Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer

The steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2) gene plays a crucial role in androgen metabolism pathway in human prostate. It encodes SRD5A2 enzyme, which catalyses testosterone to dihydrotestosterone (DHT). DHT is the main active structure binding with androgen receptor (AR). After the activation of AR, it further regulates a series of target genes in androgen metabolism pathway. However, no clear consensus has been reached on the association between the SRD5A2 V89L, A49T and TA repeat polymorphisms and prostate cancer (PCa) risk. Thus, we performed a meta-analysis of 31 association studies with 14,726 PCa cases and 15,802 controls. We found no association between PCa and 89L compared with 89V allele [odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.98-1.06, P(heterogeneity) = 0.44]. The 49T allele showed a significantly elevated effect on the high stage (Stages III-IV) of PCa risk both under the dominant genetic model (OR = 2.13, 95% CI 1.44-3.15, P(heterogeneity) = 0.65) and in the contrast T versus A allele (OR = 2.06, 95% CI 1.41-3.02, P(heterogeneity) = 0.69). There was a significantly decreased association between PCa and long TA repeat as compared versus short TA repeat (OR = 0.86, 95% CI 0.74-1.00, P(heterogeneity) = 0.79). No significant between-study heterogeneity was found in all subjects under four genetic models (dominant model, recessive model, allele comparison and homozygosity comparison) for these three polymorphisms, respectively, so the fixed effects model was used to pool the result. Our result indicated that carriers of 49T might improve the risk of PCa in higher stages (Stages III-IV), carriers of long TA repeat might decrease the risk of PCa and 89L may not be an important risk factor for PCa. However, due to the limited sample sizes, this meta-analysis did not achieve sufficiently conclusive results. Still more well-designed studies should be performed to clarify the role of these three polymorphisms in the development of PCa.     

Grade-specific prostate cancer associations of IGF1 (CA)19 repeats and IGFBP3-202A/C in blacks and whites

Carrying the cytosine-adenosine (CA)19 repeat polymorphism in insulin-like growth factor-1 (IGF1) is associated with lower serum proteins and decreased prostate cancer risk. Carrying the -202A/C genotype in insulin-like growth factor binding protein-3 (IGFBP3) also has been associated with lower serum levels of the binding protein. However, the association between this variant and prostate cancer is inconsistent. To test the hypothesis that inconsistencies are partly due to cancer grade-specific differences in strength and direction of associations, we reanalyzed data from our previous Durham Veterans Administration Hospital study of blacks and whites comprising 47 cases (19 African Americans) with Gleason sum > or = 7, 50 cases (30 African Americans) with Gleason sum < 7 and 93 controls (49 African Americans). Compared to controls, the association between carrying the IGFBP3 C allele and prostate cancer risk was in OR(Low-Gleason) = 4.0; 95% CI: 1.4-12.3 compared to OR(High-Gleason) = 1.0; 95% CI: 0.4-2.2. Association patterns were similar in African Americans (OR(Low-Gleason) = 3.6; 95% CI: 1.0-13.2 vs. OR(High-Gleason) = 1.4; 95% CI: 0.4-2.3) and whites (OR(Low-Gleason) = 5.6; 95% CI: 0.6-49.0 vs. OR(High-Gleason) = 0.6; 95% CI: 0.2-2.2). The inverse association between carrying the IGF1 (CA)19 repeat variant did not vary by grade or ethnicity. If confirmed in larger studies, these findings support the hypothesis that the association between IGFBP3 C allele and prostate cancer is grade specific in both ethnic groups.     

Evidence for an association between the SRD5A2 (type II steroid 5 alpha-reductase) locus and prostate cancer in Italian patients

We have investigated the contributions of three polymorphic markers in the SRD5A2 gene to prostate cancer in a group of Italian patients. We have genotyped cases and controls for a polymorphic (TA)n dinucleotide repeat and two functional substitutions, A49T and V89L, substituting respectively alanine with threonine at codon 49, and valine to leucine at codon 89. We found a substantially increased but not significant risk associated with the 49T mutation and a reduction of risk for the V89L substitution. In conclusion, we report on preliminary evidence for both increased and decreased risk associated with separate markers at this locus.     

Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Germline mutations in cell cycle checkpoint kinase 2 (CHEK2) have been associated with a range of cancer types, in particular of the breast and prostate. Protein-truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate than the missense I157T variant. In order to estimate the risks of colorectal cancer associated with truncating and missense CHEK2 mutations, we genotyped 1085 unselected colorectal cancer cases and 5496 controls for four CHEK2 founder mutations present in Poland. We observed an increased risk of colorectal cancer in association with the missense I157T mutation (odds ratios (OR) = 1.5; 95% CI 1.2-2.0; P = 0.002) but not with truncating mutations (OR = 1.0; 95% CI 0.5-1.8; P = 0.9); however the difference in the two OR was not statistically significant (P = 0.2). We conclude that the I157T mutation increases the risk of colorectal cancer in the population, but that truncating mutations may confer a lower risk or no increase in risk. It is important that other studies of CHEK2 mutation carriers be conducted to confirm this hypothesis.     

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.     

Caution in generalizing known genetic risk markers for breast cancer across all ethnic/racial populations

Genome-wide association studies (GWAS) have identified common variants associated with breast cancer risk among women of European and Asian ancestries. To assess the generalizability across ethnic/racial populations of a risk score derived from genotyping 12 highly replicated breast cancer GWAS hits, we performed a case-control study (2224 cases and 2827 controls) nested in the Multiethnic Cohort (MEC) study, which was initiated in 1993-1996 and consists of subjects mainly from European-American, African-American, Native Hawaiian, Japanese and Latino populations. When viewed as a summary risk score, the total number of risk alleles carried by women was significantly associated with breast cancer risk overall (OR per allele, 1.09; 95% CI, 1.06-1.12; P=2.0 × 10(-10)) and in all populations except African-Americans, in which no significant association was observed (OR, 1.03; 95% CI, 0.98-1.08). In aggregate, the number of risk alleles is strongly associated with breast cancer risk in all populations studied except African-Americans. These results emphasize the need for large-scale association studies of multiple racial/ethnic groups for discovery and characterization of risk alleles relevant to all populations in the United States.     

ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer

Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P=0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.     

The association of XRCC3 Thr241Met genetic variant with risk of prostate cancer: a meta-analysis

BackgroundPrevious studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive.Objectiveshis meta-analysis aimed to conduct a better understanding of the effects of XRCC3 Thr241Met genetic variant on prostate cancer risk.MethodsWe identified three eligible studies, 499 prostate cancer cases and 571 controls.ResultsOverall, significant associations were detected in the heterozygote comparison genetic model (CT versus (vs.) CC: OR = 0.71, 95% CI 0.53–0.94, Z =2.38, p= 0.017), and the dominant genetic model (TT/CT vs. CC: OR = 0.74, 95% CI 0.57–0.98, Z = 2.11, p =0.035). In the subgroup analysis by ethnicities, we found that this genetic variant was significantly associated with the decrease risk of prostate cancer in Caucasians for heterozygote comparison genetic model (CT vs. CC: OR = 0.66, 95% CI 0.44–0.98, Z = 2.04, p = 0.042).No publication bias was found in this study.ConclusionsResults from this meta-analysis indicate that the XRCC3 Thr241Met genetic variant is associated with prostate cancer risk.     

HPC2/ELAC2 gene variants associated with incident prostate cancer

The HPC2/ELAC2 gene on chromosome 17p11 was identified as a candidate gene for hereditary prostate cancer (HPC) susceptibility. Two HPC2 gene missense variants, Ser217Leu (Leu217) and Ala541Thr (Thr541) have been associated with incident prostate cancer cases in some studies, but not in others. We tested for possible associations between the two HPC2 gene variants and prostate cancer risk in incident prostate cancer cases (199) and healthy male controls (525) from the Calgary region. The Thr541 variant showed linkage disequilibrium with the Leu217 variant. The number of Leu217 homozygotes in the case and control groups (8.6versus 8.5%) was not statistically different. Leu217 carrier status was associated with prostate cancer risk (cases 61.8% versus controls 50.3%) (OR 1.6, 95% CI 1.15–2.23). Additional analysis found that this association was not due to the co-existence of Thr541 variant (OR1.59, P=0.009). Logistic regression found that the relationship between the log odds of being a Thr541carrier and age depends on case/control status. Thr541 carriers had an increased risk for late-onset prostate cancer (P=0.028). Prostate intraepithelial neoplasia (PIN) was more common in the Leu217 allele carriers compared to non-carriers (42.3 versus 26.7%) (OR 2.05, 95% CI 1.10–3.83), and in the Thr541 carriers compared to non-carriers (50.0 versus 34.6%) (OR 1.89, 95% CI 0.75–4.78). In summary, the HPC2 gene variants Leu217 and Thr541 were associated with an increased risk for prostate cancer and for PIN in males undergoing radical prostatectomies in the Calgary region.     

Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort

It is well established that rare mutations in BRCA2 predispose to familial breast cancer, but whether common variants at this locus contribute more modest risk to sporadic breast cancer has not been thoroughly investigated. We performed a haplotype-based study of BRCA2 among women in the Multiethnic Cohort Study (MEC), genotyping 50 SNPs spanning 109.4 kb of the BRCA2 gene. Twenty-one haplotype-tagging SNPs (including seven missense SNPs) were selected to predict the common BRCA2 haplotypes and were genotyped in a breast cancer case-control study nested in the MEC (cases, n=1715; controls, n=2502). Compared to non-carriers, we observed nominally significant positive associations for homozygous carriers of specific haplotypes in blocks 2 (haplotype 2c: OR=1.50; 95% CI, 1.08-2.09) and 3 (haplotype 3d: OR=1.50; 95% CI, 1.01-2.24). These results could be explained on the basis of a single marker in intron 24 (SNP 42: rs206340) that was correlated with these haplotypes and the homozygous state was associated with a significantly increased risk of breast cancer (AA versus GG genotypes: OR=1.59, 95% CI, 1.18-2.16; nominal P=0.005). This association was modestly stronger among women with advanced disease (OR=2.00, 95% CI, 1.30-3.08; P=0.002). In this exploratory analysis, we found little indication that common variation in BRCA2 dramatically impacts sporadic breast cancer risk. However, a significant elevation in risk was observed among approximately 6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus.     

Breast cancer: role of polymorphisms in biotransformation enzymes

We aimed at determining whether any association exists between genetic polymorphisms in epoxide hydrolase (EPHX1), NADPH-quinone oxidoreductase (NQO1), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to breast cancer. Polymerase chain reaction-restriction fragment length polymorphism-based genotyping assays were used to determine the frequency of polymorphisms in EPHX1 (exons 3 and 4), NQO1 (exon 6), GSTM1 (deletion), GSTP1 (exon 5), and GSTT1 (deletion) in a case-control study comprised of 238 patients with breast cancer and 313 healthy individuals. The distribution of genotypes in exon 6 of NQO1 was significantly different between the control group and breast cancer cases. Age-adjusted odds ratio (OR) for variant genotype NQO1*2/*2 was 3.68 (confidence interval (CI) = 1.41-9.62, P = 0.008). Association of GSTP1*2/*2 genotype as well as that of low EPHX1 activity deduced by combinations of genotypes in exons 3 and 4 with breast cancer was suggestive, but nonsignificant. Individuals simultaneously lacking GSTM1 and carrying at least one GSTP1 variant allele were at significantly higher risk of breast cancer (OR = 2.03, CI = 1.18-3.50, P = 0.010). Combinations of either GSTM1null or GSTP1*2 with low activity of EPHX1 presented significant risk of breast cancer (OR = 1.88, CI = 1.00-3.52, P = 0.049 and OR = 2.40, CI = 1.15-5.00, P = 0.019, respectively) as well. In conclusion, the results suggest that genetic polymorphisms in biotransformation enzymes may play a significant role in the development of breast cancer.     

Podocalyxin variants and risk of prostate cancer and tumor aggressiveness

We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer [odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09-4.20, P=0.03] and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23-5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01-9.15) and OR=4.42 for two deletions (95%CI=1.32-14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02-2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.     

The Cox-2 -1195 G > A polymorphism and cancer risk: a meta-analysis of 25 case-control studies

Cyclooxygenase 2 (Cox-2, a rate-limiting enzyme in the conversion of arachidonic acid to prostanoids) has been implicated in several physiological and pathological processes, and it has been reported that polymorphisms in the regulatory region of Cox-2 might influence its expression, contributing to the interindividual susceptibility to cancer. However, results from published studies on the association between the Cox-2 -1195G > A polymorphism and the risk of cancer are conflicting. We performed a meta-analysis based on 25 case-control studies, including a total of 9482 cancer cases and 12?206 controls to derive a more precise estimation of the association and its possible influence on cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall results indicated that the variant genotypes moderately increased risk of cancer (AA/AG versus GG, OR = 1.15, 95% CI: 1.02-1.31). In the stratified analysis for the -1195G > A polymorphism, a proximate association was observed in Asian populations (AA/AG versus GG, OR = 1.28, 95% CI: 1.12-1.46), but no significant association except for oesophageal cancer and 'others' was found when stratified by cancer type. In conclusion, our meta-analysis indicates that -1195G > A of Cox-2 is a low penetration risk factor for cancer.     

The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population

 Epidemiological data indicate a relationship between ultraviolet radiation, vitamin D, and prostate cancer risk. Antiproliferative effects of vitamin D require the expression of the nuclear vitamin D receptor (VDR). A three-fold increase in prostate cancer risk associated with the less active vitamin D receptor allele (the T allele from VDR TaqI polymorphism at codon 352) was reported. The role of VDR genotypes in the susceptibility to prostate cancer has not yet been studied in populations of southern Europe. In the present study, we determined VDR TaqI genotypes in Portuguese prostate cancer cases (n= 163) and controls (n= 211), a southern European population. When cases were compared with controls, we found an association of VDR T allele with prostate cancer risk (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.02–3.37; P= 0.035). This association was confirmed using logistic regression analysis (OR = 2.11, 95% CI 1.15–3.88; P= 0.015) and in particular associated to risk of prostate cancer onset in men over the age of 66 years (OR = 2.36, 95% CI 1.05–5.29; P= 0.036). Fifty percent of cases older than 66 years could be attributed to the influence of this risk factor. Our results indicate that the contribution of VDR genotypes to prostate cancer susceptibility might depend on the population studied and its geographic localization, and that VDR genotypes are important in the definition of the genetic risk profile of populations of southern Europe. Received: March 13, 2002 / Accepted: March 25, 2002     

Pooled analysis of genetic variation at chromosome 8q24 and colorectal neoplasia risk

Several different genetic variants at chromosome 8q24 have been related to prostate, breast and colorectal cancer risk with evidence of region-specific risk differentials for various tumor types. We investigated the association between 15 polymorphisms located in 8q24 regions associated with cancer risk in a pooled analysis of 2587 colorectal adenoma cases, 547 colorectal cancer cases and 2798 controls of European descent from four studies. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations. Three polymorphisms (rs10808555, rs6983267 and rs7837328) located between 128.47 and 128.54 Mb were found to be associated with colorectal tumor risk. The association was strongest for the previously reported rs6983267 variant and was similar for both adenoma (OR(per allele) = 1.16, 95% CI: 1.07-1.25, P = 0.0002) and cancer (OR (per allele) = 1.17, 95% CI: 1.01-1.35, P = 0.03). The strength of the association of the regional haplotype containing variant alleles at rs10808555, rs6983267 and rs7837328 but not rs10505476 was greater than that of any single variant of both adenoma (OR = 1.27, P = 0.0001) and cancer (OR = 1.26, P = 0.03). The risk associated with rs6983267 was stronger for multiple adenomas (OR(per allele) = 1.29, P = 5.6 x 10(-6)) than for single adenoma (OR(per allele) = 1.10, P = 0.03) with P(heterogeneity) = 0.008. This study confirms the association between colorectal neoplasia and the 8q24 polymorphisms located between 128.47 and 128.54 Mb and suggests a role for these variants in the formation of multiple adenomas.     

Association between survivin -31G > C promoter polymorphism and cancer risk: a meta-analysis

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.     

Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women

Mitochondria play important roles in cellular energy production, free radical generation, and apoptosis. In a previous report, the mitochondrial DNA (mtDNA) G10398A (Thr-->Ala) polymorphism was associated with breast cancer risk in African-American women [Cancer Res 2005;65:8028-33]. We sought to replicate the association by genotyping the G10398A polymorphism in multiple established population-based case-control studies of breast cancer in African-American women. The 10398A allele was not significantly associated with risk in any of the studies: San Francisco (542 cases, 282 controls, odds ratio OR = 1.73, 95% confidence interval CI = 0.87-3.47, P = 0.12); Multiethnic Cohort (391 cases, 460 controls, OR = 1.08, 95% CI = 0.62-1.86, P = 0.79); and CARE and LIFE (524 cases, 236 controls, OR = 0.81, 95% CI = 0.43-1.52, P = 0.50). With data pooled across the studies (1,456 cases and 978 controls), no significant association was observed with the 10398A allele (OR = 1.14, 95% CI = 0.80-1.62, P = 0.47, test for heterogeneity = 0.30). In analysis of advanced breast cancer cases (n = 674), there was also no significant association (OR = 1.18, 95% CI = 0.76-1.82, P = 0.46). Our results do not support the hypothesis that the mtDNA G10398A polymorphism is, as has previously been reported, a marker of breast cancer risk in African Americans.     

p73 G4C14-to-A4T14 gene polymorphism and interaction with p53 exon 4 Arg72Pro on cancer susceptibility: a meta-analysis of the literature

The p73 gene (1p36-33) is involved in cancer development through cell growth inhibition by inducing apoptosis in a p53-like manner. The p73 G4C14-to-A4T14 dinucleotide polymorphism, consisting of two single-nucleotide polymorphisms in the non-coding region of exon 2 that are in complete linkage disequilibrium, has been extensively studied in association with cancer risk. We performed a meta-analysis of published studies that examined the association between this p73 G4C14-to-A4T14 polymorphism and cancer by searching for relevant studies on Medline and Embase up to February 28, 2010. Pooling data from 19 case-control studies that included 6510 cancer cases and 5711 controls, we found that carriers of the p73 G4C14-to-A4T14 homozygous variant genotype (AT/AT) had an increased global risk of cancer [odds ratio (OR) = 1.30, 95% confidence interval (CI), 1.03-1.65]. There was no evidence of an effect modification of p73 AT/AT by age, gender, ethnicity or smoking status in subgroup analyses; however, a 1.35-fold statistically significant increased risk was found among individuals <55 years old. In case-only analysis, the homozygous p73 G4C14-to-A4T14 variant of p73 genotype was associated with the presence of the p53 exon 4 Arg72Pro allele (OR = 1.30, 95% CI, 1.02-1.64), which is suggestive of a biological interaction between the two genes in carcinogenesis. In conclusion, the p73 G4C14-to-A4T14 homozygous variant genotype might be a risk factor for cancer, especially in combination with the p53 exon 4 Arg72Pro polymorphism. Further studies looking at p73 G4C14-to-A4T14 and p53 exon 4 Arg72Pro interaction are required to support our findings.     

Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population

According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.