A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy

Skorecki, Karl; Lee, Jessica H.; Langefeld, Carl D.; Tzur, Shay; Wasser, Walter G.; Shemer, Revital; Hawkins, Gregory A.; Divers, Jasmin; Parekh, Rulan S.; Li, Man; Sampson, Matthew G.; Kretzler, Matthias; Pollak, Martin R.; Shah, Shrijal S.; Blackler, Daniel; Nichols, Brendan; Wilmot, Michael; Alper, Seth L.; Freedman, Barry I.; Friedman, David J.

doi:10.1093/ndt/gfw451

Cited by 30 publications

(25 citation statements)

References 26 publications

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“…Interestingly, the APOL3 LoF variant was also recently associated with nephropathy independently of the effect of the two late-onset kidney diseaserisk APOL1 variants, which are not in strong linkage disequilibrium with rs11089781 (77). A physical interaction occurs between APOL1 and APOL3 (77), and APOL1 may protect against pathogens more effectively when not bound to APOL3. Similar mechanisms may, therefore, be involved in the positive selection of the APOL1 kidney disease-risk alleles and the APOL3 LoF variant in African populations.…”

Section: Discussionmentioning

confidence: 99%

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Rausell

Luo

Lopez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a knownFUT2variant that confers resistance to intestinal viruses, and anAPOL3variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.

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Section: Discussionmentioning

confidence: 99%

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Rausell

Luo

Lopez

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, the APOL3 LoF variant was also recently associated with nephropathy independently of the effect of the two kidney disease-risk APOL1 variants, which are not in strong linkage disequilibrium with rs11089781 (69). A physical interaction occurs between APOL1 and APOL3 (69), and APOL1 may protect against pathogens more effectively when not bound to APOL3.…”

Section: Discussionmentioning

confidence: 99%

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Rausell

Luo

Lopez

et al. 2019

Preprint

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Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups.No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the known FUT2 mutant allele conferring resistance to intestinal viruses and an APOL3 variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes.Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival. Significance statement.Human genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are 3 undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival. 4

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“…9 For example, a null variant in the nearby apolipoprotein L3 gene ( APOL3 ) on chromosome 22q reproducibly interacts with APOL1 -mediated risk for CKD in targeted analyses. 10 Roles for non- APOL genes in ESRD have been sought in a genome-wide association study (GWAS) using pooled DNA, a combined Wake Forest School of Medicine (WFSM)/National Institute of Diabetes and Digestive and Kidney Disease “Family Investigation of Nephropathy and Diabetes” (FIND) report and in the African American Study of Kidney Disease and Hypertension (AASK). 11;12 Initial results suggested that variation in or near the podocin ( NPHS2 ), serologically defined colon cancer antigen 8 ( SDCCAG8 ), bone morphogenetic protein 4 ( BMP4 ), and glutathione s-transferase mu 1 genes ( GSTM1 ) might interact with APOL1 to alter risk of CKD.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strong APOL1–second gene interactions

Langefeld

Comeau

et al. 2018

Kidney International

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African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.

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A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy

Abstract: Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.

Cited by 30 publications

References 26 publications

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strong APOL1–second gene interactions

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