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      Association of APOL1 variants with mild kidney disease in first-degree relatives of African American patients with non-diabetic end stage renal disease

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          Abstract

          Familial aggregation of non-diabetic end stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene ( APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2 percent of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared to one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated GFR (MDRD equation) and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.

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          Most cited references 25

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          Longitudinal Data Analysis Using Generalized Linear Models

           KY Liang,  S Z,  K. Liang (1986)
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            The APOL1 gene and allograft survival after kidney transplantation.

            Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox-proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow-up was 26.4 ± 21.8 months. Twenty-two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty-five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long-term renal allograft survival. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
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              The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.

              Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                11 May 2012
                13 June 2012
                October 2012
                01 April 2013
                : 82
                : 7
                : 805-811
                Affiliations
                [1 ]Department of Internal Medicine - Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina
                [2 ]Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
                [3 ]Department of Internal Medicine - Section on Infectious Disease, Wake Forest School of Medicine, Winston-Salem, North Carolina
                [4 ]Department of Biochemistry and Centers for Diabetes Research and Human Genetics, Wake Forest School of Medicine, Winston-Salem, North Carolina
                Author notes
                Correspondence: Barry I. Freedman, M.D., Section on Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1053, Phone:336-716-6192, Fax: 336-716-4318, bfreedma@ 123456wakehealth.edu
                Article
                NIHMS376103
                10.1038/ki.2012.217
                3443536
                22695330
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL056266 || HL
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK084149 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK070941 || DK
                Categories
                Article

                Nephrology

                african american, kidney, apol1, screening, fsgs, end-stage renal disease

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