Genetic and environmental factors play an important role in the etiology of nephrolithiasis. This project willbuild on and extend our previous efforts (examining environmental risk factors for stone formation) byallowing us to study the risk of stone formation associated with specific genes and gene-environmentinteractions. We will take advantage of previously collected data in three large cohort studies: Nurses'Health Study I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health ProfessionalsFollow-up Study (n=51,000 men). Over a period of 14 to 24 years, information has been collectedprospectively on important exposures including diet, family history, body size measures, past medicalhistory, and medications. We have confirmed over 1600 incident cases of kidney stones in each cohort andare in the process of identifying additional incident cases (DK59583, PI Curhan). Further, we have collected24-hour urine samples from over 3000 cases and controls and will collect another ~1000 over the next threeyears; the majority of participants have performed two collections. Using a nested case-control design, theprimary objective of this project is to examine the role of specific genetic risk factors for incidentnephrolithiasis. The secondary objective is to explore interactions between the genetic factors, dietaryfactors (particularly calcium intake) and risk of incident stone formation. The final objective is to examine theimpact of these genetic factors and gene-environment interactions on 24-hour urinary excretion of relevantlithogenic factors. This project will interact with each of the other projects and cores. Polymorphisms andhaplotypes from Projects 1-3, as well as additional gene candidates identified from the Genetics Core, willgreatly enhance the scope and depth of this study, and will increase the likelihood of identifying clinicallymeaningful associations between genetic factors/diet, the urinary supersaturation of calcium salts/andkidney stone formation. A P-value of 0.001 will be used as the threshold for statistical significance to reducethe likelihood of false-positive associations. These findings should provide insight into new approaches forprevention of stone formation.
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