Genetic Epidemiology of Health Disparities in Allergy and Clinical Immunology
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Molecular mechanisms in allergy and clinical immunology (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation) Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner, MD Reviews and feature articles Genetic epidemiology of health disparities in allergy and clinical immunology Kathleen C. Barnes, PhD Baltimore, Md This activity is available for CME credit. See page 45A for important information. The striking racial and ethnic disparities in disease prevalence for common disorders, such as allergic asthma, cannot be Abbreviations used explained entirely by environmental, social, cultural, or CF: Cystic fibrosis economic factors, and genetic factors should not be ignored. CFTR: Cystic fibrosis transmembrane conductance Unfortunately, genetic studies in underserved minorities are regulator hampered by disagreements over the biologic construct of race CTLA4: Cytotoxic T lymphocyte–associated 4 and logistic issues, including admixture of different races and LD: Linkage disequilibrium ethnicities. Current observations suggest that the frequency NOS: Nitric oxide synthase of high-risk variants in candidate genes can differ between SNP: Single nucleotide polymorphism African Americans, Puerto Ricans, and Mexican Americans, and this might contribute to the differences in disease prevalence. Maintenance of certain allelic variants in the population over time might reflect selective pressures in influences (ie, gene-environment interactions). Con- previous generations. For example, significant associations versely, the quest for causal variants has been met with between markers in certain candidate genes (eg, STAT6, ADRB2, and IFNGR1) for traits such as high total IgE levels considerable success for a number of the monogenic observed in resistance to extracellular parasitic disease in one disorders, such as cystic fibrosis (CF) and sickle cell population and atopic asthma in another supports the common anemia, wherein a major gene is known and confounding disease/common variant model for disease. Herein is a factors, although not entirely absent, have much less discussion of how genetic variants might explain, at least in effect. For example, the DF508 variant in the CF trans- part, the marked disparities observed in risk to allergic asthma. membrane conductance regulator (CFTR) gene is the most (J Allergy Clin Immunol 2006;117:243-54.) common cause of CF in most populations,1 the most common fatal recessive disorder among populations of Key words: Asthma, allergy, genetics, disparities, ethnicity European descent. This variant is believed to have emerged more than 52,000 years ago during the Paleo- Despite the explosion of data on the role of genetics in lithic period from a single origin followed by diffusion the pathophysiology of both common and uncommon along a southeast-northwest gradient across Europe, re- diseases, identifying the precise genes that confer suscep- sulting in higher frequencies of the mutation in northern tibility to many complex disorders, including allergic Europe and lower frequencies toward the south.2 The asthma, remains a daunting task. Identification of these heterozygote state is believed to confer some protection genes has been hampered by variability in the clinical against cholera-induced secretory diarrhea because altered phenotype, genetic heterogeneity among human popula- CFTR expression results in modified Cl2 secretion; CFTR tions, and a failure to consider important environmental knockout murine models support this.3 The exceptionally high CF heterozygosity frequency (1 in 20) of the CFTR From The Johns Hopkins Asthma and Allergy Center. mutation supports the notion of heterozygote advantage Supported by the Allergy and Asthma Foundation of America Young and could reflect selective pressure from cholera epi- Investigator Award and National Institutes of Health grants A150024 and demics in early European history. HL066583. KCB was supported in part by the Mary Beryl Patch Turnbull In contrast, sickle cell disease, a common autosomal Scholar Program. Received for publication November 16, 2005; revised November 29, 2005; recessive disorder, caused a variant in the b-globin gene accepted for publication November 29, 2005. (HbS) believed to have spread as a protective mechanism Reprint requests: Kathleen C. Barnes, PhD, The Johns Hopkins Asthma and against malaria, which would explain the high frequency Allergy Center, 5501 Hopkins Bayview Circle, Room 3A.62, Baltimore, of this variant in African and Mediterranean populations.4 MD 21224. E-mail: [email protected]. 0091-6749/$32.00 A life-threatening complication of sickle cell disease is Ó 2006 American Academy of Allergy, Asthma and Immunology acute chest syndrome, affecting some 1 in 1085 patients 5 doi:10.1016/j.jaci.2005.11.030 with sickle cell disease. Both a promoter variant 243 244 Barnes J ALLERGY CLIN IMMUNOL FEBRUARY 2006 feature articles Reviews and (T-786C) in the endothelial nitric oxide synthase (NOS) Europe, East Asia, Oceania-Pacific, and the Americas. gene,6 or NOS3, and a polymorphism in the NOS1 gene7 There is typically good agreement between assignment have been shown to be associated with acute chest syn- to these 5 populations on the basis of genetic marker data drome. Interestingly, it has also been shown that heterozy- and self-reported ancestry.23 However, on the basis of the gous carriers of a point mutation in the promoter of the biogeographic distribution of our genetic variation, there NOS2 are protected against severe malaria,8 suggesting are actually few sound arguments for lumping individuals an overall selective advantage for variants in these genes into these specific racial categories. In the past several de- as well. Striking differences in frequencies of variants in cades, the long-standing ‘‘Multiregional Origin model’’ to nitric oxide genes have been observed when comparing explain evolution of modern human origins, which alleged populations originating in regions endemic for malaria that parallel evolution of Homo sapiens from Homo erec- (eg, African descent) with European populations (NOS1 tus took place within geographically dispersed populations CA repeat in exon 29 and intronic AAT repeat,9 NOS3 as H erectus migrated out of Africa more than 1,000,000 Glu298Asp polymorphism,10 NOS3(G894T) polymor- years ago,24 has been replaced by the Recent African phism,11 and 393 endothelial cell NOS allele12). Collec- Origin model (Out of Africa hypothesis25,26). The Recent tively, genetic studies of monogenic lung disorders African Origin model argues that H sapiens evolved in suggest that (1) the presence of high-risk variants can dif- Africa some 100,000 to 200,000 years ago (probably from fer substantially among ethnic groups, contributing to the an East African gene pool), after which its anatomically marked differences in disease prevalence among ethnic modern members migrated and replaced archaic human groups, and (2) the maintenance of these variants in the groups throughout Europe and Asia, and only within the population over time might be due to a selective advantage past 100,000 years has racial differentiation occurred. for the variant in previous generations. Historical evidence for recent expansions across Europe, Asia, the Americas, and the Pacific (dating back from 6023 thousand years ago) correlates well with pat- ETHNICITY AND RACE AS CONSTRUCTS: terns of allele frequency variation,27 with higher levels IS THERE BIOLOGIC RELEVANCE? of sustained genetic diversity in the more ancient African populations and less diversity in the younger, non-African Given the negative and in many cases devastating use of populations.28 The end result of this process is a gradation the social construct of race in our recent past,13 the use of of genetic differentiation across groups of H sapiens,29 the term in biomedical research has been met with a wide with no clear-cut boundaries defining races. In light of a range of consternation and has generated a plethora of more accurate time frame for evolution of our species, editorials variously calling for the judicious use of the con- the amount of genetic diversity across the human genome cept as a legitimate tool for identifying disease-associated is, perhaps not surprisingly, rather low. H sapiens as a spe- genes14,15 to the stance that race is biologically meaning- cies share approximately 99.6% to 99.8% of genetic mate- less.16 At the very least, most experts in the field agree that rial with each other, and only a fraction of the total genome race as a social construct represents a continuum rather (eg, approximately 10 million of 3 billion nucleotides) than a term with clear-cut boundaries, a point that has accounts for variability among populations.22 Put another been illustrated by large-scale genotyping among diverse way, human genomes vary roughly one every thousand biogeographic populations.17 (For in-depth reviews on bases (kilobase). Additionally, genetic diversity is highest this topic, see supplement in Nature Genetics.18) How- among individuals within populations (85%), and varia- ever, whether we adopt the constructs of race, ethnicity, tion between groups or populations only accounts for or self-defined group identity according to our ancestors’ approximately 15%.30 geographic origins (eg, ‘‘biogeography’’), there is no denying that health disparities, including asthma, exist among certain racial-ethnic groups in the United States. GENOMIC AND POPULATION STRUCTURE Consider,