Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes

Inter-individual differences in gene expression are likely to account for an important fraction of phenotypic differences, including susceptibility to common disorders. Recent studies have shown extensive variation in gene expression levels in humans and other organisms, and that a fraction of this variation is under genetic control. We investigated the patterns of gene expression variation in a 25 Mb region of human chromosome 21, which has been associated with many Down syndrome (DS) phenotypes. Taqman real-time PCR was used to measure expression variation of 41 genes in lymphoblastoid cells of 40 unrelated individuals. For 25 genes found to be differentially expressed, additional analysis was performed in 10 CEPH families to determine heritabilities and map loci harboring regulatory variation. Seventy-six percent of the differentially expressed genes had significant heritabilities, and genomewide linkage analysis led to the identification of significant eQTLs for nine genes. Most eQTLs were in trans, with the best result (P=7.46×10−8) obtained for TMEM1 on chromosome 12q24.33. A cis-eQTL identified for CCT8 was validated by performing an association study in 60 individuals from the HapMap project. SNP rs965951 located within CCT8 was found to be significantly associated with its expression levels (P=2.5×10−5) confirming cis-regulatory variation. The results of our study provide a representative view of expression variation of chromosome 21 genes, identify loci involved in their regulation and suggest that genes, for which expression differences are significantly larger than 1.5-fold in control samples, are unlikely to be involved in DS-phenotypes present in all affected individual

Sequence Variation and Linkage Disequilibrium in the Human T-Cell Receptor β (TCRB) Locus

The T-cell receptor (TCR) plays a central role in the immune system, and >90% of human T cells present a receptor that consists of the α TCR subunit (TCRA) and the β subunit (TCRB). Here we report an analysis of 63 variable genes (BV), spanning 553 kb of TCRB that yielded 279 single-nucleotide polymorphisms (SNPs). Samples were drawn from 10 individuals and represent four populations—African American, Chinese, Mexican, and Northern European. We found nine variants that produce nonfunctional BV segments, removing those genes from the TCRB genomic repertoire. There was significant heterogeneity among population samples in SNP frequency (including the BV-inactivating sites), indicating the need for multiple-population samples for adequate variant discovery. In addition, we observed considerable linkage disequilibrium (LD) (r(2)>0.1) over distances of ∼30 kb in TCRB, and, in general, the distribution of r(2) as a function of physical distance was in close agreement with neutral coalescent simulations. LD in TCRB showed considerable spatial variation across the locus, being concentrated in “blocks” of LD; however, coalescent simulations of the locus illustrated that the heterogeneity of LD we observed in TCRB did not differ markedly from that expected from neutral processes. Finally, examination of the extended genotypes for each subject demonstrated homozygous stretches of >100 kb in the locus of several individuals. These results provide the basis for optimization of locuswide SNP typing in TCRB for studies of genotype-phenotype association

Mid-Term Outcome of Mechanical Pulmonary Valve Prostheses: TheImportance of Anticoagulation

Introduction: Pulmonary valve replacement (PVR) is being performed more commonly lateafter the correction of tetralogy of Fallot. Most valves are replaced with an allograft or xenograft,although reoperations are a common theme. Mechanical prostheses have a less favorable reputationdue to the necessity of lifelong anticoagulation therapy and higher risk of thrombosis, but they arealso less likely to require reoperation. There is a paucity of data on the use of prosthetic valves inthe pulmonary position. We report the midterm outcomes of 38 cases of PVR with mechanicalprostheses.Methods: 122 patients who underwent PVR were studied. Thirty-eight patients, mean age 25 ±8.4 years underwent PVR with mechanical prostheses based on the right ventricular functionand the preferences of the patients and physicians. Median age of prosthesis was 1 year (range 3months to 5 years).Results: Seven (18%) patients had malfunctioning pulmonary prostheses and two patientsunderwent redo PVR. Mean International Normalized Ratio (INR) in these seven patientswas 2.1±0.8. Fibrinolytic therapy was tried and five of them responded to it well. There wasno significant association between the severity of right ventricular dysfunction, patient’s age,prostheses valve size and age of the prosthesis in the patients with prosthesis malfunction.Conclusion: PVR with mechanical prostheses can be performed with promising midtermoutcomes. Thrombosis on mechanical pulmonary valve prostheses remains a seriouscomplication, but most prosthesis malfunction respond to fibrinolytic therapy, underscoring theneed for adequate anticoagulation therapy

Fine-mapping the genetic basis of CRP regulation in African Americans: a Bayesian approach.

Basal levels of C-reactive protein (CRP) have been associated with disease, particularly future cardiovascular events. Twin studies estimate 50% CRP heritability, so the identification of genetic variants influencing CRP expression is important. Existing studies in populations of European ancestry have identified numerous cis-acting variants but leave significant ambiguity over the identity of the key functional polymorphisms. We addressed this issue by typing a dense map of CRP single-nucleotide polymorphisms (SNPs), and quantifying serum CRP in 594 unrelated African Americans. We used Bayesian model choice analysis to select the combination of SNPs best explaining basal CRP and found strong support for triallelic rs3091244 alone, with the T allele acting in an additive manner (Bayes factor > 100 vs. null model), with additional support for a model incorporating both rs3091244 and rs12728740. Admixture analysis suggested SNP rs12728740 segregated with haplotypes predicted to be of recent European origin. Using a cladistic approach we confirmed the importance of rs3091244(T) by demonstrating a significant partition of haplotype effect based on the rs3091244(C/T) mutation (F = 8.91, P = 0.006). We argue that weaker linkage disequilibrium across the African American CRP locus compared with Europeans has allowed us to establish an unambiguous functional role for rs3091244(T), while also recognising the potential for additional functional mutations present in the European genome