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 dialysis or kidney transplants at an annual cost of $30 billion dollars. The three leading causes of ESKD are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end ESKD compared to their white counterparts. Focal segmental glomerulosclerosis (FSGS) is the leading cause of primary nephritic syndrome in adults and the leading cause of ESKD in children. FSGS represents a syndrome that includes idiopathic forms and forms associated with reduced nephron numbers, hypertension, and HIV-1 infection. Previously, we used admixture mapping to localize a region on chromosome 22 associated with FSGS and HIV-associated nephropathy (HIVAN). The strongest signal was centered on MYH9, encoding myosin IIA, a plausible candidate gene. Subsequently, coding variants comprising 2 missense variants (G1 allele) in absolute linkage disequlibrium and an inframe 6 basepair deletion (G2 allele) were identified in the APOL1 gene encoding apolipoprotein 1 (APOL1). The APOL1 coding variants were more strongly associated with FSGS than were the MYH9 variants. ApoL1 provides protection against infection with Trypanosoma brucei brucei;the APOL1 G1 and G2 risk alleles restore protection against T. b. rhodesiense, a cause of sleeping sickness in heterozygotes. APOL1 G1 and G2 alleles have been under recent positive selection resulting in haplotype homozygosity across the region comprising MYH9/APOL1. 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 frequencies of G1 and G2 alleles are approximately 35% in African Americans and 60% in Yoruba from Nigeria. 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 this genetic region to determine if these risk variants are associated with other non-renal or renal phenotypes. We are also determining if APOL1 variants in the donor or recipient are associated with donor graft survival. Accomplishments 1. FSGS and collapsing glomerulopathy are common causes of nephrotic syndrome. Variants in over 20 genes have been associated with podocyte glomerulopathies, including genes critical for mitochondrial function. PDSS2 is required for synthesis of the decaprenyl tail of coenzyme Q10 in humans. The mouse gene Pdss2 is mutated in the kd/kd mouse model of collapsing glomerulopathy, a histology seen in HIV-associated nephropathy in humans. We examined the hypothesis that human PDSS2 polymorphisms are associated with FSGS or collapsing glomerulopathy by genotyping 377 cases with primary FSGS or collapsing glomerulopathy and 900 controls, for nine single nucleotide polymorphisms (SNPs) in the PDSS2 gene in a case-control study. Among European Americans (EA), a pair of proxy SNPs was significantly associated with podocyte disease, and patients homozygous for one PDSS2 haplotype had a strongly increased risk for podocyte disease. By contrast, the distribution of PDSS2 genotypes and haplotypes were similar in AA cases and controls. Thus, a PDSS2 haplotype, which has a frequency of 13% in the EA control population and a homozygote frequency of 1.2%, is associated with a significantly increased risk for FSGS and collapsing glomerulopathy in EA. Lymphoblastoid cell lines (LCLs) from FSGS patients had significantly less coenzyme Q10 than cell lines from controls;unexpectedly this finding was independent of PDSS2 haplotype. These results suggest that FSGS patients have coenzyme Q10 deficiency, and that this deficiency is manifested in patient-derived LCLs. This study was published in the American Journal of Renal Physiological. 2. A series of studies have shown that the higher rates of the most common causes of chronic kidney disease in persons of African ancestry is due to APOL1 variants that under positive selection by Human African Trypanosomiasis (HAT). These variants are found in or near the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. To explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. As we previously showed in African samples from the human genome diversity project allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). We hypothesized that two new variants that showed signals of recent selection might be associated with HAT resistance as they occurred within domains required for lysis of trypanosomes. We are now exploring the association of these new variants with HAT resistance and CKD. This study was published in the American Journal of Human Genetics. 3) To examine the role of APOL1 risk variants in African Americans with kidney disease attributed to hypertension, we studied the association of APOL1 alleles on renal end points in in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. In this cohort, randomized to two treatment arms and to two blood pressure targets there was relentless progression to end stage renal disease regardless of treatment arm. To better understand this, coding variants in the apolipoprotein L1 (APOL1) was evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a study comprising 675 AASK participant cases and 618 non-nephropathy control individuals. APOL1 G1 and G2, along with 44 ancestry informative markers, were genotyped and analyzed by logistic regression multivariable models. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, the association was strengthened with odds ratios of 4.61-6.29. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. This study was published in Kidney International. 4) The development of inhibitory antibodies to factor VIII in people with hemophilia A is a complex process involving multiple genetic and environmental factors, including the type of F8 mutation that causes the deficiency. To investigate the genetic basis for inhibitor development we developed the The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort comprising 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using the Illumina iSelect platform, we designed a panel of 13 331 single-nucleotide polymorphisms from 1081 immune response and immune modifier genes. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status. Of the 53 markers, 13 had meta P .001. Eight of the 53 were significant predictors among the discordant pairs. These results indicate that the genetic contribution to inhibitor development is complex and likely involves many genes or pathways. This study was published in Blood.
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|Gasser, David L; Winkler, Cheryl A; Peng, Min et al. (2013) Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10. Am J Physiol Renal Physiol 305:F1228-38|
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