Genetic markers for urine haptoglobin is associated with decline in renal function in type 2 diabetes in East Asians

Resham Lal Gurung,Sylvia Liu,Yiamunaa M,Su Chi Lim,Rajkumar Dorajoo,Ling Wang,Lin Guo,Xueqing Yu,Jian-Jun Liu

doi:10.1038/s41598-018-23407-1

Abstract

Urine haptoglobin (uHP) level prospectively predicts diabetic kidney disease (DKD) progression. Here, we aim to identify genetic determinants of uHP level and evaluate association with renal function in East Asians (EA) with type 2 diabetes (T2D). Genome-wide association study (GWAS) among 805 [236 Chinese (discovery) and 569 (57 Malay and 512 Chinese) (validation)] found that rs75444904/kgp16506790 variant was robustly associated with uHP level (MetaP = 1.21 × 10−60). rs75444904 correlates well with plasma HP protein levels and multimerization in EA but was not in perfect LD (r2 = 0.911 in Chinese, r2 = 0.536 in Malay) and is monomorphic in Europeans (1000 G data). Conditional probability analysis indicated weakening of effects but residual significant associations between rs75444904 and uHP when adjusted on HP structural variant (MetaP = 8.22 × 10−7). The rs75444904 variant was associated with DKD progression (OR = 1.77, P = 0.014) independent of traditional risk factors. In an additional validation-cohort of EA (410 end-stage renal disease (ESRD) cases and 1308 controls), rs75444904 was associated with ESRD (OR = 1.22, P = 0.036). Furthermore, increased risk of DKD progression (OR = 2.09, P = 0.007) with elevated uHP level through Mendelian randomisation analysis provide support for potential causal role of uHP in DKD progression in EA. However, further replication of our findings in larger study populations is warranted.

Highlights

Urine haptoglobin level prospectively predicts diabetic kidney disease (DKD) progression
We identified a robust Genome-wide association study (GWAS) signal rs75444904 as an East Asian specific variant influencing Urine haptoglobin (uHP) level
Genetic disposition to higher uHP level in type 2 diabetes (T2D) patients was associated with higher risk for DKD progression independent of traditional risk factors including hypertension, hyperglycemia, diabetes duration, dyslipidemia as well as baseline renal function and usages of medications

Summary

Introduction

Urine haptoglobin (uHP) level prospectively predicts diabetic kidney disease (DKD) progression. A study among Veterans Affairs Diabetes Trial (VADT) subjects demonstrated that increased uHP level is associated with early renal function decline in DKD patients[8]. In a recent study in Chinese cohort with median follow-up of 5.3 years, Yang et al, showed that T2D individuals with microalbuminuria and elevated uHP level are most susceptible to development of CKD, as defined by eGFR < 60 mL/min/1.73 m2 10. Whether this association of uHP and renal function is causal remains unclear. Reverse causality could lead to a statistically robust but non-causal relationship[13]

Objectives

Results

Conclusion