Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994

BACKGROUND: 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. 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. METHODS: We 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. RESULTS: Variants 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. CONCLUSIONS: Our 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.