Clinical and genetic predictors of renal dysfunctions in sickle cell anaemia in Cameroon

Abstract

SUMMARY Micro-albuminuria and glomerular hyperfiltration are primary indicators of renal dysfunctions in Sickle Cell Disease (SCD), with more severe manifestations previously associated with variants in APOL1 and HMOX1 among African Americans. We have investigated 413 SCD patients from Cameroon. Anthropometric variables, haematological indices, crude albuminuria, albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured. Patients were genotyped for 3.7 kB alpha-globin gene (HBA1/HBA2) deletion, and for variants in APOL1 (G1/G2; rs60910145, rs73885319, rs71785313) and HMOX1 (rs3074372, rs743811). The median age was 15 years; the majority presented with micro-albuminuria (60.9%; n = 248), and approximately half with glomerular hyperfiltration (49.5%; n = 200). Age, male sex, haemoglobin level, leucocyte count, mean corpuscular volume, blood pressure, body mass index and creatinine levels significantly affected albuminuria and/or eGFR. Co-inheritance of alpha-thalassaemia was protective against macro-albuminuria (p = 0.03). APOL1 G1/G2 risk variants were significantly associated with the ACR (p = 0.01) and borderline with eGFR (p = 0.07). HMOX1 - rs743811 was borderline associated with micro-albuminuria (p = 0.07) and macro-albuminuria (p = 0.06). The results revealed a high proportion of micro-albuminuria and glomerular hyperfiltration among Cameroonian SCD patients, and support the possible use of targeted genetic biomarkers for risks assessment.

Clinical and genetic factors are associated with pain and hospitalisation rates in sickle cell anaemia in Cameroon

“…Two SNPs were monomorphic in both patients and controls: HBS1L-MYB -rs9376090 and ADRA2A -rs3750635; OPRM1 -rs1799971 was monomorphic among controls and very rare (0.001) in patients. Only the 3.7del α-globin gene genotypes (p = 0.005) were out of HWE; however, this deviation was expected in view of the strong protective effect of this genetic variant on SCD, as previously reported on Cameroonians (Geard et al , 2017, Rumaney et al , 2014). The skewness of VOC, and hospitalisation, consultation rates and haematological indices, was corrected by taking their natural logarithm to approximate normal distribution.…”

“…It is therefore reasonable to envisage expending future explorations with genome-wide association studies, and targeted deep sequencing of genes in the inflammatory pathways, in SCD patients living in Africa. Nearly half of the participants (46.6 %) had frequent VOC episodes, much higher than the 5.2% reported in the CSSCD (Platt et al , 1991), revealing a particular severity of this disease in Cameroon (Wonkam et al , 2014a; Njamnshi et al , 2006; Geard et al , 2017). But this higher rate of pain could also be attributed to a selection bias, due to hospital-based recruitment, and the cross-sectional and retrospective nature of the VOC phenotype.…”

“…SNP genotyping of rs60910145 ( APOL1 ), rs73885319 ( APOL1 ) and rs743811 ( HMOX1 ) was performed using predesigned TaqMan genotyping assays (Applied Biosystems, Foster City, CA, USA), and the genotyping of rs3074372 ( HMOX1 ) and rs71785313 ( APOL1 ) variants using fragment analysis, incorporating fluorescently-labelled forward primers (Geard et al , 2017). …”

The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait

“…Similarly, α-thalassemia was significantly associated with the absence of hyperfiltration in a young adult population of SCA patients [61]. Another recent study in a cohort of 413 SCD individuals from Cameroon also demonstrated a ‘protective’ association between α-thalassemia and macroalbuminuria [62]. …”

“…Another smaller study of 152 SCD patients in Europe failed to delineate a relationship between the HMOX1 rs743811 variant and kidney disease [70]. However, another study of young SCD patients (median age 15 years) from Cameroon demonstrated a trend to association between HMOX1 rs743811 and macroalbuminuria, although this did not quite reach statistical significance ( p = 0.06) [62]. While certainly not definitely associated with kidney disease in SCD, these HMOX1 variants do warrant additional examination, particularly due to their direct influence on heme catabolism and potential pathophysiologic role.…”