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Integrating epigenetic data with genome-wide association study (GWAS) results can reveal disease mechanisms. The genome sequence itself also shapes the epigenome, with CpG density and transcription factor binding sites (TFBSs) strongly encoding the DNA methylome. Therefore, genetic polymorphism impacts on the observed epigenome. Furthermore, large genetic variants alter epigenetic signal dosage. Here, we identify DNA methylation variability between GWAS-SNP risk and non-risk haplotypes. In three subsets comprising 3128 MeDIPseq peripheral-blood DNA methylomes, we find 7173 consistent and functionally enriched Differentially Methylated Regions. 36.8% can be attributed to common non-SNP genetic variants. CpG-SNPs, as well as facilitative TFBS-motifs, are also enriched. Highlighting their functional potential, CpG-SNPs strongly associate with allele-specific DNase-I hypersensitivity sites. Our results demonstrate strong DNA methylation allelic differences driven by obligatory or facilitative genetic effects, with potential direct or regional diseaserelated repercussions. These allelic variations require disentangling from pure tissue-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes. [ABSTRACT FROM AUTHOR]

Background Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC. Results After Bonferroni correction, the joint-likelihood ratio test suggested interactions on serum triglycerides (4 SNP - SNP pairs), LDL cholesterol (2 SNP - SNP pairs) and WHR (1 SNP - SNP pair) in the 1958BC. MDR permutation model testing analysis showed one two-way and one three-way interaction to be statistically significant on serum triglycerides in the 1958BC. In meta-analysis of results from two replication cohorts (NFBC66 and Twins UK, total n = 8,183), none of the interactions remained after correction for multiple testing (Pinteraction >0.17). Conclusions Our results did not provide strong evidence for interactions between allelic variations in VDR and RXRG genes on metabolic outcomes; however, further replication studies on large samples are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR) = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the metaanalysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals. [ABSTRACT FROM AUTHOR]

Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ∼4000 and ∼133 000 individuals. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either. [ABSTRACT FROM AUTHOR]

The notion that coronary atherosclerosis and its most severe phenotype, myocardial infarction (MI), are chronic inflammatory diseases is supported by several lines of evidence. Interleukins (ILs) are important mediators and modulators of inflammation. Specific polymorphisms in the genes encoding subunits of IL-23 ( IL-12B) and its receptor ( IL-23R) have recently been consistently found to be associated with chronic immune-mediated diseases. In this study, we explored the hypothesis that these variants also affect the risk of MI. We conducted a case–control association study on a cohort of 738 British Caucasian MI patients and 716 population controls. We tested four variants (rs11209026, rs7517847, rs1343151, rs10889677) of IL-23R and the A1188C polymorphism (rs3212227) of IL-12B. There was no association of any IL-23R (rs11209026, p = 0.82; rs7517847, p = 0.87; rs1343151, p = 0.85; rs10889677, p = 0.48) or IL-12B (rs3212227, p = 0.32) polymorphisms with MI. Stratification for age, gender and other cardiovascular risk factors did not affect the findings. These results indicate that unlike other chronic inflammatory diseases, the examined variants are unlikely to be major contributors to the pathogenesis of MI. [ABSTRACT FROM AUTHOR]

Abstract A polymorphic site has been found in the human bone morphogenetic protein-4 (BMP4) gene. To our knowledge, it is the first defined polymorphism in this gene, being present with similar frequencies in Caucasian, Hispanic, and African populations. [ABSTRACT FROM AUTHOR]

Background: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80×10−14 and P=3.40×10−6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2×10−5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3×10−6) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions: We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. N Engl J Med 2007;357:443-53. [ABSTRACT FROM AUTHOR]

Introduction: Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+ CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. Recently, CD4 T stem cell memory (Tscm) cells have been identified as the hierarchical cellular apex of ATL. IFN- α , in combination with AZT, is currently the major treatment option for ATL, but therapeutic success is limited and no bona fide biomarkers for therapeutic failure are currently available. Results: In a prospective study with a five-year clinical follow-up, we found significant ex vivo antiproliferative, antiviral and immunomodulatory effects of IFN- α treatment in short-term culture of primary mononuclear cells from ATL patients ( n = 28). We detected a genotype/phenotype interaction for the −670 FAS A/G promoter polymorphism, apoptosis and proliferation in ATL patients. Surprisingly, IFN-induced apoptosis occurred only in carriers of the functional A allele (corresponding to a functional STAT1 binding site), which we experimentally validated in an independent cohort of healthy controls ( n = 20). This Fashigh proliferating and chemotherapy-resistant leukemic phenotype is in agreement with the recently discovered CD4 Tscm hierarchical apex of ATL. The same FAS −670 polymorphism also determined CD4 Tscm levels in a genome-wide twin study ( p = 7 × 10 −11 , n = 669), confirming our hypothesis. Finally, we provide in vivo evidence that CD4+ Fashigh leukemic cells can be eliminated by IFN- α +AZT combination therapy, but not AZT monotherapy. Conclusion: A genetically determined IFN/STAT1/FAS axis underscores the CD4 Tscm ATL model and helps explain the observed in vivo IFN + AZT responsiveness and chemotherapy resistance in ATL patients. [ABSTRACT FROM AUTHOR]