Text Box: DISTRIBUTION OF VARIANT GENOTYPES OF CHITOTRIOSIDASE IN TWO HEALTHY POPULATIONS AND LACK OF ASSOCIATION WITH INFECTIOUS COMPLICATIONS IN CHRONIC GRANULOMATOUS DISEASE Zhu S1,2, Lehrnbecher T2, Foster CB2, Leitman SF2, Curnutte J2, Aerts JMFG3, Chanock SJ2. 1 Henan Medical University, Third Affiliated Hospital, Zhengzhou, China 2 National Cancer Institute, National Institutes of Health, Bethesda, USA 3 University of Amsterdam, Amsterdam, The Netherlands Objective: To elucidate the distribution of variant genotypes of chitotriosidase in African Americans (AA) and Caucasian Americans, and its association with infectious complications in Chronic Granulomatous Disease (CGD). Method: Chitotriosidase is synthesized by activated macrophages and can degrade chitin-containing substrates, similar to chitinases commonly found in bacteria and fungi. Though the function of the human enzyme is not well understood, it has been suggested to fulfill a role in degration of chitin-containing pathogens. A 24 base-pair duplication in exon 10 of chitotriosidase gene, which has been localized to the long arm of chromosome 1, leads to chitotriosidase deficiency. Genotypes were analysed by amplification of region flanking exon 10 by PCR technology and size frantionation on agarose gel. Results: The frequency of variant genotypes was determined in a population of 404 normal controls (n=175 (AA) and n=229 (CA)). Overall, the distribution of variant genotypes differed significantly between AA and CA (p<0.0001). The homozygous variant genotype, HH, which is associated with deficiency of the enzyme, is rare, 2/175(1.1%) of AA and 1/229 (0.4%) of CA. Heterozygotes, HT, for each group were 14/175 (8%) in AA and 83/229 (36.3%) in CA which differed significantly (p<0.0001). Interestingly, the difference between the observed and expected frequency of variant alleles is marginally significant in CA (p=0.028), whereas there is no deviation from the Hardy-Weinberg equilibrium in AA (0.88). Since chitotriosidase (CHIT1) is located not far from the low affinity Fcg receptors on chromosome 1, two-locus analysis indicated that chitotriosidase is in disequilibrium with only FcgRIIa(p=0.0013 for AA and p= 0.013 in CA). We examined a cohort of predominantly CA patients with CGD (n=129) and found that the distribution of variant genotypes for chitotriosidase did not differ from the control CA population. When we evaluated the cohort for possible association between infectious (i.e., fungal infection, perirectal or deep abscess, or bacteremia) or immunologic (i.e., obstructive granuloma or entrocolitis) outcomes, the chitotriosidase genotype was not informative. Conclusion: variant genotypes of chitotriosidase are not associated with the risk for infections or immunologic complications in CGD. The distribution of variant genotypes of chitotriosidase varies between different populations. Our data provide a foundation for future investigation of the possible role variant genotypes of chitotriosidase might contribute to disease susceptibility or outcome. 1867