Kidney Week

Abstract: FR-PO1030

Exome-Wide Association Study for C3 Glomerulopathies

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Na, Young-Ji, Columbia University, New York, New York, United States

Young-Ji Na,

• Li, Yifu, Columbia University, New York, New York, United States

Yifu Li,

• Marasa, Maddalena, Columbia University, New York, New York, United States

Maddalena Marasa,

• Krithivasan, Priya, Columbia University, New York, New York, United States

Priya Krithivasan,

• Steers, Nicholas J., Columbia University, New York, New York, United States

Nicholas J. Steers,

• Sanchez, Elena, Columbia University, New York, New York, United States

Elena Sanchez,

• Goicoechea de jorge, Elena, Complutense University Madrid, Madrid, Spain

Elena Goicoechea de jorge,

• Praga, Manuel, Hospital 12 de Octubre, Pozuelo De Alarcon, Spain

Manuel Praga,

• Bomback, Andrew S., Columbia University, New York, New York, United States

Andrew S. Bomback,

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk,

• Rodriguez de Cordoba, Santiago, Consejo Superior de Investigaciones Cientificas, Madrid, Spain

Santiago Rodriguez de Cordoba,

• Appel, Gerald B., Columbia University College of Physicians and Surgeons, Scarsdale, New York, United States

Gerald B. Appel,

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi,

Background

C3 glomerulopathies (C3Gs) include a spectrum of rare diseases such as C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), which share phenotypic similarities and underlying genetic commonalities. Mutations in components of the complement pathway have been implicated, but the genetic underpinnings are largely unknown. The aim of this study is to use whole-exome sequencing to improve understanding of the genetic architecture of C3G.

Methods

We performed a case-control exome-wide collapsing analysis using 282 case subjects with C3Gs [C3GN, DDD, and immune complex-mediated MPGN] and 9,825 control subjects with no known kidney diseases. To identify risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples. We tested multiple models, including loss-of-function variants and non-benign nonsynonymous variants. We also applied regional intolerance model based on missense tolerance ratio (MTR).

Results

In multiple model, patients with C3G had a higher frequency of loss-of-function variants and non-benign nonsynonymous variants in Complement Factor H (P = 6.51 X 10^-07), C3 (P = 1.04 X 10^-04) in the dominant models and C5 (P = 0.0279) and CFB (P = 0.0279) in the recessive models. Rare putatively pathogenic variants were detected mainly among C3GN cases. In addition, we identified many signals that did not reach exome-wide significance but represent interesting candidate genes for C3Gs.

Conclusion

We identified excess ultra-rare variation in several known C3G genes under both dominant and recessive models. These data suggest that exome sequencing can discover rare risk alleles for C3Gs enhancing the established gene-mapping paradigms.

Funding

• NIDDK Support