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Investigator Names and Contact Information
Nora Franceschini [email@example.com]
This proposal relates to the request for scientific proposals that will expand the core research resource in WHI by adding needed genomic and phenotypic resources for kidney research in aging women, which will be available to WHI investigators. We propose to add core genotypes for characterization of chronic kidney disease (CKD) risk (APOL1 and sickle cell trait variants for women who will not be genotyped in PAGE2), and obtaining additional end-stage kidney disease (ESKD) events by linking the WHI data to the Medicare U.S. Renal Disease System (USRDS). Our overall goal is to study genes and its environmental modifiers that contribute to CKD in aging women, as proposed in the approved ancillary study AS476: "APOL1, sickle cell trait and chronic kidney disease in African Americans".
CKD is strongly associated with cardiovascular disease (CVD)1-3 and other health outcomes in aging including early mortality, disability and poor quality of life4. CKD progression to ESKD, a devastating condition requiring dialysis or kidney transplantation, is more common in African Americans compared to whites5. The higher risk in African Americans is attributed in part to variants in the APOL1 gene (G1 and G2 alleles, two copies required)6, 7, which confer 5- to 29-fold increased risk to ESKD in case-control studies, and a 2-fold risk to CKD in population studies. These risk alleles are observed in 10 to 12% of African Americans, and associate with a 4% lifetime risk of CKD in this population. Given their high prevalence and the strong genetic effects, the burden of CKD attributed to APOL1 among African Americans is likely substantial. The contribution of APOL1 genotypes to CKD and kidney function decline is less well-characterized in the population at-large. Only 10-15% of individuals with APOL1 risk alleles develop CKD. Among African Americans already with CKD, 60% experience further kidney function decline, suggesting the presence of additional genetic and/or environmental modifiers on CKD risk8.
We recently demonstrated that carriers of sickle cell trait (SCT), another common genetic condition which affects about 8% or approximately 3 million African Americans, have higher risk of CKD in a study of 15,975 African Americans from four studies9. The sickle cell mutation results from a functional single nucleotide polymorphism (SNP) involving the substitution of GTG (valine) for a GAG (glutamic acid) at the 7th amino acid position in the gene encoding beta-globin (HBB). Heterozygosity for the mutation in the presence of one normal HBB gene results in SCT. In our study, individuals with SCT showed a 58% increased risk of incident CKD (reduction in estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 at follow up, p<0.001), a 31% increased risk of rapid kidney function decline (>3 ml/min/1.73m2 per year, p=0.02), and a 88% increased risk of microalbuminuria, a measure of kidney damage (p<0.001)9. These findings suggest that SCT contributes to CKD risk observed in African Americans.
Our central hypothesis is that APOL1 and SCT risk variants interact to modify the risk of CKD in African Americans. We propose (1) to genotype the APOL1 risk alleles and the SCT variant, and (2) to obtain additional ESKD cases from the Medicare USRDS database beyond the currently funded date of June/2012. These resources will foster genetic and epidemiology research on CKD and its progression to ESKD in WHI aging women. Women have been understudied for CKD, and CKD complications likely impact healthy aging. Our preliminary data using a small subset of WHI women with sequencing and genotype data suggest poor imputation of APOL1 alleles, and support the need for direct genotyping of these alleles as requested in this proposal. This pilot study will also provide a larger set of genotypes for a study-specific reference panel for imputation of APOL1 alleles in additional African American women in WHI. Given the strong effect of APOL1 risk alleles on CKD risk in African Americans, the addition of these genotypes to WHI will impact epidemiologic and genetic research of CKD in African American aging women, which no longer can be performed without accounting for the APOL1 risk alleles.
Our hypothesis is that gene-gene interactions contribute to CKD risk and progression in African Americans. We therefore propose two aims:
Aim 1. Estimate APOL1 and SCT main and gene-gene interactive effects on CKD and incident ESKD in African American women, while accounting for lifestyle, comorbidities, and other risk factors.
Aim 2. Estimate the population impact for APOL1, SCT and their interactions on the burden of ESKD.