Introduction:
Genome wide association studies have identified genetic variants in the
Cubillin
gene (
CUBN
) that explain inter-individual variation in urine albumin-to-creatinine excretion (UACR) in populations. These studies have not included Hispanics/Latinos, the fast growing minority population in the U.S., who has also high prevalence of chronic kidney disease and its risk factors.
Hypothesis:
By leveraging on population admixture of Hispanics and using a genome wide association approach, we hypothesized that novel loci associated with UACR would be identified.
Methods:
We used data from 12,212 self-identified Hispanic individuals recruited in a community-based study, aged 18-74 years at screening (2008-2011), and randomly selected from households in four U.S. field centers (Chicago, IL; Miami, FL; Bronx, NY; San Diego, CA). Urine albumin (mg/dl) and creatinine (g/dl) were measured at the baseline exam. UACR was log-transformed for analysis. Individuals were excluded if reporting to have end-stage renal disease. Genotyping was performed using a custom Illumina Omni2.5M array. Imputation of variants was performed using 1000 Genome Project data from cosmopolitan HapMap samples. After quality control of imputed data, we performed mixed linear regression analyses that accounted for the sampling strategy and family relatedness, for variants with minor allele frequency (MAF) > 0.01 and imputation quality > 0.3. We used additive genetic models and adjusted for age, sex, and principal components which were estimated from the data. In a secondary analysis, we also examine the association of significant variants with kidney function using estimated glomerular filtration rate (eGFR) equations.
Results:
Among 12,212 participants, 41% were men, and mean age was 46 (SD =13). There was little evidence for genome wide inflation (lambda =1.024). We identified significant associations of single nucleotide polymorphisms (SNPs) with UACR at two loci:
CUBN
and
HBB
. The
CUBN
SNP (chr10:16966414, p=2.1x10-8) is an indel variant with MAF of 0.14, which was not in linkage disequilibrium with previously reported SNP rs1801239 (rsq=0.38, p=1.3x10-4) identified in individuals of European ancestry. The
HBB
SNP is a missense variant which results in an E [Glu] ⇒ A [Ala] substitution in the beta-globin chain of hemoglobin and a cause of the Mendelian disorder sickle cell anemia (rs334, T allele frequency =0.01, beta=0.44, SE=0.06, p=7.6x10-12). rs344 was not associated with eGFR in our data (p>0.05).
Conclusion:
This study identified a novel association of a sickle cell missense variant with UACR in Hispanics, and provided evidence for allelic heterogeneity at the
CUBN
locus. Our findings suggest a role for Mendelian gene variants in increased albuminuria in Hispanic populations with admixture.
Nuclear genome-wide associations with mitochondrial heteroplasmy
