It Takes a Genome: How a Clash Between Our Genes and Modern Life is Making Us Sick

by Greg Gibson

The first review of canine atopic dermatitis that I am aware of is by R. E. Halliwell (1971) The Veterinary Record 89:209-214 “Atopic disease in the dog,” as referenced in Hillier, A. and C. E. Griffin (2001) Veterinary Immunology and Immunopathology 81: 147-151 “The ACVD task force on canine atopic dermatitis (I): incidence and prevalence.”

  For a brief description of the common asthma drugs, see www.healthcentral.com/asthma/find-drug.html.

  A couple of recent reviews of the genetics and immunology behind asthma are Zhang, J., P. D. Pare, and A. J. Sandford (2007) Respiratory Research 9:4 “Recent advances in asthma genetics,” and Yamashita, M., A. Onodera, and T. Nakayama (2007) Critical Reviews in Immunology 27: 539-546 “Immune mechanisms of allergic airway disease: regulation by transcription factors.”

  the hygiene hypothesis

  David Strachan’s two papers on the hygiene hypothesis are D. P. Strachan (1989) British Medical Journal 299: 1259-1260 “Hay fever, hygiene, and household size,” and D.P. Strachan (2000) Thorax 55 (Suppl 1): S2-10 “Family size, infection and atopy: the first decade of the ‘hygiene hypothesis.’” One of several recent reviews is by E. von Mutius (2007) Immunobiology 212: 433-439 “Allergies, infections and the hygiene hypothesis—the epidemiological evidence.” Additionally, hundreds of papers examine specific environmental influences on asthma susceptibility.

  A fascinating read about polio is David M. Oshinsky’s Polio: An American Story (Oxford University Press, 2006). For a history of the March of Dimes, try David W. Rose’s March of Dimes: Images of America (Arcadia Books, 2003).

  asthma epidemiology

  Prevalence by ethnicity and age in the United States in adults is around 11 percent for Caucasians and Africans, but less than 8 percent for Hispanics, and more than 20 percent in Puerto Rico. Full data for 2005 can be found at www.cdc.gov/asthma/nhis/05/table2-1.htm.

  The association of ADAM33 with asthma was first described by P. van Eerdewegh et al. (2002) Nature 418: 426-430 “Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.” The latest research on the mechanism by which it works is described in R. G. del Mastro et al. (2007) BMC Medical Genetics 8:46 “Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene.”

  For a review of inflammation and neonatal lung development see Shi, W., S. Bellusci, and D. Warburton (2007) Chest 132: 651-656 “Lung development and adult lung diseases.”

  The roles of T-cells in asthma are discussed in M. Larché (2007) Chest 132: 1007-1014 “Regulatory T cells in allergy and asthma,” and Umetsu, D. T. and R. H. DeKruyff (2006) Immunological Reviews 212: 238-255 “The regulation of allergy and asthma,” among many other places. An early review of the clinical applications of interleukin cytokines is P. J. Barnes (2001) European Respiratory Journal 34 (Suppl): 67-77 “Cytokine modulators as novel therapies for airway disease.” Genetic associations with asthma are updated in Zhang, J., P. D. Pare, and A. J. Sandford (2008) Respiratory Research 9:4 “Recent advances in asthma genetics.” The linkage with IRAK is described in L. Balaci et al. (2007) American Journal of Human Genetics 80: 1103-1114 “IRAK-M is involved in the pathogenesis of early-onset persistent asthma.”

  An intriguing study of the maternal genotype contribution of HLA-G and the possible role of microRNAs is by Z. Tan et al. (2007) American Journal of Human Genetics 81: 829-834 “Allele-specific targeting of microRNAs to HLA-G and risk of asthma.” See also C. Ober (2005) Immunology and Allergy Clinics of North America 25: 669-679 “HLA-G: an asthma gene on chromosome 6p.”

  The genomewide association study is M. F. Moffatt et al. (2007) Nature 448: 470-473 “Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.”

  inflamed bowels and crohn’s disease

  Genomewide association studies for Crohn’s disease have been published by M. Parkes et al. (2007) Nature Genetics 39: 830-832 “Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility,” J. D. Rioux et al. (2007) Nature Genetics 39: 596-604 “Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis,” J. V. Raelson et al. (2007) Proceedings of the National Academy of Science (USA) 104: 14747-14752 “Genome-wide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci,” J. Hampe et al. (2007) Nature Genetics 39: 207-211 “A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1,” and A. Franke et al. (2007) PLoS ONE 2: e691 “Systematic association mapping identifies NELL1 as a novel IBD disease gene.” For a review, see Xavier, R. J. and D. K. Podolsky (2007) Nature 448: 427-434 “Unraveling the pathogenesis of inflammatory bowel disease.”

  The cold chain hypothesis was proposed by Hugot, J. P., C. Alberti, D. Berrebi, E. Bingen, and J. P. Cézard (2003) The Lancet 362: 2012-2015 “Crohn’s disease: the cold chain hypothesis.”

  A meta-analysis of the protective effect of hookworm infection against asthma is Leonardi-Bee, J., D. Pritchard, and J. Britton (2006) American Journal of Respiratory and Critical Care Medicine 174: 514-523 “Asthma and current intestinal parasite infection: systematic review and meta-analysis.”

  rheumatoid arthritis

  A genomewide scan for rheumatoid arthritis is described by R. M. Plenge et al. (2007) New England Journal of Medicine 357: 1199-1209 “TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study.”

  The role of the HLA in mediating arthritis via immunity to citrulline is reviewed in Klareskog, L., J. Rönnelid, K. Lundberg, L. Padyukov, and L. Alfredsson (2008) Annual Reviews of Immunology 26: 651-675 “Immunity to citrullinated proteins in Rheumatoid Arthritis.”

  Nicotine’s connection to arthritis is reviewed in Harel-Meir, M., Y. Sherer, and Y. Shoenfeld (2007) Nature Clinical Practice. Rheumatology 3: 707-715 “Tobacco smoking and autoimmune rheumatic diseases.”

  See Lie, B. A. and E. Thorsby (2005) Current Opinion in Immunology 17: 526-531 “Several genes in the extended human MHC contribute to predisposition to autoimmune diseases” for a brief discussion of the MHC in lupus. A more general review of autoimmunity is by A. M. Bowcock (2005) Annual Review of Genomics and Human Genetics 6: 93-122 “The genetics of psoriasis and autoimmunity.”

  imbalance of the immune system

  The impact of selection on the promoter of the IL4 gene is described by Rockman, M. V., M. W. Hahn, N. Soranzo, D. B. Goldstein, and G. A. Wray (2003) Current Biology 13: 2118-2123 “Positive selection on a human-specific transcription factor binding site regulating IL4 expression.”

  Chapter 5

  AIDS and the world

  Global estimates of AIDS prevalence can be found online at the following informative site: www.avert.org/worldstats.htm or at www.aidsmap.com. The latest epidemiology of AIDS is presented by J. Cohen (2007) Science 318: 1360-1361 “New estimates scale back scope of HIV/AIDS epidemic.”

  United States support policy and the ABCs of AIDS prevention are outlined by the USAID at www.usaid.gov/our_work/global_health/aids/News/abcfactsheet.html.

  Al Gore’s The Assault on Reason was published by Penguin books in 2007.

  The South African AIDS portal is www.doh.gov.za/aids/index.html.

  Journalist Jonny Steinberg has just completed a book about the epidemic: Sizwe’s Test: A Young Man’s Journey through Africa’s AIDS Epidemic (Simon and Schuster, 2008).

  For more on HAART, download the book at www.haart.com.

  from HIV to AIDS

  Severe Combined Immune Deficiency is a prime target for gene therapy in humans, as outlined for example in Cavazzana-Calvo, M., and A. Fischer (2007) Journal of Clinical Investigation 117: 1456-1465 “Gene therapy for severe combined immunodeficiency: are we there yet?”

  AIDS-related cancer is reviewed in Arora, A., E. Chiao, and S. K. Tyring (2007) Cancer Treatment Research 133: 21-67 “AIDS malignancies.” For more on Gardasil an
d HPV, see www.gardasil.com/.

  A strong statement of how we know HIV causes AIDS is O’Brien, S. J. and J. J. Goedert (1996) Current Opinion in Immunology 8: 613-618 “HIV causes AIDS: Koch’s postulates fulfilled.” This is in response to the contrary opinion expressed by P. H. Duesberg (1988) Science 241: 514-517 “HIV is not the cause of AIDS” and elsewhere. Koch’s postulates were initially published in German in 1891, but appear in T. M. Rivers (1937) Journal of Bacteriology 33: 1-12 “Viruses and Koch’s postulates.”

  why HIV is so nasty

  Drugs that inhibit the co-receptors that HIV uses to get into T-cells are reviewed in Biswas, P., G. Tambussi, and A. Lazzarin (2007) Expert Opinion in Pharmacotherapy 8: 923-933 “Access denied? The status of co-receptor inhibition to counter HIV entry,” while the co-receptors themselves are described in Arenzana-Seisdedos, F. and M. Parmentier (2006) Seminars in Immunology 18: 387-403 “Genetics of resistance to HIV infection: Role of co-receptors and co-receptor ligands.”

  The evolution of resistance by HIV to even triple cocktails of drugs is described in N. Lohse et al. (2007) Antiviral Therapy 12: 909-917 “Genotypic drug resistance and long-term mortality in patients with triple-class antiretroviral drug failure.”

  Various AIDS medications are described at www.aidsmeds.com/list.shtml.

  how to resist a virus with your genes

  The ability of HIV to evolve resistance by switching from one co-receptor to another is established in Moncunill, G., M. Armand-Ugón, E. Pauls, B. Clotet, and J. A. Esté (2008) AIDS 22: 23-31 “HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro.”

  The case for selection acting on CCR5 is challenged by P. C. Sabeti et al. (2005) PLoS Biology 3: e378. “The case for selection at CCR5-Delta32.” For a discussion of selection and inclusive fitness, see P. Schliekelman (2007) Evolution 61: 1277-1288 “Kin selection and evolution of infectious disease resistance.”

  For more on Maraviroc, search for it at http://hivinsite.ucsf.edu.

  The whole genome scan that turned up the associations between MHC and HIV traits is described in J. Fellay et al. (2007) Science 317: 944-947 “A whole-genome association study of major determinants for host control of HIV-1.”

  HIV imbalance

  The feline and simian immunodeficiency viruses are discussed in S. VandeWoude and C. Apetrei (2006) Clinical Microbiology Reviews 19: 728-762 “Going wild: lessons from naturally occurring T-lymphotropic lentiviruses.”

  The argument that HIV was released as a result of the fight against polio was made in a book by Edward Hooper, The River: A Journey Back to the Source of HIV and AIDS (Penguin, 1999). The theory was refuted using evolutionary approaches by M. Worobey et al. (2004) Nature 428: 820 “Origin of AIDS: contaminated polio vaccine theory refuted.”

  The latest data on the origin of the two viral types can be found in B. F. Keele et al. (2006) Science 313: 523-526 “Chimpanzee reservoirs of pandemic and nonpandemic HIV-1,” and Van Heuverswyn, F. and M. Peeters (2007) Current Infectious Disease Reports 9: 338-346 “The origins of HIV and implications for the global epidemic.”

  Chapter 6

  creative depression

  A useful Web site for sufferers of affective disorders is www.pendulum.org.

  Many sites list celebrities who have suffered, including www.geocities.com/coverbridge2k/artsci/famous_people_depression.html.

  Much of the information on Winston Churchill, Harrison Ford, and others was gleaned from Wikipedia and linked sites.

  The National Institute of Mental Health site is www.nimh.nih.gov/health/publications/depression/complete-publication.shtml, and the WHO’s is www.who.int/mental_health/management/depression/definition/en.

  an epidemic of mood swings

  For a brief discussion of whether depression is epidemic, see D. Summerfield (2006) Journal of the Royal Society of Medicine 99: 161-162 “Depression: epidemic or pseudo-epidemic?”

  Andrew Solomon’s book is The Noonday Demon: An Atlas of Depression (Scribner, 2001).

  bipolar and monopolar disorders

  Wikipedia is as good a place as any to get some quick background: see http://en.wikipedia.org/wiki/Clinical_depression and http://en.wikipedia.org/wiki/Bipolar_disorder.

  Major and bipolar depressive disorders are reviewed in Belmaker, R. H. and G. Agam (2008) New England Journal of Medicine 358: 55-68 “Major depressive disorder,” and Miklowitz, D. J. and S. L. Johnson (2006) Annual Review of Clinical Psychology 2: 199-235 “The psychopathology and treatment of bipolar disorder,” respectively.

  The genetic component of depression is established by McGuffin, P., F. Rijsdijk, M. Andrew, P. Sham, R. Katz, and A. Cardno (2003) Archives of General Psychiatry 60: 497-502 “The heritability of bipolar affective disorder and the genetic relationship to unipolar disorder.”

  A. Halfin (2007) American Journal of Managed Care 13: (4 Suppl) S92-S97 “Depression: the benefits of early and appropriate treatment” covers the medical and financial costs of failure to treat depression when it first appears.

  the pharmacology of despair

  The role of serotonin in depression is reviewed in Ressler, K. J. and C. B. Nemeroff (2000) Depression and Anxiety 12 (Suppl 1): 2-19 “Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders.” That of cortisol can be found in Thomson, F. and M. Craighead (2007) Neurochemical Research 33: 691-707) “Innovative Approaches for the Treatment of Depression: Targeting the HPA Axis.”

  Antidepressants are considered in J. J. Mann (2005) New England Journal of Medicine 353: 1819-1834 “The medical management of depression,” and H. J. Gijsman (2004) American Journal of Psychiatry 161: 1537-1547 “Antidepressants for bipolar depression: a systematic review of randomized, controlled trials.”

  misbehaving serotonin

  The two studies describing interactions between genes and culture are Caspi, A. et al. (2002) Science 297: 851-854 “Role of genotype in the cycle of violence in maltreated children,” and Caspi, A. et al. (2003) Science 301: 386-389 “Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.”

  For more on genes and suicide, see Bondy, B., A. Buettner, and P. Zill (2006) Molecular Psychiatry 11: 336-351 “Genetics of suicide.”

  The hypothesis that depression may be due to serotonin resistance is articulated by Smolin, B., E. Klein, Y. Levy, and D. Ben-Shachar (2007) International Journal of Neuropsychopharmacology 10: 839-850 “Major depression as a disorder of serotonin resistance: inference from diabetes mellitus type II.”

  faint genetic signals

  The genetics of depression is reviewed by D. F. Levinson (2006) Biological Psychiatry 60: 84-92 “The genetics of depression: a review,” and of bipolar disorder by T. Kato (2007) Psychiatry and Clinical Neurosciences 61: 3-19 “Molecular genetics of bipolar disorder and depression.”

  A linkage scan for bipolar disorder is described in M. B. McQueen et al. (2005) American Journal of Human Genetics 77: 582-595 “Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.” BD is one of the diseases that failed to show any associations in Wellcome Trust Case Control Consortium (2007) Nature 447: 661-678 “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.”

  The connection to variation in the serotonin transporter gene is reviewed in Uher, R. and P. McGuffin (2007) Molecular Psychiatry 13: 131-146 “The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis,” and in H. A. Mansour et al. (2005) Annals of Medicine 37: 590-602 “Serotonin gene polymorphisms and bipolar I disorder: focus on the serotonin transporter.”

  schizophrenic spectrum and other mental disturbances

  Iceland’s deCODE Genetics was reported by Michael Specter in The New Yorker (January 18, 1999, 40-51) “Decoding Iceland: the next big medical breakthroughs may result fro
m one scientist’s battle to map the Viking gene pool.”

  One of the deCODE studies of schizophrenia is Stefansson, H., V. Steinthorsdottir, T. E. Thorgeirsson, J. Gulcher, and K. Stefansson (2004) Annals of Medicine 36: 62-71 “Neuregulin 1 and schizophrenia.” The same group, and another consortium, discuss the contribution of CNV to schizophrenia in two papers in Nature released online on July 30, 2008, by H. Stefansson et al., “Large recurrent microdeletions associated with schizophrenia,” and by The International Schizophrenia Consortium, “Rare chromosomal deletions and duplications increase risk of schizophrenia.”

  Cannon, T. D. and M. C. Keller (2006) Annual Review of Clinical Psychology 2: 267-290 “Endophenotypes in the genetic analyses of mental disorders” describes how it may be more fruitful to study attributes related to schizophrenia than the disease itself.

  For an update on mental retardation see Debacker, K. and R. F. Kooy (2007) Human Molecular Genetics 2007 16 (Spec 2): R150-R158 “Fragile sites and human disease.” An intriguing link between common deletions and autism was reported by J. Sebat et al. (2007) Science 316: 445-449 “Strong association of de novo copy number mutations with autism.”