Genetic determinants of survival

The human genome comprises some 20,000 genes, or 3 billion base pairs. Vari-ation in this genetic sequence is common- and some of these variants affect gene function or the protein transcribed from it. Human characteristics are determined by the interaction of the genome with en-vironmental challenges- and differences between us thus result from variation in those challenges and in the genome itself. This is true of human susceptibility to dis-ease, and survival from it. Genetic varia-tion influences human behaviours which may predispose to health or disease; the risk of contracting an infectious disease, or of suffering diseases such as cancer or myocardial infarction; the development of complications; the response to any treat-ment administered; and thus the outcome of the disease state. Genetic studies can help shed light on the mechanisms which underpin disease processes, whilst perhaps suggesting ways in which treatment might be ‘personalised’, and novel therapeutic targets for drug development. 

More sophisticated approaches to such en-deavours are required, given the failure to identify the bulk of gene variants of influ-ence using conventional strategies.

Gene, polymorphism, survival, genome

1. Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2015 Oct 1;526(7571):75-81.

2. Pollex RL, Hegele RA. Copy number variation in the human genome and its implications for cardiovascular disease. Circulation.[Research Support, Non-U.S. Gov’t Review]. 2007 Jun 19;115(24):3130-3138.

3. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, et al. Common SNPs explain a large proportion of the heritabil-ity for human height. Nat Genet. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2010 Jul;42(7):565-569.

4. Kemkes-Grottenthaler A. Parental effects on offspring longevity--evidence from 17th to 19th century reproductive histories. Ann Hum Biol. [Historical Article]. 2004 Mar-Apr;31(2):139-158.

5. Brooks-Wilson AR. Genetics of healthy aging and longevity. Hum Genet. [Review]. 2013 Dec;132(12):1323-1338.

6. Cournil A, Legay JM, Schachter F. Evidence of sex-linked effects on the inheritance of human longevity: a population-based study in the Valserine valley (French Jura), 18-20th centuries. Proc Biol Sci. 2000 May 22;267(1447):1021-1025.

7. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. [Research Support, Non-U.S. Gov’t]. 1988 Mar 24;318(12):727-732.

8. De Moor MH, Posthuma D, Hottenga JJ, Willemsen G, Boomsma DI, De Geus EJ. Genome-wide linkage scan for exercise participa-tion in Dutch sibling pairs. Eur J Hum Genet. [Research Support, Non-U.S. Gov’t]. 2007 Dec;15(12):1252-1259.

9. De Moor MH, Liu YJ, Boomsma DI, Li J, Hamilton JJ, Hottenga JJ, et al. Genome-wide association study of exercise behavior in Dutch and American adults. Med Sci Sports Exerc. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. 2009 Oct;41(10):1887-1895.

10. Kreek MJ, Nielsen DA, Butelman ER, LaForge KS. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci. [Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov’t Review]. 2005 Nov;8(11):1450-1457.

11. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]. 2015 Oct 15;526(7573):343-350.

12. Biasin M, De Luca M, Gnudi F, Clerici M. The genetic basis of resistance to HIV infection and disease progression. Expert Rev Clin Immunol. [Research Support, Non-U.S. Gov’t Review]. 2013 Apr;9(4):319-334.

13. Lane J, McLaren PJ, Dorrell L, Shianna KV, Stemke A, Pelak K, et al. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A. Hum Mol Genet. [Multicenter StudyResearch Support, N.I.H., Extra-mural Research Support, N.I.H., Intramural Research Support, U.S. Gov’t, P.H.S.]. 2013 May 1;22(9):1903-1910.

14. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. [Research Support, Non-U.S. Gov’t]. 1992 Jul;51(1):197-205.

15. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin I-converting enzyme in human circulating mononuclear cells: ge-netic polymorphism of expression in T-lymphocytes. Biochem J. [Research Support, Non-U.S. Gov’t]. 1993 Feb 15;290 ( Pt 1):33-40.

16. Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, et al. Angiotensin-converting enzyme in the hu-man heart. Effect of the deletion/insertion polymorphism. Circulation. [Research Support, Non-U.S. Gov’t]. 1995 Sep 15;92(6):1387-1388.

17. Puthucheary Z, Skipworth JR, Rawal J, Loosemore M, Van Someren K, Montgomery HE. The ACE gene and human performance: 12 years on. Sports Med. [Review]. 2011 Jun 1;41(6):433-448.

18. Harding D, Baines PB, Brull D, Vassiliou V, Ellis I, Hart A, et al. Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism. Am J Respir Crit Care Med. [Research Support, Non-U.S. Gov’t]. 2002 Apr 15;165(8):1103-1106.

19. Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. [Comparative StudyResearch Support, Non-U.S. Gov’t]. 2002 Sep 1;166(5):646-650.

20. Hu Z, Jin X, Kang Y, Liu C, Zhou Y, Wu X, et al. Angiotensin-converting enzyme insertion/deletion polymorphism associated with acute respiratory distress syndrome among caucasians. J Int Med Res. 2010 Mar-Apr;38(2):415-422.

21. Tsantes AE, Kopterides P, Bonovas S, Bagos P, Antonakos G, Nikolopoulos GK, et al. Effect of angiotensin converting enzyme gene I/D polymorphism and its expression on clinical outcome in acute respiratory distress syndrome. Minerva Anestesiol. [Meta-Anal-ysis]. 2013 Aug;79(8):861-870.

22. Salnikova LE, Smelaya TV, Vesnina IN, Golubev AM, Moroz VV. Genetic susceptibility to nosocomial pneumonia, acute respiratory distress syndrome and poor outcome in patients at risk of critical illness. Inflammation. [Research Support, Non-U.S. Gov’t]. 2014 Apr;37(2):295-305.

23. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med. [Observational Study Research Support, Non-U.S. Gov’t]. 2015 Jan;3(1):53-60.