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. Structural proteins expressed in podocytes are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space in the kidney. 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. We subsequently fine-mapped MYH9, but no obvious functional variants were identified. These intronic variants were common in African Americans and nearly absent from Europeans;they are strongly associated with FSGS, HIVAN, and ESKD attributable to hypertension, explaining nearly all the 4-fold excess risk for CKD and ESKD observed in African Americans. 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.Accomplishments1. We studied patients with biopsy proven idiopathic focal segmental glomerulosclerosis (FSGS) and HIVAN to define more precisely the genetic risk and to determine whether APOL1-associated FSGS has a distinct clinical phenotype. We determined APOL1 genotypes for 271 African American FSGS and HIVAN cases, 168 European American FSGS cases and 939 control subjects. In the recessive model, APOL1 variants were associated with OR 17 for FSGS and 29 for HIVAN compared to subjects with no or one APOL1 risk allele. The association with HIV is a robust example of a gene-environment interaction. For FSGS associated with two APOL1 risk alleles, compared to other FSGS patients, onset age was approximately a decade earlier and progression to ESKD was significantly faster. Two APOL1 risk alleles confer an attributable risk of 67% for FSGS and HIVAN and an explained fraction of 18% for FSGS and 35% for HIVAN;this is similar to the risk conferred by smoking for small-lung-cell carcinoma. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for FSGS and those with untreated HIV disease have a 50% lefetime risk for HIVAN. These data add to the evidence base required to define the role for APOL1 genetic testing in personalized medicine. These results were published in Journal of American Society of Nephrology.2. In spite of intensive blood pressure control with angiotensin converting enzyme inhibitors in subjects enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial, there was no significant effect on renal progression endpoints (creatinine doubling or ESKD). We evaluated the role of APOL1 G1 and G2 variants for association with hypertension-attributed nephropathy in 675 AASK participants with CKD and 618 African American non-nephrology controls. In a recessive model, APOL1 risk variants were significantly associated with clinical endpoints in AASK cases versus controls. (OR 2.57;p=1.4x10-8);the effects were slightly higher in participants with baseline proteinuria. We also found that APOL1 variants were associated with higher baseline urine protein/creatinine ratios (OR 6.29;p=2.6x10-14) and higher serum creatinine during follow-up (OR 4.61;p=5.6x10-15). In summary, nephropathy risk variants in the APOL1 gene are significantly associated with CKD attributed to essential hypertension in non-diabetic AASK participants. The results were most robust in individuals with progressive renal functional decline and higher baseline levels of proteinuria. It is unlikely that these variants are associated with essential hypertension per se, as results were consistent when comparing hypertensive AASK cases to controls with and without high blood pressure. These results strongly suggest that progressive kidney disease attributed to hypertensive nephrosclerosis and characterized by focal global glomerulosclerosis, arteriolar nephrosclerosis and interstitial scarring, commonly present in the renal biopsies of AASK participants, belongs to the same disease spectrum as idiopathic FSGS and HIVAN. These results were published in Kidney International.3. APOL1 variants do not explain all of the risk for kidney disease in persons with hypertension nor do they associate with hypertension. Using a case only design, we have genotyped the AASK cohort for 1750 ancestry informative markers to detect association using an admixture mapping by linkage disequilibrium strategy. In brief, we compare each marker for ancestry using a hidden Markoff chain analysis. Regions-of-interest harboring the causal variation associated with kidney disease or hypertension, both more prevalent in African Americans, should show an increase in African ancestry relative to the rest of the genome. The genotyping and quality control steps have been completed and the software programs adapted for quantitative traits. 4. Our interest in common diseases with strong racial disparities prompted a study of keloid development in African Americans. Keloids, unlike hypertrophic scarring, overgrow the wound border and have a strong racial propensity;estimates for prevalence in the African American population range from 3-15%. With the exception of trauma, precise etiologic factors responsible for keloid formation have not been fully elucidated. Keloids are frequently associated with negative wound healing factors, such as infection, excessive tension, foreign bodies, and repetitive trauma;however, keloids may form in simple clean wounds. They generally first manifest in childhood and early adulthood;it is rare to see keloids develop after the third decade of life. We have collected multiple three-generation families segregating for keloids, where the mode of inheritance is autosomal dominant with incomplete penetrance. To date we have performed a linkage analysis using 800 microsatellite markers for 60 family members to localize the region linked to the keloid phenotype. We have obtained exome sequences for 12 affected and unaffected family members for identity by descent analysis. We have identified three regions showing LOD scores >2, but results to date suggest that the propensity to develop keloids is polygenic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010022-17
Application #
8552639
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$511,274
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Hyacinth, Hyacinth I; Carty, Cara L; Seals, Samantha R et al. (2018) Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis. JAMA Neurol 75:802-807
Franceschini, Nora; Kopp, Jeffrey B; Barac, Ana et al. (2018) Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women. JAMA Cardiol 3:712-720
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Chen, Teresa K; Tin, Adrienne; Peralta, Carmen A et al. (2017) APOL1 Risk Variants, Incident Proteinuria, and Subsequent eGFR Decline in Blacks with Hypertension-Attributed CKD. Clin J Am Soc Nephrol 12:1771-1777

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