Search

Background: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits.Methods: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity.Results: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed.Conclusions: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk. [ABSTRACT FROM AUTHOR]

Background It is unknown whether dietary quality modifies genetic association with body mass index (BMI). Objective This study examined whether dietary quality modifies genetic association with BMI. Design We calculated 3 diet quality scores including the Alternative Healthy Eating Index 2010 (AHEI-2010), the Alternative Mediterranean Diet score (AMED), and the Dietary Approach to Stop Hypertension (DASH) diet score. We examined the interactions of a genetic risk score (GRS) based on 97 BMI-associated variants with the 3 diet quality scores on BMI in 30,904 participants from 3 large cohorts. Results We found significant interactions between total GRS and all 3 diet scores on BMI assessed after 2-3 y, with an attenuated genetic effect observed in individuals with healthier diets (AHEI: P-interaction = 0.003; AMED: P = 0.001; DASH: P = 0.004). For example, the difference in BMI (kg/m²) per 10-unit increment of the GRS was smaller among participants in the highest tertile of AHEI score compared with those in the lowest tertile (0.84; 95% CI: 0.72, 0.96 compared with 1.14; 95% CI: 0.99, 1.29). Results were consistent across the 3 cohorts with no significant heterogeneity. The interactions with diet scores on BMI appeared more significant for central nervous system GRSs (P < 0.01 for 3 diet scores) than for non-central nervous system GRSs (P > 0.05 for 3 diet scores). Conclusions A higher diet quality attenuated genetic predisposition to obesity. These findings underscore the importance of maintaining a healthful diet for the prevention of obesity, particularly for those individuals with a strong genetic predisposition to obesity. This trial was registered with the Clinical Trial Registry as NCT03577639. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified over 100 single nucleotide polymorphisms (SNPs) associated with prostate cancer. However, information on the mechanistic basis for some associations is limited. Recent research has been directed towards the potential association of vitamin D concentrations and prostate cancer, but little is known about whether the aforementioned genetic associations are modified by vitamin D. We investigated the associations of 46 GWAS-identified SNPs, circulating concentrations of 25-hydroxyvitamin D (25 (OH)D), and prostate cancer (3,811 cases, 511 of whom died from the disease, compared with 2,980 controls--from 5 cohort studies that recruited participants over several periods beginning in the 1980s). We used logistic regression models with data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) to evaluate interactions on the multiplicative and additive scales. After allowing for multiple testing, none of the SNPs examined was significantly associated with 25(OH)D concentration, and the SNP-prostate cancer associations did not differ by these concentrations. A statistically significant interaction was observed for each of 2 SNPs in the 8q24 region (rs620861 and rs16902094), 25(OH)D concentration, and fatal prostate cancer on both multiplicative and additive scales (P ≤ 0.001). We did not find strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of 25(OH)D. The intriguing interactions between rs620861 and rs16902094,25(OH)D concentration, and fatal prostate cancer warrant replication. [ABSTRACT FROM AUTHOR]

Background and Aims: The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers. Methods: To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons. Results: A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99–2.54), compared to those homozygous for the wild type allele. Conclusions: Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway. [ABSTRACT FROM AUTHOR]

Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989–2006) in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions. [ABSTRACT FROM PUBLISHER]

Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case–control study nested within the Physicians’ Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis. [ABSTRACT FROM AUTHOR]

The enzymes serine hydroxymethyltransferase 1 (gene name SHMT1) and methylenetetrahydrofolate reductase (gene name MTHFR) regulate key reactions in folate-mediated one-carbon metabolism. Common genetic variants with the potential to influence disease risk exist in both genes. A prior report from the Normative Aging Study indicated no association of the SHMT1 rs1979277 SNP with cardiovascular disease (CVD), but a strong gene-gene interaction was detected with MTHFR rsl8Ol 133. We investigated the effect of the SHMT1 rsl 979277 SNP and the SHMT1 rsl 979277- MTHFR rsl8Ol 133 interaction in 2 epidemiologic cohort studies. In the Nurses' Health Study (NHS), the MTHFR rsl 801133 variant genotypes were associated with an increased CVD risk and there was an interaction between SHMT1 and MTHFR such that the association of the MTHFR rsl 801133 CT genotype (vs. CC; the IT genotype could not be evaluated) was stronger in the presence of the SHMT1 rsl 979277 TT genotype (OR = 4.34, 95% Cl = 1.2, 16.2; P= 0.049). In the Health Professionals Follow-Up Study, the MTHFR rsl 801133 genotype was not associated with CVD risk, nor was there an interaction with SHMT1 rs1979277. The association of genetic variation in the SHMT1 gene, alone and in interaction with MTHFR, in relation to CVD risk is relatively understudied at the population level and results in the NHS confirmed a past report of gene-gene interaction, which is consistent with mechanisms suggested by basic science studies. [ABSTRACT FROM AUTHOR]

Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (> or = 6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32-43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02-14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/ Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer. [ABSTRACT FROM AUTHOR]

Genes involved in the inflammation pathway have been associated with cancer risk. Genetic variants in the interleukin-6 (IL6) and prostaglandin-endoperoxide synthase-2 (PTGS2, encoding for the COX-2 enzyme) genes, in particular, have been related to several cancer types, including breast and prostate cancers. We conducted a study within the Breast and Prostate Cancer Cohort Consortium to examine the association between IL6 and PTGS2 polymorphisms and breast and prostate cancer risk. Twenty-seven polymorphisms, selected by pairwise tagging, were genotyped on 6292 breast cancer cases and 8135 matched controls and 8008 prostate cancer cases and 8604 matched controls. The large sample sizes and comprehensive single nucleotide polymorphism tagging in this study gave us excellent power to detect modest effects for common variants. After adjustment for multiple testing, none of the associations examined remained statistically significant at P = 0.01. In analyses not adjusted for multiple testing, one IL6 polymorphism (rs6949149) was marginally associated with breast cancer risk (TT versus GG, odds ratios (OR): 1.32; 99% confidence intervals (CI): 1.00–1.74, Ptrend = 0.003) and two were marginally associated with prostate cancer risk (rs6969502-AA versus rs6969502-GG, OR: 0.87, 99% CI: 0.75–1.02; Ptrend = 0.002 and rs7805828-AA versus rs7805828-GG, OR: 1.11, 99% CI: 0.99–1.26; Ptrend = 0.007). An increase in breast cancer risk was observed for the PTGS2 polymorphism rs7550380 (TT versus GG, OR: 1.38, 99% CI: 1.04–1.83). No association was observed between PTGS2 polymorphisms and prostate cancer risk. In conclusion, common genetic variation in these two genes might play at best a limited role in breast and prostate cancers. [ABSTRACT FROM PUBLISHER]

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β ( MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB. [ABSTRACT FROM AUTHOR]

Aggregate results from genome-wide association studies (GWAS), such as genotype frequencies for cases and controls, were until recently often made available on public websites because they were thought to disclose negligible information concerning an individual's participation in a study. Homer et al. recently suggested that a method for forensic detection of an individual's contribution to an admixed DNA sample could be applied to aggregate GWAS data. Using a likelihood-based statistical framework, we developed an improved statistic that uses genotype frequencies and individual genotypes to infer whether a specific individual or any close relatives participated in the GWAS and, if so, what the participant's phenotype status is. Our statistic compares the logarithm of genotype frequencies, in contrast to that of Homer et al., which is based on differences in either SNP probe intensity or allele frequencies. We derive the theoretical power of our test statistics and explore the empirical performance in scenarios with varying numbers of randomly chosen or top-associated SNPs. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk. Objective: To examine the joint effects of several type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts. Design: Nested case-control study. Setting: United States. Participants: 2809 patients with type 2 diabetes and 3501 healthy control participants of European ancestry from the Health Professionals Follow-up Study and Nurses' Health Study. Measurements: A genetic risk score (GRS) was calculated on the basis of 10 polymorphisms in 9 loci. Results: After adjustment for age and body mass index (BMI), the odds ratio for type 2 diabetes with each point of GRS, corresponding to 1 risk allele, was 1.19 (95% CI, 1.14 to 1.24) and 1.16 (CI, 1.12 to 1.20) for men and women, respectively. Persons with a BMI of 30 kg/m2 or greater and a GRS in the highest quintile had an odds ratio of 14.06 (CI, 8.90 to 22.18) compared with persons with a BMI less than 25 kg/m2 and a GRS in the lowest quintile after adjustment for age and sex. Persons with a positive family history of diabetes and a GRS in the highest quintile had an odds ratio of 9.20 (CI, 5.50 to 15.40) compared with persons without a family history of diabetes and with a GRS in the lowest quintile. The addition of the GRS to a model of conventional risk factors improved discrimination by 1% (P < 0.001). Limitation: The study focused only on persons of European ancestry; whether GRS is associated with type 2 diabetes in other ethnic groups remains unknown. Conclusion: Although its discriminatory value is currently limited, a GRS that combines information from multiple genetic variants might be useful for identifying subgroups with a particularly high risk for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a byproduct of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10-2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk. [ABSTRACT FROM AUTHOR]

The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein's transcriptional activity. We evaluated the effect of MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case-control study within the Nurses' Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3,207 women pooled from controls of three nested case-control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78-1.08) and 0.68 (95% CI, 0.53-0.87), respectively (p, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01-1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wild-type group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits. [ABSTRACT FROM AUTHOR]

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotypetagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women. [ABSTRACT FROM AUTHOR]

Determination of the relevance of both demanding classical epidemiologic criteria for control selection and robust handling of population stratification (PS) represents a major challenge in the design and analysis of genome-wide association studies (GWAS). Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility (CGEMS) project were used to evaluate the impact of PS in studies with different control selection strategies. In each of the two original case-control studies nested in corresponding prospective cohorts, a minor confounding effect due to PS (inflation factor λ of 1.025 and 1.005) was observed. In contrast, when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy, the confounding effects were larger (l of 1.090 and 1.062). A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium (pair-wise r2,0.004) was selected to infer population substructure with principal component analysis. A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error (to l of 1.032 and 1.006, respectively) than currently used methods. The overlap between sets of SNPs in the bottom 5% of p-values based on the new test and the test without PS correction was about 80%, with the majority of discordant SNPs having both ranks close to the threshold. Thus, for the CGEMS GWAS of prostate and breast cancer conducted in European Americans, PS does not appear to be a major problem in well-designed studies. A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed. [ABSTRACT FROM AUTHOR]

The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We sought to investigate whether a polymorphism in the alcohol dehydrogenase 1c (ADH1C) gene modifies the association between alcohol consumption and type 2 diabetes. RESEARCH DESIGN AND METHODS--In nested case-control studies of 640 women with incident diabetes and 1,000 control subjects from the Nurses' Health Study and 383 men with incident diabetes and 382 control subjects from the Health Professionals Follow-Up Study, we determined associations between the ADH1C polymorphism, alcohol consumption, and diabetes risk. RESULTS--Moderate to heavy alcohol consumption (>5 g/day for women and >10 g/day for men) was associated with a decreased risk of diabetes among women (odds ratio [OR] 0.45 [95% CI 0.33-0.63]) but not men (1.08 [0.67-1.75]). ADH1C genotype modified the relation between alcohol consumption and diabetes for women (Pinteraction = 0.02). The number of ADH1C*2 alleles, related to a slower rate of ethanol oxidation, attenuated the lower risk of diabetes among women consuming ≥5 g alcohol/day (Ptrend = 0.002). These results were not significant among men. Results were similar in pooled analyses (Pinteraction = 0.02) with ORs for diabetes among moderate drinkers of 0.44 (95% CI 0.21-0.94) in ADH1C*1 homozygotes, 0.65 (0.39-1.06) for heterozygotes, and 0.78 (0.50-1.22) for ADH1C*2 homozygotes compared with those for ADH1C*1 homozygote abstainers (Ptrend = 0.02). CONCLUSIONS--ADH1C genotype modifies the association between alcohol consumption and diabetes. The ADH1C*2 allele, related to a slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. This suggests that the association between alcohol consumption and diabetes may be causal but mediated by downstream metabolites such as acetate rather than ethanol itself. Diabetes 56:2388-2394, 2007 [ABSTRACT FROM AUTHOR]

This editorial comments on studies that have examined the inherited genetic causes of diseases such as prostate and breast cancer, diabetes and in this issue, coronary artery disease. The amount of data in the studies is five times more than in previous studies due to the use of microarray, or chips, that can process more than 500,000 single-nucleotide polymorphisms (SNPs) in a single sample. The author fears that this ability could result in false positive results.

BACKGROUND: Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC). OBJECTIVE: We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp3l2Asn and Lys751Gln) modify the association between arsenic and NMSC. METHODS: Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were identified through a network of dermatologists and pathology laboratories across New Hampshire. Population-based controls were frequency matched to cases on age and sex. Arsenic exposure was assessed in toenail clippings. The analysis included 880 cases of BCC, 666 cases of SCC, and 780 controls. RESULTS: There was an increased BCC risk associated with high arsenic exposure among those homozygous variant for XPA [odds ratio (OR) = 1.8; 95% confidence interval (C1), 0.9-3.7]. For XPD, having variation at both loci (3l2Asn and 751Gln) occurred less frequently among BCC and SCC cases compared with controls (OR = 0.8; 95% Cl, 0.6-1.0) for both case groups. In the stratum of subjects who have variant for both XPD polymorphisms, there was a 2-fold increased risk of SCC associated with elevated arsenic (OR = 2.2; 95% Cl, 1.0-5.0). The test for interaction between XPD and arsenic in SCC was of borderline significance (p <0.07, 3 degrees of freedom). CONCLUSIONS: Our findings indicate a reduced NMSC risk in relation to XPD Asp3l2Asn and Lys75lGln variants. Further, these data support the hypothesis that NER polymorphisms may modify the association between NMSC and arsenic. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor beta 1 (TGFB1) forms a signaling complex with transforming growth factor beta receptors 1 and 2 and has been described as both a tumor suppressor and tumor promoter. Single nucleotide polymorphisms in TGFB1 and a microsatellite in TGFBR1 have been investigated for association with risk of breast cancer, with conflicting results. Methods: We examined polymorphisms in the promoter region of the TGFB1 gene as well as the TGFBR1*6A microsatellite in the Nurses' Health Study cohort. Results: No overall associations between the L10P polymorphism of TGFB1 or the TGFBR1 microsatellite were detected. However, we observed an inverse association between the -509 C/T polymorphism of TGFB1 (p-trend = 0.04), which was stronger and more significant among women with estrogen receptor positive breast cancer. Conclusion: Polymorphisms in the promoter region of TGFB1 are not likely to be associated with large increases in breast cancer risk overall among Caucasian women. [ABSTRACT FROM AUTHOR]

Endothelial nitric oxide synthase (eNOS) gene represents a promising candidate gene for coronary heart disease (CHD) because of its impact on eNOS activity. We systematically examined the associations of eight variants of the eNOS gene (two potentially functional variants [-786T>C and Glu298Asp] and six tagging single nucleotide polymorphisms) with CHD risk in a large cohort of diabetic patients. Among 861 diabetic men (>97% Caucasian) from the Health Professionals Follow-Up Study, 220 developed CHD, and 641 men without cardiovascular disease were used as control subjects. Genotype distributions of -786T>C and Glu298Asp polymorphisms were not significantly different between case and control subjects. CHD risk was significantly higher among men with the variant allele at the rs1541861 locus (intron 8 A/C) than men without it (adjusted odds ratio 1.5 [95% confidence interval 1.1-2.1]). Moreover, among control subjects, plasma soluble vascular cell adhesion molecule concentrations were significantly higher among carriers of this allele (P 0.019) and carriers of the variant allele of the -786T>C (P 0.010), or the Glu298Asp polymorphism (P 0.002), compared with noncarriers. In conclusion, our data suggested that -786T>C, Glu298Asp, and an intron 8 polymorphism of the eNOS gene are potentially involved in the atherogenic pathway among U.S. diabetic men. Diabetes 55: 2140-2147, 2006 [ABSTRACT FROM AUTHOR]

Abstract: We previously demonstrated that a functional polymorphism in alcohol dehydrogenase type 1C (ADH1C, also known as ADH3) modifies the association between moderate alcohol consumption and high-density lipoprotein (HDL) levels and risk of myocardial infarction among older men. In this study, we investigated the effect of the ADH1C γ1 and γ2 alleles on the relationship between alcohol consumption and HDL levels among four populations with varied exposure to endogenous and exogenous estrogens: premenopausal women, middle-to-older aged men, postmenopausal women currently using postmenopausal hormones (PMH) and postmenopausal women not currently using PMH. We observed an interaction between moderate alcohol consumption and ADH1C genotype on HDL level that was similar among middle-to-older aged men and postmenopausal women not using PMH. Among the moderate drinkers (approximately a half a drink per day for women and a full drink per day for men), there was a significant 5.3mg/dL (P =0.02) higher level of multivariate adjusted HDL level comparing the γ2 homozygotes (slow oxidizers) to the γ1 homozygotes (fast oxidizers). This interaction was not present among premenopausal women or postmenopausal women using PMH, who had higher overall HDL levels irrespective of alcohol consumption. Our results confirm that ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using PMH who drink moderately. However, this was not observed among individuals with estrogen-elevated HDL levels, specifically premenopausal women and postmenopausal women taking PMH, suggesting that these populations may benefit less from alcohol consumption with respect to coronary heart disease. [Copyright &y& Elsevier]

We assessed the whole genome amplification strategy, known as multiple displacement amplification (MDA), for use with the TaqMan genotyping platform for DNA samples derived from two case-control studies nested in the Nurses' Health Study and the Physicians' Health Study. Our objectives were to (1) quantify DNA yield from samples of varying starting concentrations and (2) assess whether MDA products give an accurate representation of the original genomic sequence. Multiple displacement amplification yielded a mean 23 000-fold increase in DNA quantity and genotyping results demonstrate 99.95% accuracy across six SNPs from four genes for 352 samples included in this study. These results suggest that MDA will provide a sufficiently robust amplification of limiting samples of genomic DNA that can be used for SNP genotyping in large case-control studies of complex diseases. [ABSTRACT FROM AUTHOR]

Examines the association of polymorphism in the progesterone receptor (PR) gene with endometrial cancer risk. Detection of amino acids in the N-terminus of PR-B; Impact of estrogens on the development of endometrial cancer; Transcriptional activity of the PR-B isoform.

Our studies on interactions of a folate-metabolizing gene polymorphism and dietary intake in colorectal tumorigenesis demonstrate the potential importance of studying interactions between genotype and environmental exposure in relation to cancer risk. We observed an inverse association of a polymorphism (667C --> T, ala --> val) in the methylenetetrahydrofolate reductase (MTHFR) gene with colorectal cancer but not with colorectal adenomas. The inverse association of methionine and adverse association of alcohol with colorectal cancer were stronger among val/val individuals. These interactions were not present in studies of colorectal adenomas. Our studies illustrate that studying gene-environment interactions in relation to cancer can be of importance in clarifying cancer etiology as well as pointing to preventive dietary modifications. [ABSTRACT FROM AUTHOR]

An abstract of the article "The Influence of Genetic Polymorphism," by David J. Hunter is presented.

Objective: The authors assessed the association between the catechol-O-methyltransterase (COMT) Val158Met polymorphism and scores on the phobic anxiety scale of the Crown-Crisp Experimental Index. Method: A total of 1,234 women completed the Crown-Crisp Experimental Index phobic anxiety scale and were genotyped for the COMT polymorphism. The authors used unconditional logistic regression to compute odds ratios and 95% confidence intervals (Cls) to evaluate the association between the COMT genotype and phobic anxiety. Results: The mean scores for the three genotypes were statistically significantly different. Compared to the COMT Met/Met genotype, the age-adjusted odds ratio for scoring ≥6 compared to scoring 0 or 1 were 1.15 (95% Cl = 0.71-1.85) and 1.99 (95% Cl=1.17-3.40) for the COMT VaVMet and COMT Val/Vol genotypes, respectively; a significant gene dosage effect was observed. conclusions: Our results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the Pro12Ala polymorphism in the PPARgamma gene was associated with risk of type 2 diabetes in the Nurses' Health Study.Research Design and Methods: The study was a nested case-control study of 387 incident cases of type 2 diabetes and 771 matching control subjects nested within the Nurses' Health Study, a prospective cohort study. Association between PPARgamma genotype and incident type 2 diabetes was estimated using logistic regression.Results: Carriers of the PPARgamma variant 12Ala allele had reduced risk of type 2 diabetes compared with noncarriers. Unadjusted and adjusted odds ratios of type 2 diabetes were 0.74 (95% CI 0.55-1.00) and 0.72 (0.52-0.99), respectively.Conclusions: The results of this study provide further support for an inverse association between the PPARgamma variant 12Ala allele and risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article discusses the achievements of the genome-wide association studies (GWAS) aimed at discovering common alleles link with the risk of cancer. It references a study by J. P. A. Ioannidis et al. published within the issue. The application of GWAS to cancer epidemiology and the use of single-nucleotide polymorphisms (SNPs) in GWAS are tackled. According to the author, the challenges in gene-environment interactions have been highlighted by GWAS.

The article reflects on the findings of three studies that focused on the relationship between genetic variation at a location on human chromosome 15 and the risk of lung cancer. According to the author, the studies are all appropriately replicated and provided strong evidence for an association between single nucleotide polymorphisms (SNP) variation. However, they differ on whether the link is direct or mediated through smoking behaviour or nicotine dependence. The researchers in these studies distinguished between ever-smokers and never-smokers as part of the subjects.

This article explores whether polymorphic variations of the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) can predict different outcomes in patient undergoing surgical treatment for lumbar degenerative disc disease. The results indicate that 1 single nucleotide polymorphism is significantly associated with improvement in both absolute Disability Index score and Numerical Rating Scale back pain scores. It concludes that GCH1 may be associated with improved outcomes one year following surgery.

We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case–control study with joint P-value=1.6 × 10−9. We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability–related loci are similar to the hair color–related loci previously reported in the GWAS of hair color.Journal of Investigative Dermatology (2009) 129, 2250–2257; doi:10.1038/jid.2009.62; published online 02 April 2009 [ABSTRACT FROM AUTHOR]

Abstract: The DNA repair protein, O 6-methylguanine DNA-methyltransferase (MGMT) prevents mutations and cell death that result from aberrant alkylation of DNA. The polymorphic variants Leu84Phe, Ile143Val, and Lys178Arg are frequent in the human population. We review here studies of these and other MGMT polymorphisms and their association with risk for lung, breast, colorectal and endometrial cancer with a consideration of gene-environment interactions. In addition, we review studies of the effects of polymorphic variation on alkyltransferase activity and expression. It is formally possible that polymorphic variation could modify functions of MGMT other than its alkyltransferase activity. While it was previously reported that an alkylated form of MGMT modifies Estrogen Receptor alpha activity, from our studies we conclude that this regulation is not a major function of MGMT. Overall, the effects of polymorphic variation on protein function are subtle, and further investigation is required to provide a comprehensive mechanism that explains the observed associations of these variants with risk for cancer. [Copyright &y& Elsevier]

Background: A polymorphism in the gene for alcohol dehydrogenase type 3 (ADH3 ) alters the rate of alcohol metabolism. We investigated the relation among the ADH3 polymorphism, the level of alcohol consumption, and the risk of myocardial infarction in a nested case–control study based on data from the prospective Physicians' Health Study. Methods: We identified 396 patients with eligible newly diagnosed cases of myocardial infarction among men in the Physicians' Health Study. Of these patients, 374 were matched with 2 randomly selected control subjects each and the remaining 22 with 1 control each (total, 770 controls). The ADH3 genotype (γ1γ1, γ1γ2, or γ2γ2) was determined in all subjects. We examined the relations among the level of alcohol intake, the ADH3 genotype, and plasma high-density lipoprotein (HDL) levels in this study population and in a similar cohort of women. Results: As compared with homozygosity for the allele associated with a fast rate of ethanol oxidation (γ1), homozygosity for the allele associated with a slow rate of ethanol oxidation (γ2) was associated with a reduced risk of myocardial infarction (relative risk, 0.65; 95 percent confidence interval, 0.43 to 0.99). Moderate alcohol consumption was associated with a decreased risk of myocardial infarction in all three genotype groups (γ1γ1, γ1γ2, and γ2γ2); however, the ADH3 genotype significantly modified this association (P=0.01 for the interaction). Among men who were homozygous for the γ1 allele, those who consumed at least one drink per day had a relative risk of myocardial infarction of 0.62 (95 percent confidence interval, 0.34 to 1.13), as compared with the risk among men who consumed less than one drink per week. Men who consumed at least one drink per day and were homozygous for the γ2 allele had the greatest reduction in risk (relative risk, 0.14; 95 percent confidence interval, 0.04 to 0.45). Such men also had the highest plasma HDL levels (P for interaction = 0.05). We confirmed the interaction among the ADH3 genotype, the level of alcohol consumption, and the HDL level in an independent study of postmenopausal women (P=0.02). Conclusions: Moderate drinkers who are homozygous for the slow-oxidizing ADH3 allele have higher HDL levels and a substantially decreased risk of myocardial infarction. (N Engl J Med 2001;344:549-55.) [ABSTRACT FROM AUTHOR]