Background and aimsPolymorphisms in the first intron of FTO have been robustly replicated for associations with obesity. In the Sorbs, a Slavic population resident in Germany, the strongest effect on body mass index (BMI) was found for a variant in the third intron of FTO (rs17818902). Since this may indicate population specific effects of FTO variants, we initiated studies testing FTO for signatures of selection in vertebrate species and human populations.MethodsFirst, we analyzed the coding region of 35 vertebrate FTO orthologs with Phylogenetic Analysis by Maximum Likelihood (PAML, ω = dN/dS) to screen for signatures of selection among species. Second, we investigated human population (Europeans/CEU, Yoruba/YRI, Chinese/CHB, Japanese/JPT, Sorbs) SNP data for footprints of selection using DnaSP version 4.5 and the Haplotter/PhaseII. Finally, using ConSite we compared transcription factor (TF) binding sites at sequences harbouring FTO SNPs in intron three.ResultsPAML analyses revealed strong conservation in coding region of FTO (ω<1). Sliding-window results from population genetic analyses provided highly significant (p<0.001) signatures for balancing selection specifically in the third intron (e.g. Tajima’s D in Sorbs = 2.77). We observed several alterations in TF binding sites, e.g. TCF3 binding site introduced by the rs17818902 minor allele.ConclusionPopulation genetic analysis revealed signatures of balancing selection at the FTO locus with a prominent signal in intron three, a genomic region with strong association with BMI in the Sorbs. Our data support the hypothesis that genes associated with obesity may have been under evolutionary selective pressure.
A rare variant (rs61757459) in vaspin coding for the stop codon p.R211X is related to lower circulating vaspin concentrations. Structure analysis suggests misfolding and instability due to the absence of core structural domains. The truncated protein is detectable after recombinant expression in E. coli and in lysate, but not in supernatant of HEK293 cells.
BackgroundThe complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD.MethodsWe sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure.ResultsSequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools.ConclusionsA mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.
There is strong evidence for the heritability of lipid traits and the genetic risk of cardiovascular diseases ( 1-6 ). During the last two decades, genetic linkage studies have dominated efforts aimed at identifying genes and polymorphisms that contribute to susceptibility for common diseases ( 7 ). However, current advances in high-throughput genotyping technologies have resulted in the recent discovery of numerous loci potentially affecting variability in complex traits, including total cholesterol, LDL-cholesterol (LDL-C), HDLcholesterol (HDL-C), and/or triglycerides (TGs). More than 100 loci-infl uencing lipid phenotypes have been identifi ed in genome-wide association studies (GWASs) and replicated in independent cohorts ( 1-6, 8-11 ). Well-powered GWASs, combined with fi ne mapping of the susceptibility loci, were able to detect even variants with small effect size ( 11-14 ). Nevertheless, only 10-12% of the total variance for plasma lipid traits can be explained by these variants ( 5 ). Newly developed statistical approaches, family-based studies, or epigenetic analyses might facilitate the discovery of further novel Abstract Although numerous genes are known to regulate serum lipid traits, identifi ed variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = ف 3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identifi ed 14 loci associated with lipid phenotypes reaching P values <10؊ 5 and confi rmed signifi cant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n (HDL) = 6041; n (LDL) = 5,995; n (TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels ( P = 1.78 × 10 ؊ 7 ; Z -score = ؊ 5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1 , SCARB1 , and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels. -Keller,
Our data suggest that genetic variation in human REPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.
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