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5. Hull J, Ackerman H, Isles K, et al. Unusual haplotypic structure of IL-8, a susceptibility locus for a common respiratory virus. Am J Hum Genet 2001; 69:413–9. This study was approved by the Gambian government/Medical Research Council Joint Ethical Committee. All subjects gave informed consent to the study. Financial support: European Community (contract IC18CT980375); Wellcome Trust (to G.S.C., S.J.C., A.V.S.H.). a Deceased, March 2003. Reprints or correspondence: Prof. A. V. S. Hill, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Dr., Churchill Hospital, Oxford OX3 7BN, United Kingdom (adrian [email protected]). The Journal of Infectious Diseases 2004;189:1545–6 2004 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2004/18908-0027$15.00 Reply To the Editor—The Gambian study, which is referred to in the preceding letter by Cooke et al. [1], is an important project from which we have all obtained insight and knowledge regarding both the study of tuberculosis (TB) host susceptibility and the basic design of mycobacterial genetic studies in developing countries. Several fundamental differences between the Gambian study and ours [2] could possibly affect the interpretation of the 2 studies of the association between interleukin (IL)–8 and TB. In the Gambian study, only cases of pulmonary TB were evaluated, whereas our population consisted of cases of both pulmonary and extrapulmonary TB. In our study, 15% of the adults had extrapulmonary disease, and 56% of the pediatric patients had nonpulmonary manifestations. In Harris County, Texas (where our study takes place), the incidence of active TB in the general population is 12 cases/100,000 population, whereas in The Gambia the incidence of TB is ⭓84 cases/100,000 population [3], and the incidence of active TB in the general population has been estimated to be 0.1%/year [4]. In the Gambian study, adjustments for HIV status were intuitively performed, but it is unclear whether adjustments for other immunocompromising conditions, such as parasitic infection, were controlled for, given that the prevalence of helminthiasis in The Gambia is ⭓17% [3]—or whether it was assumed that the prevalence of such infections was similar in control subjects and case patients, in which case no adjustments would be necessary. In our study population, HIV-seronegative control subjects were recruited from local hospitals and clinics and were screened for TB, autoimmune diseases, and other infectious diseases [2]. Regarding Cooke et al.’s concern that the allele frequencies in the African American control group does not conform to Hardy-Weinberg equilibrium, we again tested this group and found, as identified by Cooke et al. [1], that the allele frequencies in the control group did differ significantly from those expected under Hardy-Weinberg equilibrium. Although we regret this miscalculation, we would like to point out that the Hardy-Weinberg test uses a number of assumptions to determine whether data on a population are in agreement with those expected; the most important of these assumptions are (1) the availability of a large population, (2) random mating (with regard to the locus studied), (3) no population subdivision/migration, (4) no natural selection, and (5) generations that are not overlapping. Although widely tested and reported in the literature, confirmation/rejection does not necessarily validate or invalidate a study. It is not correct to say that the sample or population is biased when Hardy-Weinberg equilibrium is rejected. Of real interest is whether there is an increase in the frequency of the IL-8 ⫺251 allele in the case patients, which there is. A locus that is associated with susceptibility to TB infection might have been subjected to natural selection, so a significant departure from Hardy-Weinberg equilibrium in fact strengthens our conclusions. Even though our study had only half as many case patients and control subjects as did the Gambian study [1], it is still quite obvious that the allele frequencies of IL-8 ⫺251 are significantly different (P ! .01), in both the case patients and the control subjects, when African 1546 • JID 2004:189 (15 April) • CORRESPONDENCE Americans are compared with Africans. As we continue to enroll patients in our candidate gene–based association studies in Houston, we have every intention to reanalyze our IL-8–expression data in a more robust fashion, with the additional enrolled patients. Edward A. Graviss,1,2 Xin Ma,1 and Yun-Xin Fu3 Departments of 1Pathology and 2Medicine, Baylor College of Medicine, and 3Human Genetic Center, University of Texas Health Science Center at Houston, Houston References 1. Cooke GS, Campbell SJ, Fielding K, et al. Interleukin-8 polymorphism is not associated with pulmonary tuberculosis in The Gambia. J Infect Dis 2004; 189:1545–6 (in this issue). 2. Ma X, Reich R, Wright JA, et al. Association between interleukin-8 gene alleles and human susceptibility. J Infect Dis 2003; 188:349–55. 3. Lienhardt C, Bennett S, Del Prete G, et al. Investigation of environmental and host-related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design. Am J Epidemiol 2002; 155:1066–73. 4. Bennett S, Lienhardt C, Bah-Sow O, et al. Investigation of environmental and host-related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors. Am J Epidemiol 2002; 155:1074–9. Reprints or correspondence: Dr. Edward A. Graviss, Dept. of Pathology (209E), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-3498 ([email protected]). The Journal of Infectious Diseases 2004;189:1546 2004 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2004/18908-0028$15.00