Trend tests for genetic association using a matched case-control design are studied, which allows for a variable number of controls per case. However, the tests depend on the scores based on the underlying genetic model, thus it may result in substantial loss of power when the model is misspecified. Since the mode of inheritance may be unknown for complex diseases, robust trend tests in matched case-control studies are developed. Simulation is conducted to compare the trend tests and the robust trend tests under various genetic models. The results are applied to detect candidate-gene association using an example from a case-control aetiologic study of sarcoidosis.
Chronic beryllium disease (CBD) is a hypersensitivity granulomatosis characterized by beryllium hypersensitivity (BH) and mediated by CD4+ T cells. However, all individuals with BH may not develop CBD. To examine the role of the three different human leukocyte antigen (HLA) Class II isotypes in BH with (CBD) and without clinical disease (BHWCD), we performed DNA-based typing of HLA-DPB1, HLA-DQB1, and HLA-DRB1 loci on 55 subjects with BH (25 with established CBD and 30 with BHWCD), and compared this with the results for 82 beryllium-exposed workers with no evidence of BH. The allele distribution was utilized to identify candidate amino acid epitopes that differed between the study groups. HLA-DPB1-E69 was the most important marker for BH, and did not differentiate BHWCD from CBD. A significant association with CBD was observed with HLA-DQB1-G86 (p(corr) < 0.04), and HLA-DRB1-S11 was significantly increased in CBD as compared with BHWCD (p < 0.03). These observations suggest that HLA-DPB1-E69 is a marker for susceptibility to BH and not just a progression marker for CBD. In addition, HLA amino acid epitopes on HLA-DRB1 and -DQB1, in concert with or independently of HLA-DPB1-E69, may be associated with progression to CBD.
carbon with upwelling water into these 6-phosphatase activity in the diabetic lakes. The activity of the upwelling animal. Either more of the normal enwater alone is probably about 20 percent zyme may be present, or the amount of below the recent activity (3). The activenzyme present may be unchanged but ity actually found is about 8 percent be-its properties altered in the direction of low normal; it is not possible to apply an increase in catalytic potency (or a a correction for fractionation, for there combination of both). The latter implies is probably also no equilibrium for the some structural change in the enzyme C13 content of the lakes and the atmos-which would presumably be manifested phere. in one or more measurable properties. In The difference in the C14 concentra-this connection, the very obvious possition of the atmosphere and the ocean is bility of an increase in the rate constant of considerable interest. The present for the decomposition of the enzymemeasurements may add some informa-substrate complex into products (k3) tion to the data discussed previously in must await extensive purification of the the literature (5). The new data cannot enzyme before it can be tested. However, be fitted into the picture, however, be-several kinetic parameters, such as the fore an international C14 standard is Michaelis constant (Ks), the equilibrium available. Such a standard will permit constant for inhibitor binding (Ki), and the expression of all activities relative the enthalpy of activation of the reaction to the same standard.(AH*) can be measured even in a crude H. DE VRIES system (bearing in mind the possibility Natuurkundig Laboratorium, that other substances present in the en-Groningen, Netherlands zyme preparation might affect the values of these parameters). In all of the ex-References and Notes periments reported here, conditions were 1. I acknowledge the measurement of the C13/C12
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