Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
SummaryTherapeutic approaches for “sick sinus syndrome” rely on electrical pacemakers, which lack hormone responsiveness and bear hazards such as infection and battery failure. These issues may be overcome via “biological pacemakers” derived from pluripotent stem cells (PSCs). Here, we show that forward programming of PSCs with the nodal cell inducer TBX3 plus an additional Myh6-promoter-based antibiotic selection leads to cardiomyocyte aggregates consisting of >80% physiologically and pharmacologically functional pacemaker cells. These induced sinoatrial bodies (iSABs) exhibited highly increased beating rates (300–400 bpm), coming close to those found in mouse hearts, and were able to robustly pace myocardium ex vivo. Our study introduces iSABs as highly pure, functional nodal tissue that is derived from PSCs and may be important for future cell therapies and drug testing in vitro.
Mean platelet volume (MPV) is increased in myocardial and cerebral infarction and is an independent and strong predictor for postevent morbidity and mortality. We conducted a genome-wide association study (GWAS), the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K study, and found MPV to be strongly associated with three common single-nucleotide polymorphisms (SNPs): rs7961894 located within intron 3 of WDR66 on chromosome 12q24.31, rs12485738 upstream of the ARHGEF3 on chromosome 3p13-p21, and rs2138852 located upstream of TAOK1 on chromosome 17q11.2. We replicated all three SNPs in another GWAS from the UK and in two population-based samples from Germany. In a combined analysis including 10,048 subjects, the SNPs had p values of 7.24 x 10(-48) for rs7961894, 3.81 x 10(-27) for rs12485738, and 7.19 x 10(-28) for rs2138852. These three quantitative trait loci together accounted for 4%-5% of the variance in MPV. In-depth sequence analysis of WDR66 in 382 samples from the extremes revealed 20 new variants and a haplotype with three coding SNPs and one SNP at the transcription start site associated with MPV (p = 6.8 x 10(-5)). In addition, expression analysis indicated a direct correlation of WDR66 transcripts and MPV. These findings may not only enhance our understanding of platelet activation and function, but may also provide a focus for several novel research avenues.
Contrary to the findings of Herbert et al. (Reports, 14 April 2006, p. 279), homozygous carriers of the C allele of the rs7566605 variant near the INSIG2 gene did not exhibit a significantly increased risk for obesity in a large population-based cross-sectional German study. A subgroup analysis, however, revealed that this allele significantly increased the risk for obesity in already overweight individuals.O besity is a leading health problem in many countries and results from a complex and dynamic interaction of social, environmental, and genetic factors. Herbert et al.(1) recently reported the association of the C allele in the rs7566605 polymorphism located near the INSIG2 gene with obesity in four different human samples. In a fifth sample, however, a large cohort of the Nurses Health Study (NHS), no such association was detectable (1). Therefore, we examined this association in the Study of Health in Pomerania (SHIP), a crosssectional population-based health survey from the northeastern area of Germany comprising 4310 unrelated German individuals, collected in 12 five-year age strata from 20 to 79 years (2-4). SHIP was designed to address general health and community medicine issues, with obesity as a main focus. In SHIP, 66.1% of all participants were overweight [body mass index (BMI) ≥ 25 kg/m 2 ] and 25.4% were obese (BMI ≥ 30 kg/m 2 ). Genotyping of the rs7566605 polymorphism was successful in 4089 of 4304 individuals (in six subjects, data sets were incomplete). Excluded individuals and the entire study sample did not differ with respect to age, gender, and BMI. Genotype frequencies (45.5% GG, 44.4% GC, 10.1% CC) were compatible with a HardyWeinberg equilibrium (P = 0.6769) and similar to the Caucasian samples reported in (1). Logistic regression analyses (dependent variable, obesity) and linear models (dependent variable, BMI) were performed on adjustments for age and gender. Table 1 details BMI stratified by genotype, gender, and the genotype distribution in predefined BMI strata.Mean adjusted BMI for the whole sample amounted to 27.38 ± 0.22 kg/m 2 (means ± SE; linear model), 27.16 ± 0.11 kg/m 2 , and 27.18 ± 0.10 kg/m 2 for CC, GC, and GG genotypes, respectively, and rs7566605 genotypes were not associated with BMI [P = 0.6531; 2 degrees of freedom (df)]. Odds ratios (ORs) for obesity were 1.13 (95% CI 0.97 to 1.31) and 1.20 (95% CI 0.94 to 1.54) for carriers of the GC and CC genotypes compared with GG genotypes, and thus were not significantly different (P = 0.1782, 2 df, logistic regression). This observation for obesity did not change in a recessive model (CC versus GC + GG), as pursued by Herbert et al.(1), with OR of 1.13 (95% CI 0.90 to 1.43; P = 0.2916). Likewise, the age-and gender-adjusted mean BMI of CC carriers did not differ significantly (difference from GC + GG carriers, 0.21 ± 0.23 kg/m 2 ; mean ± SE; P = 0.3593). Taken together, our data indicate that the rs7566605 variant is not associated with the overall risk for obesity in SHIP.The current scenario suggests that the rs7566605 v...
Pharmacokinetics of ezetimibe is influenced by OATP1B1 polymorphisms in healthy participants after single dose administration.
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