobular and vascular endothelial cells . Human ABCG2 gene is located 4q22 ~ 23, encoding 655 amino acid residues. ABCG2 length of 66 kb, consists of 16 exons and 15 introns , exons range of 60 ~ 332 bp . ABCG2 in the human body bears certain physiological functions, such as maintenance of cell homeostasis, blood-brain barrier , fetal blood barrier , etc., and with disease susceptibility and other related pharmacokinetics .1998 年Doyle等[1]首先在乳腺癌细胞株MCF-7/AdrVp 中检测到一种跨膜转运蛋白，称为乳腺癌耐药蛋白(breast cancer resistance protein，BCRP)，系统发育分析该基因为ABC转运蛋白超家族(ATP-binding cassette transporter superfamily,ABC transporter superfamily)G亚家族第2成员，命名为ABCG2。
Single nucleotide polymorphisms (single nucleotide polymorphisms, SNP) refers to the genomic level variations caused by a single nucleotide polymorphism in the DNA sequence , which is the most common human genetic variation one , accounting for all known polymorphisms more than 90% . As the "third generation DNA genetic marker " single nucleotide polymorphism marker loci with rich, representative , genetic stability and analysis automation features, Pharmacogenomics is the study of the molecular basis . SNP study helps to explain the individual phenotypic differences , different disease groups and individuals , especially for complex disease susceptibility and resistance to various drugs and the differences in response to environmental factors . Single nucleotide polymorphisms can be applied to molecular genetic markers , molecular markers diagnosis, epidemiological survey in screening high-risk groups , as well as the degree of risk for disease evaluation .单核苷酸多态(single nucleotide polymorphisms,SNP)是指基因组水平上由单个核苷酸变异引起的DNA序列多态性，它是人类遗传变异中最常见的一种，占所有已知多态性的90%以上。
In recent years, some of the research data , ABCG2 gene single nucleotide polymorphism may be associated with the expression and function of ABCG2 have a negligible role, in addition ABCG2 gene single nucleotide polymorphisms and drug resistance are also significant association. Therefore , ABCG2 gene single nucleotide polymorphism caused great concern of researchers , this article from ABCG2 gene single nucleotide polymorphism in the protein expression and function as well as cancer and other diseases associated with of research progress .
1ABCG2 gene SNPs and their distribution
ABCG2 gene has been found that there are more than 40 SNPs, of which the most common three ABCG2 gene SNPs were C421A, G34A and C376T. ABCG2 C421A is the first five exons 421 points base changes caused by this SNP resulting polypeptide encoded 141 glutamine becomes lysine (Q141K); G34A ABCG2 gene in exon 2 , causing the 12-bit valine into methionine (V12M), wild-type and mutant amino acids are not charged , predominantly hydrophobic in ABCG2 N terminal intracellular domain ; ABCG2 gene in the other single-core nucleotide polymorphism C376T (Q126stop), resulting in a stop codon instead of 126 glutamine . Table 1 reported ABCG2 gene coding region SNPs. Table 1ABCG2 gene coding region single nucleotide polymorphisms researchers have for East Asians , Caucasians and African population ABCG2 SNPs did a related study found that ABCG2 SNPs distributed in different populations have significant differences ( Table 2 ) . C421A detected in populations can be detected , A allele frequency in the Chinese population as high as 29.0% ~ 34.2% , Japan's population was 30.4 % ~ 35.5% Caucasian population is 8.7 % ~ 11.9% , the African population the most rare and only 0 9% ~ 5 3%; G34A polymorphism is also distributed in a variety of populations , the incidence rate in the population of Sweden was 1.7% , while the population in Vietnam incidence of up to 36.0%, ABCG2 another common gene SNP (C376T), only in the East Asian populations may be detected , the occurrence frequency of 0.4% ~ 1.9%.
2ABCG2 gene SNPs on ABCG2 protein expression and function of
Several studies reported that ABCG2 gene single nucleotide polymorphisms affect ABCG2 protein levels . Imai , etc. [ 10 ] on 124 blood samples from healthy volunteers in Japan for DNA analysis shows C421A ABCG2 expression levels cause decreased ; Furukawa , etc. [ 11 ] with the wild-type and C421A recombinant Flp-In-293 cell research ABCG2 expression levels , the results show C421A wild type expression level of approximately 50%, but mRNA levels were the same ; Kobayashi , also obtained similar results and further confirmed the differences ABCG2 protein level rather than by the transcriptional regulation caused ABCG2 mRNA levels . Poonkuzhali , etc. [ 12 ] found that single nucleotide polymorphisms with G34A Spaniards ABCG2 mRNA levels were significantly reduced. Tamura et al [ 13 ] in the study created a seven ABCG2 SNPs (V12M, Q141K, F208S, S248P, F431L, S441N, F489L) recombinant Flp-in-293 cells , which F208S, S441N most significant decline in the expression levels ; Poonkuzhali etc. [ 12 ] on the ABCG2 promoter and intron 1 single nucleotide polymorphisms studied showed low expression levels of ABCG2 15622CT carriers , 12283TC, 16702CT high expression of ABCG2 and liver -related , 1143GA associated with low expression of the small intestine , 15994CT promoter SNP significantly increased expression levels of BCRP . ABCG2 gene C376T SNP although less frequently , but because 376T allele do not express ABCG2, so C376T have a major impact on ABCG2 function . ABCG2 single nucleotide polymorphisms also may be associated with ABCG2 protein transport activity , membrane localization , substrate activity and other functions. Kondo et al [ 14 ] containing seven SNPs (V12M, Q141K, A149P, R163K, Q166E, P269S, S441N) and wild -type cDNA plasmid transfected LLC-PK1 cells and found that S441N ABCG2 protein on the membrane localization influential , S441N performance of ABCG2 positioned in the cell , and the remaining six SNPs and wild-type ABCG2 were positioned at the apical membrane . HEK293 cells infected with a recombinant adenovirus expression level and determine the ABCG2 transporter activity , found that seven SNPs on DHEA , methotrexate , polycyclic aromatic hydrocarbons and other transport activity with wild tantamount ; Tamura , etc. [ 13 ] studies have shown F208S, S441N may affect protein stability , and F208S, S248P, F431L, S441N, F489L polymorphism of SN-38, dihydroxy anthracene dione , doxorubicin, daunorubicin, etoposide , and transport activity was lower than the wild type ; Lee and other populations in Korea ABCG2 gene polymorphism study found that those who carry P269S polymorphism compared with the wild -type protein ABCG2 substrate activity decreased by 35 % to 40% , and also prove that ABCG2 protein on the bottom physical activity decreased inhibition of ATP does not matter ; Mizuarai et al found that import 421A of SF9 cell activity than the wild-type ATP decreased 1.3 times. Table 2ABCG2 single nucleotide polymorphisms in different populations distributed 3ABCG2 gene SNPs and pharmacokinetic ABCG2 expression in the placenta , heart, colon , small intestine, kidney, liver and other organs, affecting many drugs in vivo pharmacokinetics . ABCG2 gene SNPs of ABCG2 expression by affecting the level of the substrate translocation efficiency , protein activity , etc., to many drugs in vivo pharmacokinetics play a role . Urquhart , etc. [ 15 ] in the study C421A on gefitinib (gefitinib) influence the pharmacokinetics , found 421A polymorphism is leading cause of ABCG2 protein activity weakened , while 421A may increase the risk of drug toxicity , leading to carry this polymorphism in patients with diarrhea. Zhang et al study found , 421A allele causes decreased expression of ABCG2 protein will affect pravastatin (pravastatin) removal and absorption ; 421A allele was also found to carry the Chinese healthy male blood rosuvastatin (rosuvastatin) concentration ratio ABCG2 wild-type height of about 80%. Keskitalo , etc. [ 16 ] with 32 healthy people, including five 421AA, 4个421CA, 23个421CC genotype , were injected with a single dose of 40 mg fluvastatin (fluvastatin), pravastatin and simvastatin (simvastatin), washout period of one week . The results show 421CC, 421CA genotype blood concentrations of fluvastatin 421AA genotype were higher than 72% and 97%, 421CC genotype simvastatin blood concentration ratio of 111% high- 421AA genotype proved ABCG2 gene C421A SNP significantly affect fluvastatin and simvastatin lactone pharmacokinetic , and for pravastatin or simvastatin acid has a significant effect . ABCG2 transporter protein substrates including some drugs, so ABCG2 gene SNPs may affect populations carry resistance to certain drugs . Cusatis , etc. [ 17 ] In vitro studies indicate 421A carriers on the cell surface protein expression decreased in vivo in healthy volunteers showed that individuals carrying 34GG/421CA sulfasalazine (sulfasalazine) area under the concentration-time curve (AUC) than individuals carrying 34GG/421CC large 2.4 times , indicating that ABCG2 single nucleotide polymorphisms affect in vivo drug disposition , causing ABCG2 expression in the intestine individual differences , genetic variation may be differences between individual drugs determinants . Morisaki , etc. [ 18 ] found that , 421A for two hydroxyl anthracenedione (mitoxantrone), topotecan (topotecan) or SN-38 have a lower resistance . Imai et al [10 ] showed that cells 421A dihydroxy anthracene dione hydrochloride, topotecan sensitive than the wild -type 2 ~ 3 times , 421A showed low resistance ; different from the previous report , De jong other of 84 European patients blood DNA sequencing , and found that ABCG2 gene C421A irinotecan hydrochloride pharmacokinetics had no effect.
4ABCG2 gene SNPs and disease relationships
As of now , there are tens of thousands of SNPs in the human genome and is proven to be found by changing the corresponding protein expression and activity, thus affecting the body 's susceptibility to disease or tumor , affecting different types of clinical and biological behavior of the tumor . Korenaga DNA probe analysis such as the use , of 200 renal cell carcinoma (RCC) patients and 200 healthy DNA samples from patients and healthy persons contrast ABCG2 gene C421A SNP, the results show 421CC genotype frequency was significantly higher in the patient in healthy subjects , indicating that the 421A allele is a risk factor of renal cell carcinoma . Hahn , etc. [ 19 ] in prostate cancer patients for survival analysis showed ABCG2 421CC genotype 15 month survival rate than 421A allele significantly reduced. Wang Xiaoxiao , etc. [ 20 ] studied the ABCG2 gene single nucleotide polymorphisms with diffuse large B-cell lymphoma (DLBCL) relationship to the 156 cases of patients with DLBCL as the experimental group , 376 cases of healthy people as a control group , statistical analysis of BCRP gene G34A and C421A SNPs loci frequency distribution . The results showed that the experimental group 421 points CA, AA, CA + AA genotype frequencies were 51.3 %, 10.2 %, 61.5% ; control group CA, AA, CA + AA genotype frequencies were 43.1 %, 8.8 %, 51.9% , ABCG2 gene 421 genotype CA, AA genotype compared to wild- CC, patients with diffuse large B-cell lymphoma (DLBCL) increased risk of adverse factors, that is, A is the relative , the risk in younger patients showed more significant. In addition , Wang Xiaoxiao also found that ABCG2 gene G34A and C421A SNPs combined effect of DLBCL prognosis : G34A AA genotype and GG / AG genotype survival is poor, 421 points CC genotype were associated with poorer survival significant correlation . In contrast to carry 34 points (GG + GA) 421 loci (AA + CA) genotype , those with 34AA421CC showed very poor survival. Hu Lili , etc. [ 21 ] on the ABCG2 gene SNPs with diffuse large B-cell lymphoma (DLBCL) susceptibility and prognosis and Wang Xiaoxiao such findings were consistent , while Hu Lili and so on ABCG2 gene SNPs with hepatocellular carcinoma (HCC) is prognostic analysis of patients carrying ABCG2 34AA genotype G allele than in patients with poor overall survival , carrying BCRP 421CC genotype HCC patients, their risk of death in patients with the A allele containing 2.85 times .
Conclusion
ABCG2 gene SNPs current study results appear inconsistent phenomena, such as most of the studies have shown that ABCG2 single nucleotide polymorphism does not affect the mRNA expression levels , but some studies have shown that mRNA levels were affected by ABCG2 single nucleotide polymorphisms ; in disease-related research reports have similar phenomena, such as C421A and prostate cancer survival rates contrast to the results of the two studies ; addition, some ABCG2 gene SNPs and susceptibility to cancer and other diseases research shows , ABCG2 gene certain SNPs in different tumors and diseases play a different effect . All in all, about ABCG2 single nucleotide polymorphism studies is still the primary stage, the SNPs on ABCG2 function , pharmacokinetics and tumor diseases such mechanisms we are still poorly understood. But ABCG2 single nucleotide polymorphisms related research reports have shown , ABCG2 single nucleotide polymorphism on disease prevention, diagnosis and patient drug screening importance can not be ignored . ABCG2 drug genomics research has just started , it needs further study to understand the SNPs on ABCG2 function , pharmacokinetics , and the impact of cancer and other diseases . |
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