rs71785313

mixedMag 7.8

This is a inframe deletion variant in the APOL1 gene.

Key Literature Trait Associations

Focal Segmental Glomerulosclerosis

The APOL1 G2 deletion (rs71785313), in combination with the G1 variant, defines a recessive high-risk genotype conferring dramatically elevated risk of biopsy-confirmed focal segmental glomerulosclerosis (FSGS). The landmark 2010 Science study by Genovese et al. found an OR of 10.5 (95% CI 6.0–18.4) for FSGS among African Americans carrying two APOL1 risk alleles. The risk is largely recessive — individuals with a single G2 allele have minimal excess risk — and the mechanism involves gain-of-function APOL1 ion channel activity causing podocyte injury. APOL1 G2 is essentially absent in European populations, making this a population-specific risk allele of unusually large effect size.

Genovese G et al. “Association of trypanolytic ApoL1 variants with kidney disease in African Americans.” Science (new York, N.y.) (2010)

Allele DEL

OR 10.50

p 1.0e-23

N 385

Small GWAS

African American

Ge M et al. “APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis.” Human Molecular Genetics (2021)

Allele DEL

OR —

p —

Candidate gene study

multi-ancestry

HIV-associated nephropathy

Among people living with HIV of African ancestry, carrying two APOL1 high-risk alleles (including G2/rs71785313) confers dramatically elevated risk of HIV-associated nephropathy (HIVAN). A 2023 systematic review and meta-analysis of 14 studies (n=11,069) found OR 16.67 (95% CI 10.22–27.19) for HIVAN, OR 4.65 for CKD, and OR 2.58 for proteinuria among two-allele carriers. In a cohort of 431 HIV-infected African American women, those with two risk alleles had 104% higher albumin-creatinine ratios and 3.4-fold greater rates of 10% annual eGFR decline. HIV infection appears to act as a 'second hit' amplifying APOL1-mediated podocyte injury.

Waziri B et al. “Apolipoprotein L1 gene variants and kidney disease in patients with HIV: a systematic review and meta-analysis.” Journal of Nephrology (2023)

Allele DEL

OR 16.67

p —

N 11,069

Meta-analysis

multi-ancestry (predominantly African)

Jotwani V et al. “APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV.” American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation (2015)

Allele DEL

OR 2.00

p 1.0e-3

N 431

Candidate gene study

African American

Chronic Kidney Disease

Carriers of two APOL1 high-risk alleles (including G2/rs71785313) have significantly elevated rates of CKD incidence, faster eGFR decline, and markedly higher rates of progression to end-stage kidney disease. A 2021 meta-analysis of 10 prospective studies found RR 1.41 (95% CI 1.14–1.75) for CKD incidence and RR 1.70 (95% CI 1.44–2.01) for CKD-to-ESRD progression, with annual eGFR decline 0.55 mL/min/1.73m² greater than low-risk carriers. In the 121,492-participant Million Veteran Program, high-risk APOL1 genotype was associated with OR 3.94 (95% CI 3.52–4.41) for ESKD. Risk is predominantly observed in individuals of African ancestry, where ~18% carry two high-risk alleles.

Jagannathan R et al. “Association Between APOL1 Genotype and Kidney Diseases and Annual Kidney Function Change: A Systematic Review and Meta-Analysis of the Prospective Studies.” International Journal of Nephrology and Renovascular Disease (2021)

Allele DEL

OR —

β -0.550

p —

Meta-analysis

African American

Hung AM et al. “Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease.” Journal of the American Society of Nephrology : Jasn (2023)

Allele DEL

OR 3.94

p —

N 150,582

Preliminary work

African American

Ekrikpo UE et al. “Association of Genetic Polymorphisms of TGF-β1, HMOX1, and APOL1 With CKD in Nigerian Patients With and Without HIV.” American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation (2020)

Allele DEL

OR 2.54

p —

N 1,195

Preliminary work

West African (Nigerian)

Matsha TE et al. “APOL1 genetic variants, chronic kidney diseases and hypertension in mixed ancestry South Africans.” Bmc Genetics (2015)

Allele DEL

OR —

p 2.5e-2

N 859

Preliminary work

South African mixed-ancestry

Trypanosomiasis resistance

The APOL1 G2 deletion (rs71785313) evolved under strong positive selection in sub-Saharan Africa because it confers lytic activity against Trypanosoma brucei rhodesiense, the causative agent of East African sleeping sickness. The landmark 2010 Genovese et al. Science paper demonstrated in vitro trypanolytic activity of the G2 variant against T. b. rhodesiense, which had evolved resistance to the ancestral APOL1 protein. This evolutionary trade-off — protection against a lethal parasite at the cost of kidney disease susceptibility in modern environments — explains why G2 reached high frequencies (~15–20%) in West African populations despite its severe renal consequences.

Genovese G et al. “Association of trypanolytic ApoL1 variants with kidney disease in African Americans.” Science (new York, N.y.) (2010)

Allele DEL

OR —

p —

N 385

Candidate gene study

African American

Gene information from NCBI Gene. Variant classifications from ClinVar.

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