Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4

Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain- specific P/Q-type Ca2+ channel α1-subunit gene, CACNLIA4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)(n)-repeat (D19S1150), a (CAG)(n)- repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine

Anticoagulant effect of dietary fish oil in hyperlipidemia. A study of hepatic gene expression in APOE2 knock-in mice

Objective - In hyperlipidemia, dietary fish oil containing n-3 polyunsaturated fatty acids (PUFA) provokes plasma triacylglycerol lowering and hypocoagulant activity. Using APOE2 knock-in mice, the relation of these fish-oil effects with altered gene expression was investigated. Methods and Results - Male APOE2 knock-in mice, fed regular low-fat diet, had elevated plasma levels of triacylglycerol and coagulation factors. Plasma lipids and (anti)coagulant factors reduced on feeding the mice with fish oil (n-3 PUFA) or, to a lesser degree, with sunflowerseed oil (n-6 PUFA). The fish-oil diet provoked a 40% reduction in thrombin generation. Microarray (Affymetrix) and single-gene expression analysis of mouse livers showed that fish oil induced: (1) upregulation of genes contributing to lipid degradation and oxidation; (2) downregulation of genes of γ-glutamyl carboxylase and of transcription factors implicated in lipid synthesis; (3) unchanged expression of coagulation factor genes. After fish-oil diet, vitamin K-dependent coagulation factors accumulated in periportal areas of the liver; prothrombin was partly retained in uncarboxylated form. Only part of the changes in gene expression were different from the effects of sunflowerseed oil diet. Conclusions - The hypocoagulant effect of n-3 PUFA is not caused by reduced hepatic synthesis of coagulation factors, but rather results from retention of uncarboxylated coagulation factors. In contrast, the lipid-lowering effect of n-3 PUFA links to altered expression of genes that regulate transcription and fatty acid metabolism

Additional file 1: of Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease

Data NAFLD cohort. (XLSX 1353Â kb

Additional file 3: of Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease

Data IBD cohort. (XLS 44Â kb

Additional file 3: of Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease

Data IBD cohort. (XLS 44Â kb

Additional file 2: of Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease

Data HepC cohort. (XLSX 28Â kb

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 2080 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes 50 000 cosmopolitan tagged SNPs across 2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P 2.4 10(6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR ( SE, 0.048 0.008, P 7.7 10(9)) as was rs7302703-G in HOXC10 ( 0.044 0.008, P 2.9 10(7)) and rs936108-C in PEMT ( 0.035 0.007, P 1.9 10(6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 ( 0.10 0.02, P 1.9 10(6)) and rs1037575-A in ATBDB4 ( 0.046 0.01, P 2.2 10(6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait