Genetics of Pulmonary Diseases: Understanding COPD and Asthma

1. Genetics of Pulmonary Diseases 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A709, Research Building 2011/03

2. Learning Objectives l.掌握肺气肿、哮喘、囊性纤维化等肺部疾病的相关遗传学知识。 2.了解肺部疾病的遗传学研究现状。

3. Required Reading Thompson &Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● P273-274； ● P280-284。

4. Runge MS, et al. Principles of molecular medicine. 2nd ed. Humana Press, 2006

5. COPD • Chronic obstructive lung disease (COPD or emphysema)is the 4th leading cause of mortality and affects more than 16 million people in the US, a number that has increased about 40% since 1982.

7. Pulmonary Emphysema----α1-AT deficiency • In white populations, α1-AT deficiency affects about 1 in 5000 persons, and 2% are carriers. • α1-AT deficiency is an important AR condition associated with a substantial risk of COPD and cirrhosis of the liver.

8. Α1-AT deficiency ● α1-AT belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins. ●α1-AT’s principal role is to bind and inhibit elastase, particularly elastase released from neutrophils in the lower respiratory tract, to maintain protease/antiprotease balance. ● A dozen or so α1-AT alleles are associated with an increased risk of lung or liver disease, but only the Z allele (Glu342Lys) is relatively common.

9. α1-ATgene: 14q32.1, 5 exons, 10.2 kb.α1-ATpr.:a 52-kDa glycoproteincomposed of 394 AAsand 12% carbohydratecontent.

10. α1-AT gene • The α1-AT alleles are grouped into four classes: (i) normal, (ii) deficiency, (iii) null alleles, and (iv) dysfunctional alleles. • The typical normal allele is Pi*M; the most important deficiency alleles are Pi*Z, Pi*P, and Pi*S.

11. The most frequent deficiency allele, Pi*Z, causes plasma concentrations of α1-AT of about 12–15% of normal in the homozygous genotypePi*ZZ and 64% in the heterozygote (Pi*MZ). MS heterozygotes have 86% of the MM homozygote activity. The molecular genetic diagnosis is facilitated by the presence of variant restriction enzyme sites.

12. The α1-AT gene is expressed in liver cells (hepatocytes).

13. Both sickle cell disease and α1-AT deficiency associated with homozygosity for the Z allele are examples of inherited conformational diseases. (The liver disease associated with the Z allele is thought to result from a novel property of the mutant protein—its tendency to aggregate, trapping it within the RER of hepatocytes. The molecular basis of the Z protein aggregation is a consequence of structural changes in the Z protein that predispose to the formation of long bead-like necklaces of mutant α1-AT polymers.)

14. Α1-AT Deficiency as an Ecogenetic Disease • Ecogenetics: The interaction of genetics with the environment. • Ecogenetic disorder: A disorder resulting from the interaction of a genetic predisposition to a specific disease with an environmental factor.

16. Asthma • Asthma is a complex disease affecting over 300 million individuals in the developed world. 90% of all asthma cases, including asthma in adults, have their origin in childhood.

17. Asthma : Basic pathobiology

18. Asthma : Basic pathobiology

29. Genetic Heterogeneity • Allelic heterogeneity:In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus. • Eg: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF).