Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID‐metabolizing enzymes central to NSAID metabolism including UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three‐SNP genotype in UGT1A6 (G–A–A; Ala7–Thr181–Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04–14.45 and OR 1.34; 95% CI 1.10–1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P‐interaction = 0.02), a three‐SNP genotype within UGT2B4 and ibuprofen use (P‐interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P‐interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.     

Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei,China

The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population‐based case–control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% CI: 0.16–0.55; P: 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value <0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; P_interaction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; P_interaction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH‐containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy. Environ. Mol. Mutagen., 2009. Published 2009 Wiley‐Liss, Inc.     

Polymorphisms of inflammation‐related genes and colorectal cancer risk: a population‐based case–control study in China

The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation‐related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population‐based case–control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation‐related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene–gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation‐related genes on CRC risk.     

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery

To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP‐arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of CRC are associated with shorter disease free survival (DFS). However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of CRC cell lines to chemoradiotherapy (CRT). We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with DFS. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with expression levels of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients. In conclusion, we show that several CRC risk SNPs detect subpopulations of rectal cancer patients with poor prognosis, and that rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to CRT.     

The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos

Background Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of arachidonate 5‐lipoxygenase‐activating protein (ALOX5AP) and leukotriene A₄ hydrolase (LTA4H) in asthma have been inconclusive. Objective To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans. Methods The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single‐nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analysed for associations with asthma and asthma‐related phenotypes in 687 parent–child trios of Mexican and Puerto Rican origin. Results In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P=0.007 and 0.05, respectively). Among the Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (odds ratio=0.78, P=0.02) and baseline lung function (P=0.018) in Puerto Ricans. A gene–gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P=0.003, in the combined sample). Conclusion Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations. Cite this as: M. Via, A. De Giacomo, H. Corvol, C. Eng, M. A. Seibold, C. Gillett, J. Galanter, S. Sen, H. Tcheurekdjian, R. Chapela, J. R. Rodríguez‐Santana, W. Rodríguez‐Cintrón, S. Thyne, P. C. Avila, S. Choudhry and E. González Burchard on behalf of the Genetics of Asthma in Latino Americans (GALA) Study, Clinical & Experimental Allergy, 2010 (40) 582–589.     

The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: Haplotype associations and gene–environment interactions

UDP‐glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene‐environment interactions. UGT1A haplotype analysis found that the T‐G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR = 0.28, 95% CI = 0.11–0.69) and for the distal colon (OR = 0.32, 95% CI = 0.12–0.91)], and that the C‐T‐G haplotype in the 3′ region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.10–5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI = 1.21–5.04) and in females (OR = 3.08, 95% CI = 1.08–8.74). An interaction was found between high NSAID use and the A‐G‐T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub‐site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk. © 2014 Wiley Periodicals, Inc.     

Cumulative effects of genetic markers and the detection of advanced colorectal neoplasias by population screening

Genetic markers associated with colorectal cancer may be used in population screening for the early identification of patients at elevated risk of disease. We genotyped 3059 individuals with no cancer family history for eight markers previously associated with colorectal cancer. After colonoscopy, the genetic profile of cases with advanced colorectal neoplasia (213) was compared with the rest (2846). rs2066847 and rs6983267 were significantly associated with the risk of advanced colorectal neoplasia but with limited effect on their own [odds ratio (OR) 1.59; 95% confidence interval (CI) 1.02–2.41; p = 0.033 and OR 1.45; 95% CI 1.02–2.12; p = 0.044, respectively]. Cumulative effects, in contrast, were associated with high risk: the combination of rs2066847, rs6983267, rs4779584, rs3802842 and rs4939827 minimized the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it, for example, for at least two cumulated risk markers, OR is 2.57 (95% CI 1.50–4.71; corrected p‐value 0.0079) and for three or more, OR is 3.57 (95% CI 1.91–6.96; corrected p‐value 0.00074). The identification of cumulative models of – otherwise – low‐risk markers could be valuable in defining risk groups, within an otherwise low‐risk population (no cancer family history).     

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of ischemic stroke in Han Chinese of eastern China

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke.This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China.A total of 690 ischemic stroke cases and 767 controls were recruited.The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.On the basis of that,two polymorphisms of the ALOX5AP gene (rs10507391 and rs12429692) were determined by TaqMan genotyping assay.In addition,plasma leukotriene B4 (LTB4) levels were analyzed in these subjects.There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes.Haplotype analysis and stratification analysis according to sex,age,body mass index,hypertension,and diabetes also showed negative association.Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls (70.06±14.75 ng/L vs 57.34±10.93 ng/L;P=0.000) and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels (P=0.000).The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China.     

Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia

Current evidence suggests that apoptosis and the cell cycle system play an important role in cancer development. To identify susceptible genetic markers in these mechanisms, we did an association study in 63 patients and 148 controls. A total of 304 SNPs in 31 gene regions were selected. We evaluated an association at a gene region level by computing the minimum P-value (minP) and doing the false discovery rate (FDR) test. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (P(trend)<0.05). There were statistically significant associations for CASP7 (rs12416109 and rs3814231, P(trend) = 0.002 and 0.009, respectively, minP = 0.013, FDR = 0.042) and CASP14 (rs8110862, P(trend)<0.001, minP = 0.002, FDR = 0.027). This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development.     

Evaluation of SNPs in miR‐146a,miR196a2 and miR‐499 as low‐penetrance alleles in German and Italian familial breast cancer cases

Recently, the SNPs rs11614913 in hsa‐mir‐196a2 and rs3746444 in hsa‐mir‐499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa‐mir‐146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for disease‐causing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164, rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164, rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset. © 2009 Wiley‐Liss, Inc.     

Association of dietary and supplemental folate intake and polymorphisms in three FOCM pathway genes with colorectal cancer in a population‐based case‐control study

Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate‐mediated one‐carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population‐based case‐control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00?2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14?3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05?1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00?2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene‐diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene‐diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC. © 2013 Wiley Periodicals, Inc.     

The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility

Background: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl‐LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB₄ in airway disease. LTA₄ hydrolase and 5‐lipoxygenase activating protein have key roles in LTB₄ production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB₄ production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Methods: Three hundred and forty‐one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper‐responsiveness, FEV₁) were undertaken using the Family Based Association Test. Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042–0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41–3.32). Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB₄ in disease pathogenesis.     

Investigation of the Relationship Between Prostate Cancer and MSMB and NCOA4 Genetic Variants and Protein Expression

Two genome‐wide association studies (GWAS) identified the β‐microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow‐up studies demonstrate that the variant allele directly affects expression of the MSMB‐encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population‐based study of 1,323 cases and 1,268 age‐matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.     

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.     

Calcium‐sensing receptor gene polymorphism (rs7652589) is associated with calcium nephrolithiasis in the population of Yi nationality in Southwestern China

The calcium‐sensing receptor (CaSR) gene plays an important role in regulating the Ca²⁺ balance and reducing the risk for calcium stones. In this study, we evaluated the association of CaSR polymorphisms with calcium nephrolithiasis in the population of Yi nationality in Southwestern China. Biochemical variables were evaluated in 624 calcium nephrolithiasis patients and 470 age‐matched healthy controls without a history of nephrolithiasis. CaSR polymorphisms rs7652589, rs1501899, rs1801725 (Ala986Ser), rs1042636 (Arg990Gly) and rs1801726 (Gln1011Glu) were investigated between the calcium nephrolithiasis patients and healthy controls, using direct sequencing. Compared with the healthy controls, serum creatinine and 24‐hour urine calcium levels were significantly higher in calcium nephrolithiasis patients. Among these five polymorphisms, the genotypic and allelic frequency distributions of rs7652589 SNP was significantly associated with the risk of calcium nephrolithiasis. However, there were no genotypic or allelic distribution differences for rs1501899, rs1801725, rs1042636, and rs1801726 polymorphisms between calcium nephrolithiasis patients and healthy controls. Moreover, the association between rs7652589 SNP genotypes and the biochemical variables was not found. Our study showed that CaSR rs7652589 polymorphism had a significant effect on the risk of developing calcium nephrolithiasis in the population of Yi nationality in Southwestern China.     

Association study between CYP24A1 gene polymorphisms and cancer risk

CYP24A1, an essential gene in regulation of vitamin D, has been reported to play an important role in enhancing immune activity and inhibiting tumorigenesis. Previous studies proposed that rs2585428, rs4809960, rs6022999 and rs6068816 in CYP24A1 gene might be greatly associated with cancer risk. To validate the findings, we here investigated the associations of these four polymorphisms and colorectal cancer (CRC) risk in a central Chinese population (426 colon cancer patients, 361 rectal cancer patients and 800 healthy controls). The genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by sequencing. Our results revealed that the rs4809960 and rs6022999 were strongly associated with the CRC risk, especially with the colon cancer risk. Moreover, the analysis of haplotypes consisting of rs2585428(G > A), rs4809960(T > C), rs6022999(A > G) and rs6068816(C > T) indicated that haplotype ATGC significantly decreased the CRC risk, especially the colon cancer risk. Haplotype GCAT significantly increased the CRC risk, especially the rectal cancer risk. However, haplotype ACAC was only found to be associated with increased risk of CRC. To improve the statistical strength, an updated meta-analysis was further performed. The results showed that rs2585428 was associated with cancer risk in Caucasian population, rs4809960 was associated with breast cancer risk in Caucasian population, and rs6022999 was associated with cancer risk in Asian population. Collectively, the rs4809960 and rs6022999 may be the genetic biomarkers for prediction of colon cancer risk in Chinese population, the rs2585428 and rs6022999 may link to cancer susceptibility in Caucasian population and in Asian population respectly.     

Single nucleotide polymorphisms of ataxia telangiectasia mutated and the risk of papillary thyroid carcinoma

Genetic factors associated with susceptibility to papillary thyroid carcinoma (PTC) are not well known. We evaluated the association between single nucleotide polymorphisms (SNPs) of ataxia telangiectasia mutated (ATM) and the risk of PTC. A total of 437 histologically confirmed PTC cases and 184 cancer‐free controls without thyroid nodules were recruited. Genotypes with respect to five ATM SNPs (rs189037, rs664677, rs373759, rs664143, and rs4585) were determined by the TaqMan assay, and odds ratios and 95% confidence intervals were obtained by logistic regression analysis. Linkage disequilibria and haplotypes were examined from the genotype data. When evaluated separately the genotype distributions of the five ATM SNPs were similar in the PTC cases and controls. Three ATM SNPs (rs373759, rs664143, and rs4585) were found to be in strong linkage disequilibrium (D′ = 1.00, P < 0.001). When the three haplotypes (C‐A‐G), (T‐G‐T), and (C‐G‐T) of these three ATM SNP sites were analyzed, ATM haplotype (C‐G‐T) +/? was associated with a lower risk of PTC than ATM haplotype (C‐G‐T) ?/? (P = 0.03) after adjusting for age and gender. Our results suggest that genetic polymorphisms of ATM may play an important role in the development of thyroid cancer in the Korean population. Environ. Mol. Mutagen. 56:70–76, 2015. © 2014 Wiley Periodicals, Inc.     

Glutathione peroxidase tagSNPs: associations with rectal cancer but not with colon cancer

Glutathione peroxidases (GPXs) are selenium-dependent enzymes that reduce and, thus, detoxify hydrogen peroxide and a wide variety of lipid hydroperoxides. We investigated tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis from adenoma to cancer. A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r(2) ≥ 0.90, MAF ≥ 4%) identified 21 tagSNPs. We used an identical Illumina platform to genotype GPX SNPs in three population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal component analysis (PCA); multiple logistic regression was used for single SNPs. Analyses were adjusted for age, sex, and study center and restricted to non-Hispanic white participants. Analyses of cancer endpoints were stratified by molecular subtypes. Without correction for multiple testing, one polymorphism in GPX2 and three polymorphisms in GPX3 were associated with a significant risk reduction for rectal cancer at α = 0.05, specifically for rectal cancers with TP53 mutations. The associations regarding the three polymorphisms in GPX3 remained statistically significant after adjustment for multiple comparisons. The PCA confirmed an overall association of GPX3 with rectal cancer (P = 0.03). No other statistically significant associations were observed. Our data provide preliminary evidence that genetic variability in GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for differences in underlying pathogenetic mechanisms for colon and rectal cancer.