Chronic kidney disease (CKD), affecting over 26 million Americans, frequently leads to kidney failure. More than 100,000 individuals develop end stage kidney disease (ESKD) annually and nearly 500,000 receive kidney transplants or are ongoing dialysis patients at an annual cost of $30 billion dollars. Previously, we used admixture mapping to localize a region on chromosome 22 associated with focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN). Subsequently, we and others showed that APOL1 coding variants within this region comprising 2 missense variants in absolute linkage disequilibrium (G1 allele) and an in frame 6 base pair deletion (G2 allele) were responsible for the association, with OR of 7, 19, and 27 for hypertensive ESKD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN), respectively. ApoL1 provides protection against infection with Trypanosoma brucei brucei. The APOL1 risk alleles emerged recently in sub-Saharan Africa, but are found in other regions of the world as a result of the African Diaspora. The combined frequencies of G1 and G2 alleles are approximately 35% in African Americans. These alleles explain nearly all the excess risk of kidney disease in African Americans, thus providing a genetic basis for a major global health disparity. We have continued our studies of APOL1 to determine if the risk variants are associated with other non-renal or renal phenotypes that show racial disparities, such as papillary renal cancer and cardiovascular disease, in collaborative studies with intramural and extramural investigators. We have now extended our research to investigate the independent and interactive effects of sickle cell trait on cardiovascular and kidney diseases. Accomplishments 1) Sickle cell trait (SCT) and the risk of end stage renal disease (ESKD) in African Americans (AA). Compared to whites, African Americans have nearly 4-fold increased risk for ESKD, much of which is attributable to APOL1 renal risk variants. We sought to determine if SCT and hemoglobin C trait had an independent role in ESKD. We evaluated nearly 10,000 African Americans enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) and determined that incident rates for carries of SCT were 2-fold higher than for non-carriers (8.5 versus 4.0/1000 person years), with a hazards ratio (HR) for ESKD of 2.2, which is similar to the risk incurred by carriage of APOL1 renal risk variants. These results have important public health policy implications for genetic counseling of SCT carriers with chronic kidney disease. 2) Using genetic data provided by our laboratory, academic investigators found that a tripartite complex of suPAR (soluble urokinase plasminogen activator receptor), APOL1 risk variants, and integrin is responsible for decline in kidney function. Mechanistically, the APOL1 variant alleles have a higher affinity for suPAR, which augments integrin activation leading to proteinuria in mice. In humans decline in kidney function in patients with APOL1 high risk genotypes is positively correlated with suPAR levels. 3) The role of APOL1 risk variants in cardiovascular disease is conflicted with some studies showing a protective association and others reporting a susceptible or no association. We found that APOL1 high risk genotypes were not associated with hypertension in young adults with preserve kidney function enrolled in the CARDIA study and were not associated with cardiovascular disease (CVD) in persons with chronic kidney disease (CKD). On the other hand, we find a 2-fold increased risk of stroke and trend towards increased risk of myocardial infarction in patients without the well-established CVD risk factors of diabetes or chronic kidney disease. In participants with albuminuria, chronic kidney disease or diabetes, we found no association between APOL1 and CVD events. Previous studies reporting a positive association between APOL1 and CVD were performed in the general population whereas studies reporting a negative (protective) or no association were performed on cohorts with CKD or diabetes, which masked the independent association of APOL1 with CVD. 4) Constitutive expression of both wildtype and variant APOL1 in transgenic mice causes loss of pups and preeclampsia and death of the mothers. Incidence rates for preeclampsia are higher for African Americans and Africans compared to Europeans. In two cohorts, we found that carriage of APOL1 high risk genotypes by the fetus, but not the mother, increases the risk of preeclampsia by two-fold. We are now investigating genetic modifiers of APOL1-associated preeclampsia and RNA transcriptional profiles in APOL1 high and low risk placentas from mothers with and without preeclampsia to better understand the pathogenic mechanisms and perturbed pathways. 5) In a collaboration with researchers at John Hopkins University, we performed a genome wide association study to identify genetic factors associated with decline in glomerular filtration rate. We identified and replicated SNPs in the LINC00923 RNA gene expressed in the kidney with CKD progression in both European- and African Americans. 5) Hemophilia A is a congenital bleeding disorder that is characterized by recurrent hemorrhages into major joints. We performed a genome wide association study to identify genetic factors associated with abnormalities in range of motion (ROM) in the major joints in children with hemophillia enrolled in a longitudinal cohort study. We found a number of genetic variants that were associated with either increased or decreased ROM abnormalities but none that reached the genome-wide significance threshold. However, this study supports the likelihood that genetic variants contribute to risk for hemophilic arthropathy and paves the path for future studies to advance precision treatment to improve outcomes in the hemophilic population. 6) We have also contributed DNA samples, genotyping data, and expertise to several important genetic studies. Mesoamerican samples collected in remote villages in Oaxaca Mexico over 20 years ago have been used for a series of studies to understand the genetic architecture of asthma in Hispanics. The same samples were used in the Simons Genome Diversity project that sequenced genomes for 300 individuals representing 142 diverse populations. This study revealed key features of the landscape of human diversity, rate of the accumulation of mutations since the divergence of non-Africans compared to Africans, and that the ancestry of indigenous Australians, New Guineans, and Andamanese is shared with other non-Africans, indicating that these groups were not from an earlier dispersal out of Africa. These insights will be important not only for understanding the history of modern humans but also in understanding the role of environmental factors that shaped the human genome and contribute to genetic diversity and population-specific susceptibility to disease.
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