Genomic medicine最新文献

Individual genomics has arrived, personal decisions to make use of it are a new reality. What are the implications for the patient-physician relationship? In this article we address three factors that call the traditional concept of confidentiality into question. First, the illusion of absolute data safety, as shown by medical informatics. Second, data sharing as a standard practice in genomics research. Comprehensive data sets are widely accessible. Third, genotyping has become a service that is directly available to consumers. The availability and accessibility of personal health data strongly suggest that the roles in the clinical encounter need to be remodeled. The old ideal of physicians as keepers of confidential information is outstripped by the reality of individuals who decide themselves about the way of using their data.

Single Nucleotide Polymorphisms (SNPs) are being intensively studied to understand the biological basis of complex traits and diseases. The Genetics of human phenotype variation could be understood by knowing the functions of SNPs. In this study using computational methods, we analyzed the genetic variations that can alter the expression and function of the CFTR gene responsible candidate for causing cystic fibrosis. We applied an evolutionary perspective to screen the SNPs using a sequence homology-based SIFT tool, which suggested that 17 nsSNPs (44%) were found to be deleterious. The structure-based approach PolyPhen server suggested that 26 nsSNPS (66%) may disrupt protein function and structure. The PupaSuite tool predicted the phenotypic effect of SNPs on the structure and function of the affected protein. Structure analysis was carried out with the major mutation that occurred in the native protein coded by CFTR gene, and which is at amino acid position F508C for nsSNP with id (rs1800093). The amino acid residues in the native and mutant modeled protein were further analyzed for solvent accessibility, secondary structure and stabilizing residues to check the stability of the proteins. The SNPs were further subjected to iHAP analysis to identify htSNPs, and we report potential candidates for future studies on CFTR mutations.

Cleidocranial dysplasia (CCD; MIM 119600) is a rare autosomal dominant disorder characterized by facial, dental, and skeletal malformations. To date, rearrangement and mutations involving RUNX2, which encodes a transcription factor required for osteoblast differentiation on 6p21, has been the only known molecular etiology for CCD. However, only 70% patients were found to have point mutations, 13% large/contiguous deletion but the rest of 17% remains unknown. We ascertained a family consisted of eight affected individuals with CCD phenotypes. Direct sequencing analysis revealed no mutations in the RUNX2. Real time quantitative PCR were performed which revealed an exon 2 to exon 6 intragenic deletion in RUNX2. Our patients not only demonstrated a unique gene change as a novel mechanism for CCD, but also highlight the importance of considering "deletion" and "duplication" in suspected familial cases before extensive effort of gene hunting be carried.

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for MI include hypertension, hypercholesterolemia or dyslipidemia, diabetes mellitus, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Disease prevention is an important strategy for reducing the overall burden of MI, with the identification of markers for disease risk being key both for risk prediction and for potential intervention to lower the chance of future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to coronary heart disease (CHD) or MI, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. In this review, we summarize both candidate loci for CHD or MI identified by linkage analyses and candidate genes examined by association studies. We also review in more detail studies that have revealed the association with MI or CHD of polymorphisms in MTHFR, LPL, and APOE by the candidate gene approach and those in LTA and at chromosomal region 9p21.3 by genome-wide scans. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of CHD and MI.

Genomic medicine research requires substantial time and resources to obtain phenotype data. The electronic health record offers potential efficiencies in addressing these temporal and economic challenges, but few studies have explored the feasibility of using such data for genetics research. The main objective of this study was to determine the association of two genetic variants located on chromosome 9p21 conferring susceptibility to coronary heart disease and type 2 diabetes with a variety of clinical phenotypes derived from the electronic health record in a population of morbidly obese patients. Data on more than 100 clinical measures including diagnoses, laboratory values, and medications were extracted from the electronic health records of a total of 709 morbidly obese (body mass index (BMI) >/= 40 kg/m(2)) patients. Two common single nucleotide polymorphisms located at chromosome 9p21 recently linked to coronary heart disease and type 2 diabetes (McPherson et al. Science 316:1488-1491, 2007; Saxena et al. Science 316:1331-1336, 2007; Scott et al. Science 316:1341-1345, 2007) were genotyped to assess statistical association with clinical phenotypes. Neither the type 2 diabetes variant nor the coronary heart disease variant was related to any expected clinical phenotype, although high-risk type 2 diabetes/coronary heart disease compound genotypes were associated with several coronary heart disease phenotypes. Electronic health records may be efficient sources of data for validation studies of genetic associations.

The 3' untranslated regions (3' UTRs) of human protein-coding genes play a pivotal role in the regulation of mRNA 3' end formation, stability/degradation, nuclear export, subcellular localisation and translation, and hence are particularly rich in cis-acting regulatory elements. One recent addition to the already large repertoire of known cis-acting regulatory elements are the microRNA (miRNA) target sites that are present in the 3' UTRs of many human genes. miRNAs post-transcriptionally down-regulate gene expression by binding to complementary sequences on their cognate target mRNAs, thereby inducing either mRNA degradation or translational repression. To date, only one disease-associated 3' UTR variant (in the SLITRK1 gene) has been reported to occur within a bona fide miRNA binding site. By means of sequence complementarity, we have performed the first systematic search for potential miRNA-target site mutations within a set of 79 known disease-associated 3' UTR variants. Since no variants were found that either disrupted or created binding sites for known human miRNAs, we surmise that miRNA-target site mutations are not likely to represent a frequent cause of human genetic disease.

The concept of 'evidence-based medicine' dates back to mid-19th century or even earlier. It remains pivotal in planning, funding and in delivering the health care. Clinicians, public health practitioners, health commissioners/purchasers, health planners, politicians and public seek formal 'evidence' in approving any form of health care provision. Essentially 'evidence-based medicine' aims at the conscientious, explicit and judicious use of the current best evidence in making decisions about the care of individual patients. It is in fact the 'personalised medicine' in practice. Since the completion of the human genome project and the rapid accumulation of huge amount of data, scientists and physicians alike are excited on the prospect of 'personalised health care' based on individual's genotype and phenotype. The first decade of the new millennium now witnesses the transition from 'evidence-based medicine' to the 'genomic medicine'. The practice of medicine, including health promotion and prevention of disease, stands now at a wide-open road as the scientific and medical community embraces itself with the rapidly expanding and revolutionising field of genomic medicine. This article reviews the rapid transformation of modern medicine from the 'evidence-based medicine' to 'genomic medicine'.