Genome-wide association studies of albuminuria: towards genetic stratification in diabetes?

Abstract

Genome-wide association studies (GWAS) have been very successful in unraveling the polygenic structure of several complex diseases and traits. In the case of albuminuria, despite the large sample size achieved by some studies, results look sparse with a limited number of loci reported so far. This review searched for GWAS studies of albumin excretion, albuminuria, and proteinuria. The resulting picture sets elements of uniqueness for albuminuria GWAS with respect to other complex traits. So far, very few loci associated with albuminuria have been validated by means of genome-wide significant evidence or formal replication. With rare exceptions, the validated loci are ethnicity specific. Within a given ethnicity, variants are common and have relatively large effects, especially in the presence of diabetes. In most cases, the identified variants were functional and a biological involvement of the target genes in renal damage was established. Recently reported variants associated with albuminuria in diabetes may be potentially combined into a genetic risk score, making it possible to rank diabetic patients by increasing risk of albuminuria. Validation of this model is required. To expand the understanding of the biological basis of albumin excretion regulation, future initiatives should achieve larger sample sizes and favor a transethnic study design.

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

“…There have been a few albuminuria GWASs in the past decade [10–12, 31], all exploring the common genetic variants (MAF>5%), but in the current study we examined low-frequency and rare variants, particularly from the coding region (exome) of the genome.…”

The UMOD Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

“…29,38 The strong transethnic differences in renal function regulation are especially highlighted in the study of albuminuria. 32 For the UACR trait, a few but well characterized loci have been identified, including the CUBN gene identified in European, black, and Southern American populations 39,40 ; the RAB38 and HS6ST1 genes identified in diabetic European ancestry subjects 27 ; the BCL2L11 gene identified via genome-wide admixture analysis in Amerindians 41 ; and the HBB gene identified via candidate gene approach but showing genome-wide significance in Africans and Southern Americans. 42 In contrast with the successful GWASs of CKD-defining traits, it has been difficult to perform GWASs of clinically defined CKD (i.e., kidney damage or GFR,60 ml/min per 1.73 m 2 for at least 3 months).…”

“…Of note, the latter GWASs have been successful in small-to modestsized cohorts in identifying common alleles that confer large effects. 12 To date, without including studies on diabetic nephropathy, there are .20 GWASs of CKD-defining traits, 10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] including one in pediatric subjects 25 and two on renal decline. 24,30 Of these studies, only a few considered the study of CKD in addition to eGFRcrea or UACR.…”

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

“…Levels of UACR have a heritable component in population-based studies and groups at high risk of CKD, such as certain indigenous populations or persons with diabetes 16–20 . However, the identification of genetic loci for UACR through genome-wide association studies (GWAS) has proven difficult, and detected loci showed variable effects across ancestries or disease groups 21 . Initial GWAS of UACR identified only two genome-wide significant loci, CUBN 22,23 and HBB 24 .…”