The Association of Podocin R229Q Polymorphism With Increased Albuminuria or Reduced Estimated GFR in a Large Population-Based Sample of US Adults

Köttgen, Anna; Hsu, Charles C.; Coresh, Josef; Shuldiner, Alan R.; Berthier-Schaad, Yvette; Gambhir, Tejal Rami; Smith, Michael W.; Boerwinkle, Eric; Kao, W.H. Linda

doi:10.1053/j.ajkd.2008.02.306

« Previous Next »American Journal of Kidney Diseases
Volume 52, Issue 5 , Pages 868-875, November 2008

The Association of Podocin R229Q Polymorphism With Increased Albuminuria or Reduced Estimated GFR in a Large Population-Based Sample of US Adults

Anna Köttgen, MD, MPH
- Johns Hopkins University, Baltimore, MD
Charles C. Hsu, PhD
- Johns Hopkins University, Baltimore, MD
Josef Coresh, MD, PhD
- Johns Hopkins University, Baltimore, MD
Alan R. Shuldiner, MD
- University of Maryland, Baltimore, MD
Yvette Berthier-Schaad, PhD
- Johns Hopkins University, Baltimore, MD
- Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD
Tejal Rami Gambhir, MPH
- Johns Hopkins University, Baltimore, MD
Michael W. Smith, PhD
- Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD
- Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD
Eric Boerwinkle, PhD
- University of Texas, Houston, TX
W.H. Linda Kao, PhD, MHS
- Johns Hopkins University, Baltimore, MD
- Address correspondence to W.H. Linda Kao, PhD, MHS, 615 N Wolfe St, Rm W6513, Baltimore, MD 21205

Received 8 November 2007; accepted 14 February 2008. published online 22 May 2008.

Background

Rare mutations in nephrosis 2 (NPHS2), encoding podocin, are found in patients with familial and sporadic steroid-resistant nephrotic syndrome and focal segmental glomerular sclerosis. The objective of this study is to assess the contribution of the commonly reported functional podocin polymorphism R229Q to kidney disease in the population at large and replicate a prior study of an association of R229Q and albuminuria in the general population.

Study Design

Large sample of the Atherosclerosis Risk in Communities (ARIC) Study, a population-based prospective study.

Setting & Participants

4,424 white and 3,746 black middle-aged adults.

Predictor

Genotype at the R229Q polymorphism in podocin.

Outcomes

Urinary albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) as measures of kidney damage/dysfunction.

Measurements

Crude and multivariable adjusted linear and logistic regression models.

Results

R229Q allele frequencies were 3.7% in 4,424 white and 0.6% in 3,746 black individuals. No significant association of R229Q with increased ACR or decreased eGFR was observed (adjusted odds ratio of ACR ≥ 30 mg/g in RQ/QQ versus RR carriers, 1.18; 95% confidence interval, 0.76 to 1.84; adjusted odds ratio of eGFR < 60 mL/min/1.73 m² in RQ/QQ versus RR carriers, 1.18; 95% confidence interval, 0.76 to 1.83). As expected, the established kidney disease risk factors hypertension and diabetes mellitus were associated strongly with measures of kidney damage/dysfunction, but the R229Q polymorphism was not associated with an additional increase in kidney disease measures.

Limitations

Single measurement of ACR, subsample of all ARIC participants.

Conclusion

No significant association of the relatively rare R229Q variant and ACR or eGFR was found in either white or black individuals. The phenotypic effect of a variant as R229Q would have to be of great magnitude to meaningfully contribute to the risk of kidney disease on a population level. The importance of such variants in the general population, as well as replication studies, can be evaluated best in large community-based studies that allow for accounting of established disease risk factors.

Index Words: NPHS2, podocin, albuminuria, association study, functional variant, population-based sample