Single Nucleotide Polymorphisms In Linkage Disequilibrium Research Articles

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Copper dyshomeostasis leading to a labile Cu(2+) not bound to ceruloplasmin ("free" copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two "strong LD" blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10-2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11-2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23-2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41-3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.

Association of p21 SNPs and risk of cervical cancer among Chinese women

BackgroundThe p21 codon 31 single nucleotide polymorphism (SNP), rs1801270, has been linked to cervical cancer but with controversial results. The aims of this study were to investigate the role of p21 SNP-rs1801270 and other untested p21 SNPs in the risk of cervical cancer in a Chinese population.MethodsWe genotyped five p21 SNPs (rs762623, rs2395655, rs1801270, rs3176352, and rs1059234) using peripheral blood DNA from 393 cervical cancer patients and 434 controls.ResultsThe frequency of the rs1801270 A allele in patients (0.421) was significantly lower than that in controls (0.494, p = 0.003). The frequency of the rs3176352 C allele in cases (0.319) was significantly lower than that in controls (0.417, p < 0.001).The allele frequency of other three p21 SNPs showed not statistically significantly different between patients and controls. The rs1801270 AA genotype was associated with a decreased risk for the development of cervical cancer (OR = 0.583, 95%CI: 0.399 - 0.853, P = 0.005). We observed that the three p21 SNPs (rs1801270, rs3176352, and rs1059234) was in linkage disequilibrium (LD) and thus haplotype analysis was performed. The AGT haplotype (which includes the rs1801270A allele) was the most frequent haplotype among all subjects, and both homozygosity and heterozygosity for the AGT haplotype provided a protective effect from development of cervical cancer.ConclusionsWe show an association between the p21 SNP rs1801270A allele and a decreased risk for cervical cancer in a population of Chinese women. The AGT haplotype formed by three p21 SNPs in LD (rs1801270, rs3176352 and rs1059234) also provided a protective effect in development of cervical cancer in this population.

P249 Could an Intronic SNP in the Alpha-1-Antitrypsin Gene Confer Protection to Chronic Obstructive Pulmonary Disease?

Chronic obstructive pulmonary disease (COPD) results from complex interactions between both environmental and genetic factors. This is evidenced by the considerable variation found in the risk of developing COPD despite...

Linking disease associations with regulatory information in the human genome

Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify “functional SNPs” that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.

Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity

Environmental factors including excessive caloric intake lead to disordered lipid metabolism and fatty liver disease (FLD). However, FLD demonstrates heritability suggesting genetic factors are also important. We aimed to use a candidate gene approach to examine the association between FLD and single nucleotide polymorphisms (SNPs) in lipid metabolism genes in the adolescent population-based Western Australian Pregnancy (Raine) Cohort. A total 951 seventeen year-olds underwent hepatic ultrasound, anthropometric and biochemical characterization, DNA extraction and genotyping for 57 SNPs in seven lipid metabolism genes (ApoB100, ATGL, ABHD5, MTTP, CETP, SREBP-1c, PPARα). Associations were adjusted for metabolic factors and Bonferroni corrected. The prevalence of FLD was 16.2% (11.4% male vs 21.2% female, P=0.001). Multivariate analysis of metabolic factors found suprailiac skinfold thickness (SST) to be the major predictor of FLD in females and males (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08-1.15, P=1.7×10(-10) and OR 1.17, 95%CI 1.13-1.22, P=2.4×10(-11) , respectively). In females, two SNPs in linkage disequilibrium from the CETP gene were associated with FLD: rs12447924 (OR 2.16, 95%CI 1.42-3.32, P=0.0003) and rs12597002 (OR=2.22, 95%CI 1.46-3.41 P=0.0002). In lean homozygotes, the probability of FLD was over 30%, compared with 10-15% in lean heterozygotes and 3-5% in lean wild-types. However, these associations were modified by SST, such that for obese individuals, the probability of FLD was over 30% in all genotype groups. Cholesteryl ester transfer protein gene polymorphisms are associated with an increased risk of FLD in adolescent females. The effect is independent of adiposity in homozygotes, thereby placing lean individuals at a significant risk of FLD.

Using Whole-Genome Sequence Data to Predict Quantitative Trait Phenotypes in Drosophila melanogaster

Predicting organismal phenotypes from genotype data is important for plant and animal breeding, medicine, and evolutionary biology. Genomic-based phenotype prediction has been applied for single-nucleotide polymorphism (SNP) genotyping platforms, but not using complete genome sequences. Here, we report genomic prediction for starvation stress resistance and startle response in Drosophila melanogaster, using ∼2.5 million SNPs determined by sequencing the Drosophila Genetic Reference Panel population of inbred lines. We constructed a genomic relationship matrix from the SNP data and used it in a genomic best linear unbiased prediction (GBLUP) model. We assessed predictive ability as the correlation between predicted genetic values and observed phenotypes by cross-validation, and found a predictive ability of 0.239±0.008 (0.230±0.012) for starvation resistance (startle response). The predictive ability of BayesB, a Bayesian method with internal SNP selection, was not greater than GBLUP. Selection of the 5% SNPs with either the highest absolute effect or variance explained did not improve predictive ability. Predictive ability decreased only when fewer than 150,000 SNPs were used to construct the genomic relationship matrix. We hypothesize that predictive power in this population stems from the SNP–based modeling of the subtle relationship structure caused by long-range linkage disequilibrium and not from population structure or SNPs in linkage disequilibrium with causal variants. We discuss the implications of these results for genomic prediction in other organisms.

Genome-wide association study of the age of onset of childhood asthma

Childhood asthma is a complex disease with known heritability and phenotypic diversity. Although an earlier onset has been associated with more severe disease, there has been no genome-wide association study of the age of onset of asthma in children. We sought to identify genetic variants associated with earlier onset of childhood asthma. We conducted the first genome-wide association study of the age of onset of childhood asthma among participants in the Childhood Asthma Management Program (CAMP) and used 3 independent cohorts from North America, Costa Rica, and Sweden for replication. Two single nucleotide polymorphisms (SNPs) were associated with earlier onset of asthma in the combined analysis of CAMP and the replication cohorts: rs9815663 (Fisher P= 2.31 × 10(-8)) and rs7927044 (P= 6.54 × 10(-9)). Of these 2 SNPs, rs9815663 was also significantly associated with earlier asthma onset in an analysis including only the replication cohorts. Ten SNPs in linkage disequilibrium with rs9815663 were also associated with earlier asthma onset (2.24 × 10(-7) <P< 8.22 × 10(-6)). Having 1 or more risk alleles of the 2 SNPs of interest (rs9815663 and rs7927044) was associated with lower lung function and higher asthma medication use during 4 years of follow-up in CAMP. We have identified 2 SNPs associated with earlier onset of childhood asthma in 4 independent cohorts.

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

Single Nucleotide Polymorphisms in the PRDX3 and RPS19 and Risk of HPV Persistence and Cervical Precancer/Cancer

BackgroundHost genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer.Methodology/Principal FindingsWe assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1113 genes in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 women with persistent carcinogenic HPV infection (median persistence of 25 months) and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women from the Guanacaste, Costa Rica HPV natural history cohort. For gene and SNP associations, we computed age-adjusted odds ratio and p-trend. Three comparisons were made: 1) association with CIN3/cancer (compared CIN3/cancer cases to random controls), 2) association with persistence (compared HPV persistence to random controls), and 3) progression (compared CIN3/cancers with HPV-persistent group). Regions statistically significantly associated with CIN3/cancer included genes for peroxiredoxin 3 PRDX3, and ribosomal protein S19 RPS19. The single most significant SNPs from each gene associated with CIN3/cancer were PRDX3 rs7082598 (P trend<0.0001), and RPS19 rs2305809 (P trend=0.0007), respectively. Both SNPs were also associated with progression.Conclusions/SignificanceThese data suggest involvement of two genes, RSP19 and PRDX3, or other SNPs in linkage disequilibrium, with cervical cancer risk. Further investigation showed that they may be involved in both the persistence and progression transition stages. Our results require replication but, if true, suggest a role for ribosomal dysfunction, mitochondrial processes, and/or oxidative stress, or other unknown function of these genes in cervical carcinogenesis.

Interaction of a 17q12 variant with both fetal and infant smoke exposure in the development of childhood asthma‐like symptoms

Gene variants on chromosome 17q12-21 are associated with an increased risk of childhood-onset asthma, a risk known to be modified by environmental tobacco smoke (ETS). To assess whether the association of rs2305480 on chromosome 17q12 in the GSDML gene with asthma-like symptoms in the first 4 years of life is modified by smoke exposure during fetal and early postnatal life. We used data from two independent prospective cohort studies from fetal life onwards in the Netherlands. We genotyped rs2305480 and assessed maternal smoking during pregnancy and ETS exposure at the age of 2. Asthma-like symptoms, defined as any reported wheezing, shortness of breath or dry nocturnal cough, were reported by parents when the children were 1, 2, 3, and 4 years. Analyses were based on a total group of 4461 Caucasian children. The G risk-allele of rs2305480 was associated with asthma-like symptoms [overall odds ratio 1.17 (1.11, 1.24), 2.66E-9]. The effect of rs2305480 on asthma-like symptoms was stronger among children who were exposed to smoke during fetal life (P-interaction = 0.04). Smoke exposure in early postnatal life was also associated with an increased effect of the 17q12 single nucleotide polymorphism (SNP) on asthma-like symptoms (P-interaction = 5.06E-4). These associations were consistent in both cohorts. A 17q12 variant, rs2305480, was associated with asthma-like symptoms in preschool children, and this association was modified by smoke exposure already during fetal life, and in infancy. Further investigation regarding SNPs in linkage disequilibrium with rs2305480 in relation to pathophysiological pathways is needed.

SNP discovery, gene diversity, and linkage disequilibrium in wild populations of Populus tremuloides

The use of single-nucleotide polymorphisms (SNPs) as molecular markers in plant studies has become increasingly common. With the development of these markers, there is an interest in determining levels of variation in natural populations. Here, we identify and characterize levels of SNPs in wild populations of aspen (Populus tremuloides Michx.). Four populations were sampled from Alberta and British Columbia in Western Canada. A total of 35 gene regions were selected for analysis. The loci selected are mainly involved in wood formation and include regions from genes for lignin biosynthesis, cellulose biosynthesis, and other cell wall compounds and a number of transcription factors. Other genes included those coding for growth hormones, disease resistance, and light responses. Primers were developed from conserved regions in multi-species EST alignments. Regions were PCR amplified, and products (approximately 500 to 1,000 bp) were assessed for levels of SNPs using Ecotilling. From a total of approximately 25 kb 462 SNPs were identified, over 18 SNPs/kb. Thus, SNPs are an abundant and potentially useful molecular marker in aspen. Gene diversity (heterozygosity) varied in the gene regions, with an overall average of H T = 0.18. Although gene diversity was considerable, genetic differentiation was low with the overall F ST value being 0.004. A surrogate measure of linkage disequilibrium (LD) was calculated, and overall, the LD was shown to decay relatively rapidly with distance along the gene region. The results obtained from the wood formation genes in this study will enable further targeting of regions for association studies on lignin and cellulose variation in aspen and other Populus species.

The C-681G Polymorphism of the PPAR-γ Gene Is Associated with Susceptibility to Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of fatty acid in the liver, a common disease in the world. The research of single nucleotide polymorphisms (SNPs) provides a new approach for managing NAFLD. SNPs may increase or decrease the functions of the target genes and their encoding proteins. Peroxisome proliferator-activated receptor (PPAR) plays a key role in modulating metabolism of hepatic triglycerides and consequently magnitude of NAFLD. In this study, we investigated the effect of three SNPs in the PPAR-γ gene i.e. rs10865710 (C-681G), rs7649970 (C-689T) and rs1801282 (C34G, also termed Pro12Ala) on susceptibility to NAFLD. The participants were selected from our epidemiological survey. Totally 169 participants were enrolled in NAFLD group, and 699 healthy subjects were included as controls. PCR-RFLP was applied to detect the SNPs. The G allele frequency of rs10865710 in NAFLD group (41.1%) was significantly higher than that (34.8%) in controls (p = 0.03). Differences in other two loci (rs7649970 and rs1801282) were not statistically significant between the two groups (p > 0.05). This result was confirmed by haplotype analysis. The GCC haplotype (a set of 3 adjacent SNPs in linkage disequilibrium, corresponding to the three alleles of above polymorphisms in order) was a risk factor for the susceptibility to NAFLD (p = 0.03). This study has revealed that the G allele of rs10865710 in the PPAR-γ gene is associated with the increased susceptibility to NAFLD. Our findings may provide novel diagnostic biomarkers and therapeutic targets for NAFLD.

Common Genetic Variation of Blood Pressure Traits and Their Relation to End-Organ Damage

### Study Hypothesis Initial genome-wide association studies (GWAS) for hypertension, a common cardiovascular risk factor, have delivered unexpectedly few and modest associations. The authors of the International Consortium for Blood Pressure Genome-Wide Association Studies set out to identify novel genetic variants in relation to blood pressure, intermediate phenotypes, and cardiovascular disease risk. A joint effort combining data on 200 000 individuals of European descent increased the power to detect DNA variants with small effect sizes. ### How Was the Hypothesis Tested? The authors used a staged approach for discovery, replication, and biological translation of their findings. At the identification stage, they performed a meta-analysis on genome-wide single nucleotide polymorphism (SNP) associations and off-treatment systolic and diastolic blood pressure measurements, as well as the dichotomous variable of hypertension, based on 29 studies (n≈70 000 individuals). In 3 resource-efficient sequential follow-up steps of de novo genotyping and SNP look-up in existing GWAS datasets, top hits were validated in >133 000 independent individuals of European descent. Sex and body mass index interaction analyses were performed for the top GWAS findings to understand potential effect modification. To identify possible causal mechanisms, top GWAS loci were looked up in diverse existing expression SNP data sets for cis -acting gene expression. In addition, neighboring nonsynonymous coding SNPs (linkage disequilibrium r 2 >0.8) were searched because amino acid sequence alterations harbor high potential to provide mechanistic insights. Furthermore, genetic loci were investigated in relation to ≈300 serum metabolites in >10 000 individuals of metabolomic and lipidomic studies. More than 6000 copy number variation-tagging SNPs were available for the correlation of structural genomic variation and blood pressure …

A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13

The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV(1) (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

DistiLD Database: diseases and traits in linkage disequilibrium blocks

Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of hundreds of diseases. However, there is currently no database that enables non-specialists to answer the following simple questions: which SNPs associated with diseases are in linkage disequilibrium (LD) with a gene of interest? Which chromosomal regions have been associated with a given disease, and which are the potentially causal genes in each region? To answer these questions, we use data from the HapMap Project to partition each chromosome into so-called LD blocks, so that SNPs in LD with each other are preferentially in the same block, whereas SNPs not in LD are in different blocks. By projecting SNPs and genes onto LD blocks, the DistiLD database aims to increase usage of existing GWAS results by making it easy to query and visualize disease-associated SNPs and genes in their chromosomal context. The database is available at http://distild.jensenlab.org/.

A flexible genome‐wide bootstrap method that accounts for rankingand threshold‐selection bias in GWAS interpretation and replication study design

The phenomenon known as the winner's curse is a form of selection bias that affects estimates of genetic association. In genome-wide association studies (GWAS) the bias is exacerbated by the use of stringent selection thresholds and ranking over hundreds of thousands of single nucleotide polymorphisms (SNPs). We develop an improved multi-locus bootstrap point estimate and confidence interval, which accounts for both ranking- and threshold-selection bias in the presence of genome-wide SNP linkage disequilibrium structure. The bootstrap method easily adapts to various study designs and alternative test statistics as well as complex SNP selection criteria. The latter is demonstrated by our application to the Wellcome Trust Case Control Consortium findings, in which the selection criterion was the minimum of the p-values for the additive and genotypic genetic effect models. In contrast, existing likelihood-based bias-reduced estimators account for the selection criterion applied to an SNP as if it were the only one tested, and so are more simple computationally, but do not address ranking across SNPs. Our simulation studies show that the bootstrap bias-reduced estimates are usually closer to the true genetic effect than the likelihood estimates and are less variable with a narrower confidence interval. Replication study sample size requirements computed from the bootstrap bias-reduced estimates are adequate 75-90 per cent of the time compared to 53-60 per cent of the time for the likelihood method. The bootstrap methods are implemented in a user-friendly package able to provide point and interval estimation for both binary and quantitative phenotypes in large-scale GWAS.

Human population dispersal “Out of Africa” estimated from linkage disequilibrium and allele frequencies of SNPs

Genetic and fossil evidence supports a single, recent (<200,000 yr) origin of modern Homo sapiens in Africa, followed by later population divergence and dispersal across the globe (the "Out of Africa" model). However, there is less agreement on the exact nature of this migration event and dispersal of populations relative to one another. We use the empirically observed genetic correlation structure (or linkage disequilibrium) between 242,000 genome-wide single nucleotide polymorphisms (SNPs) in 17 global populations to reconstruct two key parameters of human evolution: effective population size (N(e)) and population divergence times (T). A linkage disequilibrium (LD)-based approach allows changes in human population size to be traced over time and reveals a substantial reduction in N(e) accompanying the "Out of Africa" exodus as well as the dramatic re-expansion of non-Africans as they spread across the globe. Secondly, two parallel estimates of population divergence times provide clear evidence of population dispersal patterns "Out of Africa" and subsequent dispersal of proto-European and proto-East Asian populations. Estimates of divergence times between European-African and East Asian-African populations are inconsistent with its simplest manifestation: a single dispersal from the continent followed by a split into Western and Eastern Eurasian branches. Rather, population divergence times are consistent with substantial ancient gene flow to the proto-European population after its divergence with proto-East Asians, suggesting distinct, early dispersals of modern H. sapiens from Africa. We use simulated genetic polymorphism data to demonstrate the validity of our conclusions against alternative population demographic scenarios.

Abstract 5603: Common genetic variations in VDR, CYP27B1 and CYP24A1 genes and breast cancer risk in African American and European American women in the Women's Circle of Health Study

Abstract Common single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) have been examined with breast cancer risk in populations of European ancestry. Because of the striking differences in vitamin D levels and in SNP linkage disequilibrium (LD) between African Americans (AA) and European Americans (EA), it is hypothesized that associations of VDR SNPs with breast cancer risk may differ by race. A total of 67 multi-population tagSNPs in the VDR, CYP27B1 and CYP24A1 genes were genotyped in 928 breast cancer cases (547 AA and 381 EA) and 843 controls (461 AA and 382 EA) recruited through the Women's Circle of Health Study (WCHS), a case-control study based in New York City and seven counties in New Jersey. Cochran-Armitage test for trend was used for single SNP analysis, and LD block-based haplotype analysis was performed, with multiple comparisons corrected by permutation. In addition, 25-hydroxyvitamin D (25OHD) levels were measured in the banked serum samples from 242 AA and 187 EA healthy women. Four VDR SNPs were associated with breast cancer risk in AA women, and rs2239186 remained significant (p=0.03) after multiple comparison correction. Women with the AG/GG genotype of rs2239186 had a lower risk of breast cancer (OR=0.53, 95% CI=0.35-0.79) than those with the AA genotype, consistent with a three-SNP haplotype carrying the G allele of rs2239186 (OR=0.55, 95% CI=0.38-0.81) in AA women. In EA women, 2 SNPs in the VDR gene and 3 SNPs in the CYP24A1 gene were associated with breast cancer risk. EA women with the TT genotype of the VDR SNP rs11608702 had a significantly increased risk (OR=1.88, 95% CI=1.14-3.09), which were confirmed in an analysis of a two-SNP haplotype carrying the T allele (OR=1.44, 95% CI=1.12-1.85). In addition, a four-SNP haplotype in the CYP24A1 gene was associated with reduced cancer risk in EA women (OR=0.67, 95% CI=0.51-0.88). When stratified by menopausal status, the association of rs7975232 in VDR in EA women was stronger in postmenopausal women (OR=2.24, 95% CI=1.19-4.21); and the association of another VDR SNP rs886441 in AA women was stronger in premenopausal women (OR=2.27, 95% CI=1.32-3.90). Lastly, we found significant differences in 25OHD levels between AA and EA women; the least square mean and standard error were 14.9±0.5 vs 21.4±0.6 ng/mL (p&amp;lt;0.0001), respectively, after adjusting for age, BMI and season of blood collection. Dietary intake of vitamin D helped explain only 3% of the circulating levels. In conclusion, we found different SNPs associated with breast cancer risk between AA and EA women. Our findings support the hypothesis that the role of vitamin D-related genetic variations may be race-specific, possibly due to differences in linkage disequilibrium structure and in endogenous vitamin D levels between the two groups. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5603. doi:10.1158/1538-7445.AM2011-5603

Abstract 289: Associations between germline genotype and efficacy and safety outcomes in a phase III study of sunitinib (SU) and FOLFIRI in metastatic colorectal cancer (mCRC)

Abstract Introduction: SU is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. In a phase III mCRC study, adding SU to FOLFIRI did not improve progression-free survival (PFS) vs. FOLFIRI/placebo. Potential correlations were investigated between germline genotype and safety/efficacy endpoints among patients (pts) in this trial. Methods: Blood sample donation for genotype analysis was optional. Selection of genes and polymorphisms was based on prior reported associations. Twenty-one single-nucleotide polymorphisms (SNPs) in 10 genes (VEGF-A, VEGFR-2, CYP1A1, ABCG2, ABCB1, ABCC2, MTHFR, UGT1A1, FLT1 and FLT3) were analyzed by TaqMan allelic discrimination assay or fragment analysis, using DNA isolated from peripheral blood samples. All 21 polymorphisms were analyzed for associations with efficacy (PFS; overall survival [OS]) and selected safety endpoints. Results were adjusted for multiple testing of SNPs in linkage disequilibrium. Results: Genotyping was performed in 139/768 pts (18%). Age and gender were similar between genotyped and non-genotyped pts, but the genotyped subset had fewer non-Caucasians (13% vs. 39%; Fisher's exact P&amp;lt;0.0001). Therefore, the statistical analysis reported here included Caucasians only. OS was superior in genotyped vs. non-genotyped pts (log rank P&amp;lt;0.0001). For the FOLFIRI/placebo arm only, the ABCC2 gene SNP rs717620 was associated with increased grade 3/4 diarrhea for those with the T allele (0/37 for C/C, 2/15 for C/T, 2/2 for T/T; Fisher's exact P=0.0003), and remained statistically significant after multiple testing adjustment. In the SU/FOLFIRI arm only, the common homozygous genotype A/A in the CYP1A1 gene at rs1048943 was associated with increased grade 3/4 neutropenia (39/59 for A/A, 1/6 for A/G, # of G/G = 0; Fisher's exact P=0.028), but lost significance after multiple testing adjustment. In the FOLFIRI/placebo arm only, a weak association was observed between poorer PFS and the common homozygous genotype T/T for the rs1045642 SNP (C3435T) in the ABCB1 gene (median [T/T] = 36 weeks [95% CI 24.9-40.6]; median [T/C] = 45 weeks [41.9-83.6]; median [C/C] = 55.1 weeks [31.8-55.1], HR [T/C vs. T/T] = 0.21 [95% CI 0.07-0.64]; HR [C/C vs. T/T] = 0.23 [95% CI 0.07-0.81]; log rank P=0.008; not significant after multiple testing adjustment). Conclusions: Presence of the T allele in the ABCC2 gene at rs717620 was associated with increased risk of grade 3/4 diarrhea in a small number of Caucasian pts receiving FOLFIRI/placebo. No significant associations were identified between genotype and safety/efficacy endpoints in pts who received SU/FOLFIRI. As OS was superior in genotyped vs. non-genotyped pts, correlative findings may not be extrapolated beyond the genotyped subset. Further analysis of baseline characteristics is underway in the genotyped group to investigate this difference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2011-289

Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping

Background:Exposure to ionising radiation is a well-established risk factor for multiple types of tumours, including malignant brain tumours. In the 1950s, radiotherapy was used to treat Tinea Capitis (TC) in thousands of children, mostly of North-African and Middle Eastern origin, during the mass migration to Israel. The over-representation of radiation-associated meningioma (RAM) and other cancers in specific families provide support for inherited genetic susceptibility to radiation-induced cancer.Methods:To test this hypothesis, we genotyped 15 families segregating RAM using high-density single-nucleotide polymorphism (SNP) arrays. Using the family-based association test (FBAT) programme, we tested each polymorphism and haplotype for an association with RAM.Results:The strongest haplotype associations were attained at 18q21.1 (P=7.5 × 10−5), 18q21.31 (P=2.8 × 10−5) and 10q21.3 (P=1.6 × 10−4). Although associations were not formally statistically significant after adjustment for multiple testing, the 18q21.1 and 10q21.3 associations provide support for a variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL and CTNNA3 genes as risk factors for RAM.Conclusion:These findings suggest that any underlying genetic susceptibility to RAM is likely to be mediated through the co-inheritance of multiple risk alleles rather than a single major gene locus determining radiosensitivity.