When we zoomed in on HLA in UK Biobank + 100KGP, we found:
👉 HLA-DQB1*03:19 strongly enriched in APOL1 carriers with early kidney failure (OR ~24, p=0.001) and West Africa!

Those with high-risk APOL1 also had:
🔹 Elevated steroid-sensitive nephrotic syndrome (SSNS) polygenic risk score
🔹 Signal driven by the HLA region

This suggested a second “immune hit.”

Among patients of African ancestry, high-risk APOL1 was hugely enriched:
📈 52% in uKF vs 8% in ancestry-matched controls.
Odds ratio ~9.

So APOL1 alone explains a lot. But we noticed something more…

Unexplained kidney failure (uKF) affects ~15% of patients needing dialysis/transplant.
We used whole-genome sequencing + large-scale case-control analyses (218 cases, >26k controls) to dissect the genetic architecture.

👉 17% of cases had a monogenic diagnosis (COL4A, NPHP1, etc).