GWAS in people of Middle Eastern descent reveals a locus protective of kidney function—a cross-sectional study

Abstract

Background Type 2 diabetes is one of the leading causes of chronic kidney failure, which increases globally and represents a significant threat to public health. People from the Middle East represent one of the largest immigrant groups in Europe today. Despite poor glucose regulation and high risk for early-onset insulin-deficient type 2 diabetes, they have better kidney function and lower rates of all-cause and cardiovascular-specific mortality compared with people of European ancestry. Here, we assessed the genetic basis of estimated glomerular filtration rate (eGFR) and other metabolic traits in people of Iraqi ancestry living in southern Sweden. Methods Genome-wide association study (GWAS) analyses were performed in 1201 Iraqi-born residents of the city of Malmö for eGFR and ten other metabolic traits using linear mixed-models to account for family structure. Results The strongest association signal was detected for eGFR in CST9 (rs13037490; P value = 2.4 × 10−13), a locus previously associated with cystatin C-based eGFR; importantly, the effect (major) allele here contrasts the effect (minor) allele in other populations, suggesting favorable selection at this locus. Additional novel genome-wide significant loci for eGFR (ERBB4), fasting glucose (CAMTA1, NDUFA10, TRIO, WWC1, TRAPPC9, SH3GL2, ABCC11), quantitative insulin-sensitivity check index (METTL16), and HbA1C (CAMTA1, ME1, PAK1, RORA) were identified. Conclusions The genetic effects discovered here may help explain why people from the Middle East have better kidney function than those of European descent. Genetic predisposition to preserved kidney function may also underlie the observed survival benefits in Middle Eastern immigrants with type 2 diabetes.

Identification of ligand and receptor interactions in CKD and MASH through the integration of single cell and spatial transcriptomics

“…Moreover, there is evidence that ERBB4-IR plays a role in CKD [ 47 , 50 ] and diabetic nephropathy [ 51 , 52 ]. While these studies support the importance of ERBB4 in renal diseases in mice, limited human results are available to support these findings [ 53 ]. Our data suggests that expression of ERBB4 is increased in human CKD and plays a role in the pathogenesis by increased paracrine signaling between proximal tubules, descending thin limb cells and endothelial cells.…”

Epigenome wide association study in peripheral blood of pregnant women identifies potential metabolic pathways related to gestational diabetes

“…Although our DMPs are different from their work, the location of both our CPGs and theirs are in the body region, meaning that the biological response may be similar. Finally, different studies have shown an association between polymorphisms in CAMTA1 and carbohydrate metabolism such as blood lipid traits and blood pressure [ 30 ], fasting glucose [ 31 ] and T2DM [ 32 ].…”

Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis

“…Two complex fundamental features define DKD: the decline of estimated glomerular filtration rate (eGFR) and the presence of proteinuria; hence, it would be better to combine these phenotypes during analysis, to incorporate DM and hypertension-related CKD. However, previous research on GWAS phenotypes for DKD or CKD was confined to the assessment of single phenotypes, such as uric acid, eGFR, ESRD, and proteinuria, and failed to focus on defining DKD [11][12][13][14][15][16][17][18][19]21]. Hypertension is both an underlying risk factor and a consequence of DKD due to persistent high blood pressure in the arteries around the kidney [22].…”

“…In addition, although there are few studies on decreased renal function in middle Eastern descent [21], Japanese [17,27] and Han Chinese [18] populations, most studies were conducted on the European and African-American populations [7,[12][13][14][15][16]19]. There is a need for GWAS on DKD in large-scale Korean multicohorts.…”