Genomic medicine最新文献

Genetic diseases are recognized to be one of the major categories of human disease. Traditionally genetic diseases are subdivided into chromosomal (numerical or structural aberrations), monogenic or Mendelian diseases, multifactorial/polygenic complex diseases and mitochondrial genetic disorders. A large proportion of these conditions occur sporadically. With the advent of newer molecular techniques, a number of new disorders and dysmorphic syndromes are delineated in detail. Some of these conditions do not conform to the conventional inheritance patterns and mechanisms are often complex and unique. Examples include submicroscopic microdeletions or microduplications, trinucleotide repeat disorders, epigenetic disorders due to genomic imprinting, defective transcription or translation due to abnormal RNA patterning and pathogenic association with single nucleotide polymorphisms and copy number variations. Among these several apparently monogenic disorders result from non-allelic homologous recombination associated with the presence of low copy number repeats on either side of the critical locus or gene cluster. The term 'disorders of genome architecture' is alternatively used to highlight these disorders, for example Charcot-Marie-Tooth type IA, Smith-Magenis syndrome, Neurofibromatosis type 1 and many more with an assigned OMIM number. Many of these so called genomic disorders occur sporadically resulting from largely non-recurrent de novo genomic rearrangements. Locus-specific mutation rates for genomic rearrangements appear to be two to four times greater than nucleotide-specific rates for base substitutions. Recent studies on several disease-associated recombination hotspots in male-germ cells indicate an excess of genomic rearrangements resulting in microduplications that are clinically underdiagnosed compared to microdeletion syndromes. Widespread application of high-resolution genome analyses may offer to detect more sporadic phenotypes resulting from genomic rearrangements involving de novo copy number variation.

Background/aims Several studies have reported varying results of the influence of ACE gene on ACEI/ARB therapy. The efficacy of high dose ARB and its influence on ACE gene have not been explored. This is a 6 year randomised trial in IgA nephritis comparing high dose ARB (Losartan 200 mg/day) with normal dose ARB (Losartan 100 mg/day), normal dose ACEI (20 mg/day) and low dose ACEI (10 mg/day). Results Patients on high dose ARB had significantly lower proteinuria, 1.0 +/- 0.8 gm/day compared to 1.7 +/- 1.0 g/day in the other groups (P = 0.0005). The loss in eGFR was 0.7 ml min(-1)year(-1) for high dose ARB compared to 3.2-3.5 ml min(-1)year(-1) for the other three groups (P = 0.0005). There were more patients on high dose ARB with improvement in eGFR compared to other three groups (P < 0.001). Comparing patients with the three ACE genotypes DD, ID and II, all three groups responded well to therapy with decrease in proteinuria (P < 0.002). Only those on low dose ACEI (10 mg/day) with the I allele had increased in ESRF (P = 0.037). Conclusion High dose ARB is more efficacious in reducing proteinuria and preserving renal function when compared with normal dose ARB and ACEI, and also obviates the genomic influence of ACE gene polymorphism on renal survival.

Pharmacogenetic tests allow medications to be tailored to individual patients to improve efficacy and reduce drug toxicity. In 2005, the International Society of Pharmacogenomics (ISP) made recommendations for undergraduate medical teaching in pharmacogenetics. We aimed to establish the quantity and scope of this in British medical schools. An electronic survey was sent to all British medical schools. Nineteen out of 34 (56%) medical schools responded. Sixteen of the 19 (84%) respondents provided pharmacogenetics teaching, usually 1-2 h in total. Only four (21%) medical schools offered the four or more hours of teaching recommended by the ISP. However, 10 of 16 (63%) schools felt the amount of pharmacogenetic teaching offered was sufficient. The quantity of undergraduate teaching of pharmacogenetics is low. However, a majority of UK medical schools teach it, covering a broad scope of elements. It is encouraging that future clinicians are being provided with the knowledge to deliver pharmacogenetics into clinical practice.