Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

We hypothesized that single-nucleotide polymorphisms (SNPs) of genes involved in environmental endocrine disruptors (EEDs) metabolism might influence the risk of male genital malformations. In this study, we explored for association between 384 SNPs in 15 genes (AHR, AHRR, ARNT, ARNT2, NR1I2, RXRA, RXRB, RXRG, CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP3A4, CYP17A1 and CYP19A1) and risk of cryptorchidism (CO) and hypospadias (HS) in 334 Japanese (JPN) males (141 controls, 95 CO and 98 HS) and 187 Italian (ITA) males (129 controls and 58 CO). In the JPN study group, five SNPs from ARNT2 (rs2278705 and rs5000770), CYP1A2 (rs2069521), CYP17A1 (rs4919686) and NR1I2 (rs2472680) were significantly associated at both allelic and genotypic levels with risk of at least one genital malformation phenotype. In the ITA study group, two SNPs in AHR (rs3757824) and ARNT2 (rs1020397) were significantly associated with risk of CO. Interaction analysis of the positive SNPs using multifactor dimensionality reduction demonstrated that synergistic interaction between rs2472680, rs4919686 and rs5000770 had 62.81% prediction accuracy for CO (P=0.011) and that between rs2069521 and rs2278705 had 69.98% prediction accuracy for HS (P=0.001) in JPN population. In a combined analysis of JPN and ITA population, the most significant multi-locus association was observed between rs5000770 and rs3757824, which had 65.70% prediction accuracy for CO (P=0.055). Our findings indicate that genetic polymorphisms in genes involved in EED metabolism are associated with risk of CO and HS.     

Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study)

Genome-wide scans in Icelandic, Australian/New Zealand and Finnish pedigrees have provided evidence for maternal susceptibility loci for pre-eclampsia on chromosome 2, although at different positions (Iceland: 2p13 and 2q23, Australia/New Zealand: 2p11-12 and 2q22, Finland: 2p25). In this project, a large population-based (n=65 000) nested case-control study was performed in Norway to further explore the association between positional candidate genes on chromosome 2q and pre-eclampsia, using single-nucleotide polymorphisms (SNPs). DNA samples from 1139 cases (women with one or more pre-eclamptic pregnancies) and 2269 controls (women with normal pregnancies) were genotyped using the Applied Biosystems SNPlex high-throughput genotyping assay. In total, 71 SNPs within positional candidate genes at 2q22-23 locus on chromosome 2 were genotyped in each individual. Genotype data were statistically analysed with the sequential oligogenic linkage analysis routines (SOLAR) computer package. Nominal evidence of association was found for six SNPs (rs1014064, rs17742134, rs1424941, rs2161983, rs3768687 and rs3764955) within the activin receptor type 2 gene (ACVR2A) (all P-values <0.05). The non-independence of statistical tests due to linkage disequilibrium between SNPs at a false discovery rate of 5% identifies our four best SNPs (rs1424941, rs1014064, rs2161983 and rs3768687) to remain statistically significant. The fact that populations with different ancestors (Iceland/Norway-Australia/New Zealand) demonstrate a common maternal pre-eclampsia susceptibility locus on chromosome 2q22-23, may suggest a general role of this locus, and possibly the ACVR2A gene, in pre-eclampsia pathogenesis.     

Significant association between nonsyndromic oral clefts and arylhydrocarbon receptor nuclear translocator (ARNT)

The etiology of nonsyndromic oral clefts (cleft lip, cleft palate, or cleft lip and palate) is still controversial, but is considered to involve both genetic and environmental factors. One of suspected environmental factors is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) found in tobacco, herbicides, contaminated soil, and food. TCDD administered during organogenesis in mice causes a high incidence of CP in fetuses. There is ample evidence that aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), and cytochrome P450 1A1 (CYP1A1) are involved in TCDD metabolism. We assessed whether there is any association in the Japanese population of nonsyndromic oral clefts with single nucleotide polymorphisms (SNPs) in the AHR, ARNT, and CYP1A1 genes using transmission disequilibrium test (TDT) and case-control study. We identified and investigated three SNPs in ARNT; 567G/C (V189V), IVS12-19T/G, and 2117C/T (P706L). Two amino acid substitutions, R554L in AHR and I462V in CYP1A1, were also investigated. In the TDT, the C allele of ARNT 567G/C was preferentially transmitted to patients (P = 0.033). When a haplotype consisting of 567G/C and IVS12-19T/G in ARNT was considered, the preferential transmission of the CT (567C-IVS12-19T) haplotype was observed (P = 0.0012). In a case-control study, a significant association of IVS12-19T/G in ARNT was observed (P = 0.021). The SNPs studied in AHR and CYP1A1 were not associated with the disease. Our results suggest that ARNT is involved in the development of nonsyndromic oral clefts in the Japanese population.     

Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women

Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.     

Comprehensive association analyses of IGF1, ESR2, and CYP17 genes with adult height in Caucasians

Human adult height is closely related to body growth that is regulated by multiple cytokines or hormones like growth hormone (GH) and estrogen. Our study focused on three potential candidate genes to human height, namely IGF1 (insulin-like growth factor 1), ESR2, and CYP17. We genotyped 43 single nucleotide polymorphisms (SNPs) and tested their associations in 1873 subjects from 405 nuclear families, using both the family-based quantitative transmission disequilibrium test (QTDT) and population-based ANOVA methods. Both analyses consistently detected that two novel SNPs of IGF1, rs5742694 and rs2033178, were significantly associated with human height, with the P-values of 0.0097 and 0.0057 in QTDT analyses, 0.0002/0.004 (sample 1/sample 2) and 8.46 x 10(-5)/1.92 x 10(-5) in ANOVA analyses. For ESR2, significant associations were only detected in women (rs1256061: QTDT P=0.002, ANOVA P=0.002/0.012; rs17766755: QTDT P=0.019, ANOVA P=0.023/0.006; rs1256044: QTDT P=0.022, ANOVA P=0.002/0.034). Haplotype analyses corroborated our single-SNP results. However, no association was detected between CYP17 and human height. In conclusion, we identified the important effects of IGF1 and ESR2 on adult height variation in Caucasians, and first suggested the potential sex-specific effect of ESR2 on height variation in Caucasian women. It will be valuable for other independent studies to replicate and confirm these findings.     

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

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

A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations

To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.     

17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom

BackgroundAlthough an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies.ObjectiveWe investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated.MethodsStudy subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A).ResultsSixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192).ConclusionWe found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.     

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension

The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [-9.57 (-16.22, -2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi-experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intake.     

Effect of heterogeneity on the chromosome 10 risk in late-onset Alzheimer disease

With the exception of ApoE (APOE), no universally accepted genetic association has been identified with late-onset Alzheimer disease (AD). A broad region of chromosome 10 has engendered continued interest generated from both preliminary genetic linkage and candidate gene studies. To better examine this region, we combined unbiased genetic linkage with candidate gene association studies. We genotyped 36 SNPs evenly spaced across 80.2 Mb in a family-based data set containing 1,337 discordant sibling pairs in 567 multiplex families to narrow the peak region of linkage using both covariate and subset analyses. Simultaneously, we examined five functional candidate genes (VR22, LRRTM3, PLAU, TNFRSF6, and IDE) that also fell within the broad area of linkage. A total of 50 SNPs were genotyped across the genes in the family-based data set and an independent case-control data set containing 483 cases and 879 controls. Of the 50 SNPs in the five candidate genes, 22 gave nominally significant association results in at least one data set, with at least one positive SNP in each gene. SNPs rs2441718 and rs2456737 in VR22 (67.8 Mb) showed association in both family-based and case-control data sets (both P=0.03). A two-point logarithmic odds (LOD) score of 2.69 was obtained at SNP rs1890739 (45.1 Mb, P=0.03 in 21% of the families) when the families were ordered from low to high by ApoE LOD score using ordered subset analysis (OSA). These data continue to support a role for chromosome 10 loci in AD. However, the candidate gene and linkage analysis results did not converge, suggesting that there is more extensive heterogeneity on chromosome 10 than previously appreciated.     

Association study of aromatase gene (CYP19A1) in essential hypertension

Background: As aromatase-deficient mice, which are deficient in estrogens, reportedly have reduced blood pressure, the aromatase gene (CYP19A1) is thought to be a susceptibility gene for essential hypertension (EH). The aim of the present study was to investigate the relationship between CYP19A1 and EH by examining single nucleotide polymorphisms (SNPs).Methods: Five SNPs in the human CYP19A1 gene (rs1870049, rs936306, rs700518, rs10046 and rs4646) were selected, and an association study was performed in 218 Japanese EH patients and 225 age-matched normotensive (NT) individuals.Results: There were significant differences between these groups in the distribution of genotypes rs700518 and rs10046 in male subjects, and genotypes rs700518, rs10046 and rs4646 in female subjects. On multiple logistic regression analysis, a significant association between rs700518 (p=0.023) and rs10046 (p=0.036) in male subjects and rs700518 in female subjects (p=0.018) was noted. Interestingly, the risk genotypes of rs700518 and rs10046 showed a sex-dependent inverse relationship. Both SBP and DBP levels were higher in total (cases and controls) male subjects with the G/G genotype with rs700518 or the T/T genotype with rs10046 than in male subjects without the G/G genotype or T/T genotype. SBP levels were lower in female subjects with the G/G genotype with rs700518 than in female subjects without G/G. The A-T haplotype constructed with rs1870049 and rs10046 was a susceptibility marker for EH.Conclusions: We confirmed that rs700518 and rs10046, as well as a haplotype constructed with rs1870049 and rs10046, in the human CYP19A1 gene can be used as genetic markers for gender-specific EH.     

Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease

Linkage studies have defined susceptibility regions for late-onset Parkinson disease (PD) on chromosomes 1 and 2, but specific genetic variants have not been definitively identified. Here we report the results of a case-control study to identify disease-associated single nucleotide polymorphisms (SNPs) in these loci. In the initial phase of our study, we genotyped two putative functional SNPs in ubiquitin-specific protease 24 (USP24), a biological candidate gene within the chromosome 1 linkage region, and scanned the chromosome 2 linkage peak with 43 SNPs in a sample set of 224 PD cases and 186 matched controls. Both USP24 SNPs were significantly associated with disease risk (p = 0.0037 for rs1165222:T > C, p.Thr195ILe, and p = 0.037 for rs13312:C > G, a SNP in the 3'-untranslated region), and one marker, rs1048603:C > T, p.Arg1123Cys, in USP40 was significant from the chromosome 2 scan (p = 0.038). Further genotyping of the region surrounding these initial markers led us to identify 19 additional SNPs with strong disease association. In the second phase, we genotyped the 22 significant markers in an additional 110 cases and 162 controls, which together with part of the initial sample set (201 cases and 149 controls) constitute an expanded sample set of 311 age- and gender-matched case-control pairs. Twenty-one markers were significant in the expanded sample set (most significant allelic p-value: 0.0006 for rs287235:C > G on chromosome 1, and 0.005 for rs838552:T > C on chromosome 2), and six SNPs in USP24 remained significant after conservatively adjusting for testing 27 markers (pBonferroni = 0.017-0.049). It is unlikely that population stratification contributed to this finding, as population stratification was undetectable in our sample set using 78 null markers. Our data suggest that genetic variants in USP24 and USP40 affect the risk for late-onset PD, which is consistent with the predicted role of the ubiquitination pathway in PD etiology.     

Association of SLC11A1 (NRAMP1) polymorphisms with pulmonary Mycobacterium avium complex infection

Although genetic variants in SLC11A1 (NRAMP1) have been associated with mycobacterial diseases, these findings have not been extensively validated in pulmonary Mycobacterium avium complex (MAC) infection. This study investigated the genomic structure of SLC11A1 and its association with MAC infection. Nineteen polymorphic loci were genotyped in European descendents and the Japanese population. Linkage disequilibrium (LD) structures and frequencies of major haplotypes differed between these 2 populations. Tag single nucleotide polymorphisms (SNPs) were chosen from the data set, and 6 polymorphic sites were genotyped in 122 pulmonary MAC cases and 211 controls from Japan. We observed that the T allele of rs2279014 in the 3' untranslated region was associated with protection from MAC disease when comparing allele frequencies with an odds ratio of 0.582 (95% confidence interval 0.379-0.894, p = 0.013). The frequencies of haplotypes constructed with the above 6 variants did not differ between cases and controls. Allele-specific expression imbalance of SLC11A1 mRNA was evaluated in peripheral blood cells from heterozygous individuals, but no difference was observed among haplotypes. Although the significance was modest, rs2279014 is in strong LD with nearby SNPs and further studies are required for conclusive validation.     

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

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

The role of genetic breast cancer susceptibility variants as prognostic factors

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.     

IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells

Genome-wide association (GWA) studies revealed a number of singlenucleotide polymorphisms (SNPs) significantly associated withtype 1 diabetes (T1D). In an attempt to confirm some of thesecandidate associations, we genotyped 2046 Caucasian patientsand 2417 normal controls from the United States for SNPs infive genomic regions. While no evidence was obtained for fourgenomic regions (rs2929366/NM_144715 on chromosome 3, rs9127/Q7Z4C4on chromosome 5, rs1445898/CAPSL on chromosome 5 and rs2302188/NM_033543on chromosome 19), we provide strong evidence for associationbetween T1D and multiple SNPs in the IFIH1 linkage disequilibrium(LD) block on chromosome 2q. Among the 10 SNPs genotyped forthe 2q region, four SNPs located within the IFIH1 gene or atthe 5' region of IFIH1 showed significant association with T1Din the Georgia population [odds ratio (OR) = 1.7–1.9]with the best P-value found at SNP rs1990760 (P = 8 x 10^–8and OR = 1.9). Several SNPs outside of the IFIH1 gene also showedsignificant but weaker associations. Furthermore, IFIH1 geneexpression levels in peripheral blood mononuclear cells aresignificantly correlated with IFIH1 genotypes, and higher IFIH1levels are found in individuals with the susceptible genotypes(P = 0.005). Thus, both genetic association and gene expressiondata suggest that IFIH1 is the most plausible candidate geneimplicated in T1D in this LD block.     

Large-scale fine mapping of the HNF1B locus and prostate cancer risk

Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.     

Effect of 5-haplotype of dysbindin gene (DTNBP1) polymorphisms for the susceptibility to bipolar I disorder.

We investigated a possible association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). Five SNPs within DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761, and rs2619522) were genotyped for 151 patients with BID and 478 controls. We observed a significant protective association of the haplotype A-C-G-T-A (all SNPs, P = 0.00016) and particularly G-T-A (the last three SNP, P = 0.00007) within DTNBP1 variants investigated. Single marker and subgroup (e.g., psychotic features, age at onset, family history, etc.) analyses showed no significant association. Although the association was due to a small number of subjects, specific DTNBP1 haplotypes, previously associated with schizophrenia, may be also associated with BID. Adequately powered studies from different ethnicities will be necessary to confirm our findings.