No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned

The steroid 5-alpha reductase type II gene (SRD5A2) encodes the enzyme which converts testosterone (T) to the more active androgen dihydrotestosterone. A non-synonymous single-nucleotide polymorphism, A49T (rs9282858), in SRD5A2 has been implicated in prostate cancer risk; however, results have been inconsistent. In 1999, we reported a strong association between the A49T variant and prostate cancer risk among African-Americans and Latinos in the Hawaii-Los Angeles Multiethnic Cohort (MEC). We report here an updated analysis of MEC data including the five major ethnic groups of the MEC, an increased sample size, improved genotyping technology and a comprehensive meta-analysis of the published literature. We found a non-statistically significant positive association between prostate cancer risk and carrying either the AT or TT genotype [odds ratio (OR) = 1.16, 95% confidence interval (CI) 0.79-1.69] in the MEC. This finding is in contrast to our previous results of ORs of 3.28 and 2.50 for the association between prostate cancer risk and the variant in African-American and Latino men, respectively; this can be accounted for by genotyping error in our earlier study. Meta-analysis of the published literature, including the current MEC data, shows a summary OR of 1.13 (95% CI 0.95-1.34) for the A49T variant with prostate cancer risk among sporadic, unselected cases. After evaluating more than 6000 cases and 6000 controls, there is little evidence of a role for the SRD5A2 A49T variant in prostate cancer risk. Overall, this report highlights the importance of rigorous genotyping quality control measures and replication efforts in genetic association studies.     

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.     

No association of ERCC1 C8092A and T19007C polymorphisms to cancer risk: a meta-analysis

ERCC1 (excision repair cross complementation group 1) is a subunit of the nucleotide excision repair complex, which can perform DNA strand incision correction of DNA damage. Association studies on the ERCC1 polymorphisms (C8092A and T19007C) in cancer had shown conflicting results. We performed a meta-analysis from all eligible case-control studies to assess the purported associations. Overall, the 19007C allele (3 853 patients and 4 349 controls) showed no significant effect on cancer risk compared to 19007T allele (P=0.39, odds ratio (OR)=0.95; 95% confidence interval (CI) 0.85-1.06, P(heterogeneity)=0.001) in all subjects. Meta-analysis under other genetic contrasts did not reveal any significant association of T19007C to cancer in all subjects, Caucasians and Asians. The 19007C allele (2 279 patients and 2 808 controls) showed no significant effect on lung cancer risk compared to 19007T allele (P=0.72, OR=0.94, 95% CI 0.69-1.29, P(heterogeneity)=0.0001) in all subjects. No significant effect of 8092A allele (3 865 patients and 3 750 controls) on cancer risk in all subjects (P=0.85, OR=1.01, 95% CI 0.94-1.08, P(heterogeneity)=0.92) and in Caucasians and Asians compare to 8092C. No evidences of association of C8092A (501 patients and 620 controls) to squamous cell carcinoma were found. The accumulated evidence indicated ERCC1 T19007C and C8092A might not be risk factors for cancer. Significant between-study heterogeneity existed in T19007C, which arose from a study showing significant protecting effect of 19007C allele compare to 19007T allele in smokers. More studies based on larger, stratified case-control population should be required to further evaluate the role of ERCC1 C8092A and T19007C polymorphisms in different cancer, especially in smokers.     

A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus

To more precisely estimate the association between interferon regulatory factor 5 (IRF5) polymorphisms and systemic lupus erythematosus (SLE) risk, we surveyed studies on the association of IRF5 rs2204640, rs10954213, rs729302 or rs2280714 with SLE using PubMed, Embase and Web of Science up to February 2011. Two investigators independently assessed the data quality and extracted the data. A total of 17 comparisons from ten relevant studies involving 6403 patients and 7475 controls were included to analyse the association between IRF5 rs2004640 and SLE risk (odds ratio, OR = 1.41, 95% confidence interval (CI) 1.34-1.49, P = 0.000). As for rs10954213, there were ten comparisons from six relevant studies involving 3461 patients and 3692 controls were included to analyse the association between IRF5 rs10954213 and SLE risk (OR = 1.23, 95% CI 1.08-1.39, P = 0.002). And this meta-analysis also showed a significant association of rs729302 (OR = 0.78, 95% CI 0.74-0.83, P = 0.000), rs2280714 (OR = 0.90, 95% CI 0.83-0.98, P = 0.021) with SLE. In a subgroup analysis by ethnicity, significantly increased SLE risk was associated with IRF5 rs2004640 T allele in populations of European, Asian and Latin American origin, and the rs10954213 A allele is significantly associated with SLE in European origin but not in Asian origin. This meta-analysis suggested that IRF5 gene polymorphism was associated with SLE in multiple ethnic populations.     

Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region

Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies reported ambiguous findings. We examined 932 ischaemic stroke patients from a Swedish population-based stroke register, and 396 control subjects. We assessed possible associations between ischaemic stroke and nine preselected SNPs in the chromosome regions of the PDE4D gene, including rs12188950 (SNP45) and rs3887175 (SNP39); the ALOX5AP gene, including rs17222814 (SG13S25) and the promoter region of the MHC class II transactivator, MHC2TA. The T allele of SNP45 showed negative association with ischaemic stroke (odds ratio, OR=0.72; 95% confidence interval (CI): 0.58-0.91; P=0.0055). Among hypertensive subjects, this influence of the T allele of SNP45, and the T allele of SNP39, were more pronounced (with OR=0.52; 95% CI: 0.37-0.73; P=0.0001 and OR=0.57; 95% CI: 0.41-0.79; P=0.0007, respectively). These SNPs also interacted with hypertension with a relative excess risk due to interaction of -1.66 (P=0.0002) for SNP45 and -1.65 (P=0.0005) for SNP39. The P-values remained significant after correction for multiple testing. Among nonhypertensives, the A allele of SG13S25 indicated increased stroke risk (OR=1.82; 95% CI: 1.21-2.74; P=0.0039; not significant after Bonferroni correction). SNP45 was associated with ischaemic stroke even when controlling for hypertension, diabetes, heart disease and smoking. Our meta-analysis of 13 studies (including ours) showed no overall influence of SNP45 on ischaemic stroke. However, the 13 studies may differ because of nonrandom causes, as suggested by the heterogeneity test (P=0.042). This might support previously undetected mechanisms causing fluctuating ischaemic stroke risk.European Journal of Human Genetics (2008) 16, 1117-1125; doi:10.1038/ejhg.2008.62; published online 9 April 2008.     

Transforming Growth Factor β1-509C/T and +869T/C Polymorphisms on the Risk of Upper Digestive Tract Cancer: A Meta-Analysis Based on 10,917 Participants

The aim of this study was to assess the relationships between transforming growth factor β1-509C/T (rs1800469) and +869T/C (rs1800470) polymorphisms and the risk of upper digestive tract cancer (UDT cancer) by using a meta-analysis. We interrogated the databases of Medline, Embase and Wanfang (Chinese literature database) (latest update; December 15, 2011). Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were used to assess the strength of the associations. In total, 20 case-control studies were included in this meta-analysis. Overall, both TGF β1-509C/T and +869T/C polymorphisms were not associated with risk of UDT cancer [-509C/T: OR (95%CI) = 1.10 (0.99-1.22) for TT vs. C carries, P(heterogeneity) = 0.10; +869T/C: OR (95%CI) = 1.04 (0.88-1.23) for CC vs. T carriers, P(heterogeneity) = 0.02]. Subgroup analyses indicated that the -509T allele was associated with increased risk of UDT cancer in population-based studies (OR = 1.16 (1.04-1.31), P(heterogeneity) = 0.31 for TT vs. C carriers) and in small sample-sized studies (OR = 1.45 (1.15-1.84), P(heterogeneity) = 0.56 TT vs. C carriers). All subgroup analyses for the TGF β1+869T/C polymorphism indicated null association except for hepatocellular carcinoma. Interestingly, both the TGF β1-509T allele and the +869C allele were associated with decreased risk of hepatocellular cancer based on limited original studies. This meta-analysis indicated that TGF β1-509C/T rather than +869T/C is a potential risk factor for UDT cancer.     

TSP1 and MMP9 genetic variants in sporadic prostate cancer

Angiogenesis plays an important role in the initiation and progression of many malignancies including prostate cancer (PCa). Therefore, genes implicated in angiogenic pathways could be susceptibility candidate genes for this malignancy. In this respect, we investigated the impact of functional genetic variants of TSP1 (N700S) and MMP9 (-1562 C/T) genes on the development and progression of PCa. This case-control study included 101 PCa patients and 106 healthy controls analyzed by polymerase chain reaction -restriction fragment length polymorphism assay. No association was observed between any of the TSP1 genotypes and PCa risk or severity; however, subjects carrying one copy of the MMP9 T allele exhibited threefold higher risk of developing PCa (OR = 2.86; P = 0.004). Regarding prognostic value, a significant association was found between the occurrence of the MMP9 T allele and the high-grade tumor (OR = 3.21; P = 0.004) and the advanced disease (OR = 2.47; P = 0.026). We also analyzed the effect of the combined genotypes on PCa risk. The patients with two high-risk genotypes exhibited 2.8-fold higher risk of developing PCa than those with only low-risk genotypes, but the association was not statistically significant. These findings suggest that MMP9 polymorphism is an independent risk factor of PCa development and aggressiveness.     

Endothelial nitric oxide synthase gene polymorphisms and prostate cancer risk in Serbian population

Genome-wide association studies (GWAS) have identified over 46 SNPs associated with human prostate cancer (PCa). Some studies have shown correlation of the nitric oxide synthase (NOS) NOS3 gene polymorphisms with the risk and/or progression of PCa. This study aimed to evaluate the association of NOS3 gene polymorphisms (−786T>C, −764A>G, −714G>T, −690C>T, −649G>A and 894G>T) with PCa risk and progression. 150 patients with PCa, 150 patients with BPH and 100 age-matched healthy controls were recruited in this study. Genotyping of promoter polymorphisms was performed by bi-directional DNA sequencing, and for 894G>T by RFLP analysis. There was no significant association between the alleles and genotypes of these genetic variants and PCa risk. For −786T>C polymorphism, we found that C allele is associated with absence of metastases, assuming dominant genetic model (P = 0.049; OR, 0.50; 95% CI, 0.25–1.00). It was found that, compared with NOS3 −690C>T variant CC genotype, CT and TT genotypes confer decreased risk of developing metastases (dominant model, P = 0.015, OR, 0.24; 95% CI, 0.07–0.88) and show association with low clinical tumour stage, compared with stages T₃ and T₄ (dominant model, P = 0.046, OR, 0.20; 95% CI, 0.04–1.02). Genetic variants −764A>G, −714G>T, −649G>A were not detected in our study group. There is evidence of an inverse correlation of the NOS3 894G>T minor allele with high serum PSA (>20 ng/ml) (dominant model, P = 0.013, OR, 0.37; 95% CI, 0.17–0.82). Our results suggest that NOS3 gene polymorphisms are genetic susceptibility factors for the progression of PCa and patient outcome.     

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.     

Steroid hormone genotypes ARStuI and ER325 are linked to the progression of human prostate cancer

Steroid hormones and their receptors are involved as initiators or promoters in prostate carcinogenesis. The intrauterine-perinatal period and maternal estrogen and testosterone levels have been proposed to be of etiologic importance in prostate tumorigenesis and cancer progression. The objective of this study was to analyze genetic polymorphisms in the androgen receptor ARStuI by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and in the estrogen receptor ER325 by PCR-single-strand conformational polymorphism (PCR-SSCP). In our study of 170 prostate cancer patients, ARStuI and ER325 genotypes and their association with disease progression and metastasis were analyzed. Age-adjusted logistic regression analysis indicates the association of ARStuI S1 allele with high-grade tumor (P = 0.033; OR = 3.0, 95% CI = 1.1-8.3) and the association of ER325 with high-grade tumor (P = 0.003; OR = 3.0, 95% CI = 1.4-6.4), advanced disease (P = 0.020; OR = 2.4, 95% CI = 1.1-5.1), risk of progression (P = 0.027; OR = 2.5, 95% CI = 1.1-5.7) and the presence of metastatic disease (P = 0.006; OR = 3.1, 95% CI = 1.4-6.8). In summary, this study has demonstrated androgen receptor (ARStuI) and estrogen receptor (ER325) genetic polymorphisms in prostate cancer patients and its association with disease progression and metastasis. Our results support the hypothesis that genetic factors related to steroid hormone receptors may influence the behavior of human prostate cancer.     

South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer

The androgen receptor (AR) gene possesses polymorphic CAG tandem repeats and the repeat length has been inversely related to the risk of prostate cancer (PCa). The distinct ethnic variation in the CAG repeat length may be correlated to differences in PCa risk in different populations. To evaluate the CAG repeat length in the AR gene and the implications for PCa, we screened 87 PCa patients and 120 control subjects from South India. The mean CAG repeat length in PCa patients was significantly smaller than that of controls (17.0 vs 20.7; P<0.001). Men with 19 CAG repeats had a significantly increased risk of cancer compared to those with >19 CAG repeats (age-adjusted OR=7.01; 95% CI=3.52–13.94; P<0.001). However, no significant association was observed between CAG repeats and age of onset or prostate-specific antigen levels. Although there was a trend towards shorter CAG repeat length in high grades of cancer, it was not significant (P=0.085). Thus, our results suggest an association between short CAG repeats in the AR gene and PCa risk in South Indian men. Further, we propose that CAG repeats could be used as a prognostic marker for PCa diagnosis.     

The +874T/A polymorphism in the interferon-γ gene and tuberculosis risk: an update by meta-analysis

The +874T/A polymorphism in the interferon-γ (IFN-γ) gene has been extensively examined for association to tuberculosis (TB); however, results of different studies have been inconsistent. The aim of this study was to comprehensively analyze the genetic risk of the +874T/A polymorphism in IFN-γ gene for TB by meta-analysis. A total of 4553 cases and 4631 controls in 21 case-control studies were included in this meta-analysis. The results indicated that the variant T allele carriers had a 27% decreased risk of TB, when compared with the homozygote AA (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.61-0.87 for TT + TA versus AA). In the subgroup analysis by ethnicity, significant decreased risks were associated with T allele carriers in Asians (OR= 0.71, 95% CI = 0.52-0.97, p = 0.03) but not in Caucasians (OR = 0.87, 95% CI = 0.65-1.17, p = 0.37). Our results suggest that the IFN-γ +874T/A polymorphism contributes to susceptibility to TB.     

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 CTLA-4 gene polymorphism and ankylosing spondylitis: a case-control study

Aims: The aim of our study was to evaluate the association between CTLA-4 polymorphisms (+49A/G, -318C/T and CT60A/G) and ankylosing spondylitis (AS) susceptibility. Methods: A total of 120 AS cases and healthy controls, matched on the age and gender, were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) were used to determine the gentypes of +49A/G, -318C/T and CT60A/G polymorphisms. Genotype distribution in control group was assessed by Hardy Weinberg Equilibrium (HWE) test. Odds ratio (OR) with 95% confidence interval (95% CI) were adopted to evaluate the relationship of CTLA-4 polymorphisms and AS susceptibility. Results: In our study, genotype distribution of the three polymorphisms in control group was consistent with the HWE (P > 0.05). The genotype analysis showed that AA genotype of + 49A/G polymorphism could increase the risk for AS (OR=2.357, 95% CI=1.127-4.930). Moreover, the frequency of A allele was also presented as a risk factor for AS. Additionally, AA genotype and A allele of CT60A/G appeared to be related with AS susceptibility (OR=2.610, 95% CI=1.047-6.510; OR=1.751, 95% CI=1.160-2.641). However, the T allele of -318C/T appeared to be a protective factor for AS (OR=0.383, 95% CI=0.228-0.643). Conclusion: In summary, there existed significant association between CTLA-4 gene polymorphisms and increased or decreased risk for AS.     

The E-cadherin (CDH1)--160 C/A polymorphism and prostate cancer risk: a meta-analysis

Published data on the association between E-cadherin (CDH1) -160 C/A polymorphism and prostate cancer (PCA) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A logistic regression approach proposed for molecular association studies was used to estimate a biological model of the gene effect. A total of 11 studies including 2637 cases and 2673 controls were involved in this meta-analysis. Logistic regression analysis indicated that the CDH1 -160 C/A genotypes were associated with PCA risk. The genetic model test indicated that the genetic model was most likely to be dominant (CA+AA vs CC). Overall, meta-analysis indicated that the -160A allele carriers (CA+AA) had a 21% elevated risk of PCA, when compared with the homozygotes (CC) (odds ratio (OR)=1.21; 95% confidence interval (CI): 0.97-1.51; P=0.090, P(heterogeneity)=0.001). In the subgroup analyses by ethnicity, significantly elevated risks were associated with -160 variant genotypes (CA+AA) in both European and Asian populations (OR=1.24; 95% CI: 1.08-1.43; P=0.003, P(heterogeneity)=0.220 and OR=1.54; 95% CI: 1.23-1.93; P<0.001, P(heterogeneity)=0.200). However, no significant associations were found in Africans (OR=0.59; 95% CI: 0.32-1.09; P=0.090, P(heterogeneity)=0.070). Although some modest bias could not be eliminated, this meta-analysis suggests that the CDH1 -160A allele is a low-penetrant risk factor for developing PCA, especially in Europeans and Asians.     

Association of genetic variants in CFTR gene, IVS8 c.1210-12T[5_9] and c.1210-35_1210-12GT[8_12], with spermatogenetic failure: case-control study and meta-analysis

It has been proposed that the genetic variants of IVS8 c.1210-12T[5_9] and adjacent c.1210-35_1210-12GT[8_12] in cystic fibrosis transmembrane conductance regulator gene might contribute to the spermatogenetic failure, but numerous genetic association studies that aimed to test this hypothesis reported conflicting results. So, in order to clarify such inconsistencies, we first conducted an original case-control study in Chinese Han population that consisted of 126 non-obstructive azoospermia, 169 severe oligospermia and 213 fertile male controls, and subsequently performed a meta-analysis of the available data, including our results. Our case-control study revealed that the frequencies of the T[5] allele and the T[5]+GT[12] combination in patients with non-obstructive azoospermia were both significantly higher than those in the fertile controls (13.1 versus 2.8%, P<0.01; 97.0 versus 41.7%, P<0.01, respectively), thus indicating a high risk susceptibility to non-obstructive azoospermia for males with T[5] allele or T[5]+GT[12]. However, as for the patients with severe oligospermia, both the T[5] allele frequency and T[5]+GT[12] did not differ from that for the control subjects (4.4 versus 2.8%, P>0.01; 53.3 versus 41.7%, P>0.01, respectively). In addition, our meta-analysis showed a significant increased risk of non-obstructive azoospermia for males with T[5] allele [odds ratio (OR) 3.45, 95% confidence intervals (CI) 2.29-5.20, P=0.000] and T[5]+GT[12] (OR 7.57, 95% CI 2.53-22.65, P=0.000) compared with males carrying other alleles. By contrast, neither T[5] allele itself nor T[5]+GT[12] combination had any effects on the risk of severe oligospermia (OR 0.96, 95% CI 0.42-2.21, P=0.002; OR 1.33, 95% CI 0.64-2.76, P=0.447). On the basis of these results, it can be concluded that the T[5] allele itself, or in combination with GT[12] repeat, may increase the susceptibility risk of non-obstructive azoospermia, but not that of severe oligospermia.     

Genetic variations of interleukin-8, CXCR1 and CXCR2 genes and risk of acute pyelonephritis in children

Acute pyelonephritis (APN) is the most severe form of urinary tract infection, the etiopathogenesis of which is still not well understood. Previous studies demonstrated that chemotaxis of neutrophils into the tissue and across the infected epithelial layer is a key step in rapid bacterial clearance. Variations within genes encoding the major chemokine interleukin-8 and its receptors CXCR1 and CXCR2 are therefore attractive candidates for participation in genetic predisposition to APN. The aim of our study was to evaluate the association of single nucleotide polymorphisms (SNPs) -251 T/A, +781 C/T, +1633 C/T and +2767 A/T in the IL-8 gene, +2608 G/C in the CXCR1 gene and +1208 C/T in the CXCR2 gene with susceptibility to APN in the Slovak population. PCR-SSP and PCR-RFLP were used to genotype SNPs in 147 children with APN (62 with recurrent and 85 with episodic form) and 215 healthy individuals. Statistical analysis revealed significantly increased frequency of CXCR1 +2608 C allele (P = 0.0238, OR = 2.452, 95% CI = 1.147-5.243) and GC genotype (P = 0.0201, OR = 2.627, 95% CI = 1.188-5.810) and lower frequency of CXCR2 +1208 T allele (P = 0.0408, OR = 0.645, 95% CI = 0.429-0.972) and TT+TC genotypes (P = 0.0497, OR = 0.5273, 95% CI = 0.288-0.964) in patients with recurrent APN compared with healthy controls. Furthermore, the A allele of IL-8 -251 T/A SNP was also significantly overrepresented in patients with recurrent APN when compared with those with only single episode of APN (P = 0.0439, OR = 1.627, 95% CI = 1.019-2.599). Our results indicate that the minor CXCR1 +2608 C allele is associated with significantly increased susceptibility to APN in childhood, while the CXCR2 +1208 T allele confers protection from recurrent APN. Moreover, allele A of the IL-8 -251 T/A may also increase the risk of developing recurrent attacks after the first-time APN.     

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.