Abstract
BackgroundAlbuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria.MethodsWe evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models.ResultsVariants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group.ConclusionsOur findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.
Highlights
Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease
Our results only minimally support a role for such polymorphisms in the establishment of normal urinary albumin excretion, since all but one individual genotype and few haplotypes were significantly associated with continuous log(ACR) after adjustment for multiple testing
This C-reactive protein (CRP) variant was the only polymorphism significantly associated with singlethreshold albuminuria in codominant models after correcting for multiple testing (FDR-P < 0.0001)
Summary
Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. Persistent kidney damage is a defining criterion for chronic kidney disease, a condition that exists in at least 12% of adults in the United States using data from 1999-2004 [1,2]. Albuminuria serves not just as an important marker of kidney damage and as a prognostic factor for the progression of kidney disease. In the U.S population, the estimated prevalence of microalbuminuria (typically defined as urinary albuminto-creatinine ratio (ACR) between 30 and 299 mg/g) is approximately 3% in adults without adverse health conditions, but is approximately 17% in hypertensive persons and approximately 29% in those with diabetes [6]
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