Serum α-Tocopherol Concentration in Relation to Subsequent Colorectal Cancer: Pooled Data From Five Cohorts

Background Numerous monoclonal antibodies (MAbs) have been produced to antigens found in human melanomas. Three of the best characterized melanoma antigens include the melanoma-associated glycoproteins (MAGs) defined by two reagent families—the ME491 family (including ME491, 8-1H, and 8-2A) and the NKI/C-3 family (including NKI/C-3 and NKI/black-13)—as well as the neuroglandular antigen (NGA) defined by MAbs LS59, LS62, and LS140. These three antigens have significant similarities in tissue distribution, biosynthesis, and structure. The ME491 MAG has been cloned, mapped, and sequenced. Numerous non-melanoma-associated proteins (Sm23, CO-029, R2, TAPA-1, CD9, CD37, CD53, and CD63) have recently been shown to have significant homology to this sequence. Purpose We conducted this study to investigate the similarity between the two MAG antigens and NGA. Methods Several reagents defining the three different melanoma antigens were compared, using competition immunoprecipitation, immunoas-say, and inhibition radioimmunoassay techniques. Results Immunoassay experiments show that MAbs defining the three melanoma antigens bind to affinity-purified ME491 antigen and inhibit each other from binding in an inhibition radioimmunoassay. Competition immunoprecipitation ex-periments demonstrate that the ME491 and NKI/C-3 antibodies bind to NGA. Rabbit anti-ME491 idiotype serum recognizes determinants shared by NKI/C-3 and the anti-NGA MAbs. A competition immunoprecipitation experiment also confirms the identity of CD63, as defined by MAb RUU-SP 2.28, with the three melanoma antigens. Conclusion These data indicate that the MAGs defined by ME491 and NKI/C-3 as well as the anti-NGA antibodies are epitopes of the same molecule, which is identical to CD63 by both immunochemical and molecular genetic investigations. Implications Our results indicate that the data obtained in studies of these three melanoma antigens may be pooled, and we propose that the molecule recognized by these reagents be classified as CD63. [J Natl Cancer Inst 84:422-429, 1992

Alcohol Intake and Risk of Coronary Heart Disease in Younger, Middle-Aged, and Older Adults

BACKGROUND: Light-to-moderate alcohol consumption is associated with a reduced risk of coronary heart disease (CHD). This protective effect of alcohol, however, may be confined to middle-aged or older individuals. CHD Incidence is low in men younger than 40 and in women younger than 50 years and for this reason, study cohorts rarely have the power to investigate effects of alcohol on CHD risk in younger adults. This study examined whether the beneficial effect of alcohol on CHD depends on age. METHODS AND RESULTS: A pooled analysis of eight prospective studies from North America and Europe including 192,067 women and 74,919 men free of cardiovascular diseases, diabetes, and cancers at baseline. Average daily alcohol intake was assessed at baseline using a food frequency or diet history questionnaire. An inverse association between alcohol and risk of coronary heart disease was observed in all age groups: hazard ratios among moderately drinking men (5.0–29.9 g/day) aged 39–50, 50–59, and 60+ years were 0.58 (95% C.I. 0.36 to 0.93), 0.72 (95% C.I. 0.60–0.86), and 0.85 (95% C.I. 0.75 to 0.97) compared with abstainers. However, the analyses indicated a smaller incidence rate difference (IRD) between abstainers and moderate consumers in younger adults (IRD=45 per 100,000; 90% C.I. 8 to 84), than in middle-aged (IRD=64 per 100,000; 90% C.I. 24 to 102) and older adults (IRD=89 per 100,000; 90% C.I. 44 to 140). Similar results were observed in women. CONCLUSIONS: Alcohol is also associated with a decreased risk of CHD in younger adults; however, the absolute risk was small compared with middle-aged and older adults

Heterogeneity of Associations between Total and Types of Fish Intake and the Incidence of Type 2 Diabetes: Federated Meta-Analysis of 28 Prospective Studies Including 956,122 Participants.

The association between fish consumption and new-onset type 2 diabetes is inconsistent and differs according to geographical location. We examined the association between the total and types of fish consumption and type 2 diabetes using individual participant data from 28 prospective cohort studies from the Americas (6), Europe (15), the Western Pacific (6), and the Eastern Mediterranean (1) comprising 956,122 participants and 48,084 cases of incident type 2 diabetes. Incidence rate ratios (IRRs) for associations of total fish, shellfish, fatty, lean, fried, freshwater, and saltwater fish intake and type 2 diabetes were derived for each study, adjusting for a consistent set of confounders and combined across studies using random-effects meta-analysis. We stratified all analyses by sex due to observed interaction (p = 0.002) on the association between fish and type 2 diabetes. In women, for each 100 g/week higher intake the IRRs (95% CIs) of type 2 diabetes were 1.02 (1.01-1.03, I2 = 61%) for total fish, 1.04 (1.01-1.07, I2 = 46%) for fatty fish, and 1.02 (1.00-1.04, I2 = 33%) for lean fish. In men, all associations were null. In women, we observed variation by geographical location: IRRs for total fish were 1.03 (1.02-1.04, I2 = 0%) in the Americas and null in other regions. In conclusion, we found evidence of a neutral association between total fish intake and type 2 diabetes in men, but there was a modest positive association among women with heterogeneity across studies, which was partly explained by geographical location and types of fish intake. Future research should investigate the role of cooking methods, accompanying foods and environmental pollutants, but meanwhile, existing dietary regional, national, or international guidelines should continue to guide fish consumption within overall healthy dietary patterns

Genome-wide association meta-analysis of fish and EPA plus DHA consumption in 17 US and European cohorts

Background Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. Objective To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. Design We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. Results Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (Freq(A) = 0.015) was associated with 0.029 servings/day (similar to 1 serving/month) lower fish consumption (P = 1.96x10(-8)). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10(-7)). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA. Conclusions These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.Peer reviewe

Gene x dietary pattern interactions in obesity : analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.Peer reviewe

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been