Keke Zhou

Association of Sequence Variants on Chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) With Glioma Susceptibility in a Chinese Population

Two genome-wide association studies of glioma in European populations identified 14 genetic variants strongly associated with risk of glioma, but it is unknown whether these variants are associated with glioma risk in Asian populations. The authors genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma (glioblastoma; n = 312), in a Chinese population (2004-2009). Overall, the authors identified 3 susceptibility loci for glioma risk at 20q13.33 (RTEL1 rs6010620 (P = 2.79 × 10(-6))), 11q23.3 (PHLDB1 rs498872 (P = 3.8 × 10(-6))), and 5p15.33 (TERT rs2736100 (P = 3.69 × 10(-4))) in this study population; these loci were also associated with glioblastoma risk (20q13.33: RTEL1 rs6010620 (P = 3.57 × 10(-7)); 11q23.3: PHLDB1 rs498872 (P = 7.24 × 10(-3)); 5p15.33: TERT rs2736100 and TERT rs2736098 (P = 1.21 × 10(-4) and P = 2.84 × 10(-4), respectively)). This study provides further evidence for 3 glioma susceptibility regions at 20q13.33, 11q23.3, and 5p15.33 in Chinese populations.

Polymorphisms of LIG4 and XRCC4 Involved in the NHEJ Pathway Interact to Modify Risk of Glioma

Although the role of environmental risk factors in the etiology of gliomas remains to be elucidated, accumulative epidemiological evidence suggests that genetic factors, such as variants in genes involved in DNA repair, may also play an important role. LIG4 and XRCC4 are known to form a complex and are functionally linked in the repair of double‐stranded DNA breaks. To determine whether LIG4 and XRCC4 polymorphisms are associated with susceptibility to glioma and whether there are interactions between LIG4 and XRCC4, we conducted a case–control study of 771 glioma patients and 752 cancer‐free controls, assessed the associations between glioma risk and 20 tagging SNPs, and evaluated their potential gene–gene interactions using the multifactor dimensionality reduction (MDR), interaction dendrogram, and entropy analysis. In the single‐locus analysis, only one variant, the LIG4 SNP2 rs3093739:T>C (P‐permutation=0.009) was significantly associated with risk of developing glioma. Haplotype analysis revealed an association of glioma risk with genetic variants in LIG4 block 1 (global P=0.011), and XRCC4 blocks 2 and 4 (both global P<0.0001). Moreover, the MDR analysis suggested a significant three‐locus interaction model involving LIG4 SNP4 rs1805388:C>T, XRCC4 SNP12 rs7734849:A>T, and SNP15 rs1056503:G>T. Further dendrogram and graph analysis indicated a more‐than‐additive effect among these three loci. These results suggested that these variants may contribute to glioma susceptibility. Hum Mutat 29(3), 381–389, 2008.

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital-based case-control study

In mammalian cells, X‐ray repair cross‐complementing group3 (XRCC3) plays an important role in the DNA double‐strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in the XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to gliomas. In this study, we used a haplotype‐based approach to investigate whether 4 tagging single nucleotide polymorphisms of the XRCC3 gene are associated with risk of gliomas in 771 glioma patients and 752 cancer‐free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, and haplotype associations were estimated using Haplo.Stat. After adjustment for age and sex, the variant G allele of rs861530 and T allele of rs3212092 were significantly associated with an increased risk of gliomas (AG/GG versus AA: adjusted OR = 1.44, 95% CI = 1.15–1.80, p = 0.001 and CT/TT versus CC: adjusted OR = 1.66, 95% CI = 1.12–2.46, p = 0.013, respectively). Consistent with these results, XRCC3 haplotype “GGCC” containing rs861530 G allele and haplotype “AGTC” containing rs3212092 T allele were also significantly associated with an elevated risk of gliomas compared with the common haplotype “AGCC” (adjusted OR = 1.35, 95% CI = 1.14–1.58, p = 0.000 and adjusted OR = 1.67, 95% CI = 1.11–2.52, p = 0.015, respectively). Our results suggest that common genetic variants in the XRCC3 gene may modulate glioma risk.

Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population

Vascular endothelial growth factor A (VEGFA), one of the most predominant mediators of pathologic angiogenesis, plays a critical role in glioma carcinogenesis and development via promoting tumor growth. We hypothesized that VEGFA polymorphisms may influence glioma risk. We recently genotyped 9 VEGFA single‐nucleotide polymorphisms (SNPs) in 766 glioma patients and 824 cancer‐free controls selected from a Chinese population. We evaluated the glioma risk conferred by individual SNPs, haplotypes as well as cumulative SNP effect. In the single‐locus analysis, we found that rs2010963 (G+405C, G‐634C) [odds ratio (OR) = 1.29; 95% confidence interval (CI) = 1.04–1.58; GC/CC vs. GG] and rs3025030 (OR = 2.21; 95% CI = 1.18–4.14; CC vs. GG/GC) were associated with increased risk for glioma, and rs3024994 (OR = 0.66; 95% CI = 0.47–0.94; CT/TT vs. CC) was associated with reduced glioma risk, albeit insignificant after Bonferroni correction for multiple comparisons. The haplotype‐based analysis revealed that AGG in block 1 and ATT, ACT in block 2 were associated with 20–40% reductions in glioma risk. The inverse association of haplotype AGG containing rs2010963G remained significant after correction for multiple testing (p = 0.002, pcorrected = 0.022). The aforementioned 3 SNPs revealed a significant cumulative risk effect; the increased risk for glioma was 1.38‐fold for each additional adverse genotype he or she carries (ptrend = 8.4 × 10−5). Our findings suggested that VEGFA variants may be involved in glioma risk. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.

Fine mapping analysis of a region of 20q13.33 identified five independent susceptibility loci for glioma in a Chinese Han population

Genome-wide association studies have identified the susceptibility single nucleotide polymorphisms (SNPs) of glioma at chromosome 20q13.33, and the replication study conducted among Chinese Han population also confirmed the susceptibility locus rs6010620 is located in this region. To identify other genetic variants in 20q13.33, we genotyped 13 common tagging SNPs and imputed 86 additional SNPs in a region ∼100 kb at 20q13.33 among 1027 controls and 987 cases. Among 99 SNPs, five independent susceptibility loci (20-62315594 in RTEL1, 20-62335293 in adenosine diphosphate ribosylation factor-related protein 1, rs3761121 in ZGPAT, rs1058319 in SLC2A4RG and rs5019252 in ZBTB46) were identified for glioma. Two of the five SNPs (20-62335293, P = 3.09 × 10(-10) and rs1058319, P = 1.26 × 10(-11)) satisfied the threshold of genome-wide significance (P < 10(-8)). Further stratified analysis revealed that 20-62315594 was only significantly associated with glioblastoma (GBM) risk [P = 1.71 × 10(-8) for trend test, adjusted odds ratio (OR) = 1.99, 95% confidence interval (CI) = 1.57-2.52]. Other four SNPs were significantly associated with both GBM and astrocytoma. The risk of glioma increased with the increase of the number of risk alleles (P = 1.94 × 10(-11), for trend test, adjusted OR = 1.43, 95% CI = 1.29-1.58), and the individuals who carried 7-10 risk alleles had a 2.64-fold increased risk of glioma development compared with those who carried 0 risk allele (P = 8.71 × 10(-7), adjusted OR = 2.64, 95% CI = 1.79-3.88). Our results indicated a complex effect contributing to glioma risk at 20q13.33, which may provide a new insight into glioma development. Both variants and genes in this region should be considered in future studies designed to investigate the biological functions.

A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population

BackgroundThe human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes.MethodsThe APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations.ResultsThe significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014.ConclusionsOur results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.

Fine Mapping of a Region of Chromosome 11q23.3 Reveals Independent Locus Associated with Risk of Glioma

Background A single nucleotide polymorphism (SNP) at locus 11q23.3 (rs498872) in the near 5′-UTR of the PHLDB1 gene was recently implicated as a risk factor for gliomas in a genome-wide association study, and this involvement was confirmed in three additional studies. Methodology/Principal Findings To identify possible causal variants in the region, the authors genotyped 15 tagging SNPs in the 200 kb genomic region at 11q23.3 locus in a Chinese Han population-based case-control study with 983 cases and 1024 controls. We found evidence for an association between two independent loci (both the PHLDB1 and the ACRN1 genes) and a predisposition for gliomas. Among the multiple significant SNPs in the PHLDB1 gene region, the rs17749 SNP was the most significant [P = 1.31×10−6 in a recessive genetic model]. Additionally, two novel SNPs (rs2236661 and rs494560) that were independent of rs17749 were significantly associated with glioma risk in a recessive genetic model [P = 1.31×10−5 and P = 3.32×10−5, respectively]. The second novel locus was within the ARCN1 gene, and it was associated with a significantly reduced risk for glioma. Conclusions/Significance Our data strongly support PHLDB1 as a susceptibility gene for glioma, also shedding light on a new potentially candidate gene, ARCN1.

Single nucleotide polymorphisms of matrix metallopeptidase 3 and risk of gliomas in a Chinese Han population

Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer‐free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03–1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02–1.27), males (adjusted OR = 1.19, 95%CI = 1.05–1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07–1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07–1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06–1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas.