Elevated MBL Concentrations Are Not an Indication of Association Between the <i>MBL2</i> Gene and Type 1 Diabetes or Diabetic Nephropathy

Kaunisto, Mari A.; Sjolind, L; Sallinen, Riitta; Pettersson-Fernholm, Kim; Saraheimo, Markku; Fröjdö, Sara; Forsblom, Carol; Fagerudd, Johan; Hansen, Troels Krarup; Flyvbjerg, Allan; Wessman, Maija; Groop, Per‐Henrik

doi:10.2337/db08-1495

Cited by 33 publications

(23 citation statements)

References 24 publications

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“…In Kaunisto’s study, significant evidence of association was observed for rs920727 with patients with end-stage renal disease (ESRD) and normal UAE. However, after adjustment for the potential confounders no evidence of the association was observed [2]. In Hansen’s study, high MBL genotypes were significantly more frequent in diabetic patients with nephropathy than those with normal UAE, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 [7].…”

Section: Discussionmentioning

confidence: 94%

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Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy

Zhang

Zhuang

et al. 2013

PLoS ONE

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ObjectiveTo investigate the association of Mannose-binding lectin (MBL) and the MBL2 gene with type 2 diabetes and diabetic nephropathy and the influence of MBL2 polymorphisms on serum MBL levels.MethodsThe study population included 675 type 2 diabetic patients with or without nephropathy and 855 normoglycemic controls. The single nucleotide polymorphisms (SNPs) of rs1800450, rs1800451, and rs11003125 of the MBL2 gene were determined by the Multiplex Snapshot method. Serum MBL levels were measured by enzyme-linked immune sorbent assay.ResultsRs1800450 and rs11003125 SNPs demonstrated strong linkage disequilibrium in the study population (r2 = 0.97). The haplotypes constructed from the G allele of rs1800450 and the C allele of rs11003125 increased the risk for type 2 diabetes (OR = 1.2, 95% CI = 1.1–1.4, P = 0.01). For rs1800450, GG and GA genotypes were associated with type 2 diabetes (P = 0.02, 0.01, respectively). For rs11003125, the GC genotype frequency was significantly different between patients and controls (18.1% vs. 24.9%, P = 0.001). Analyses of genotypes and allele frequency distributions among patients with normal UAE, microalbuminuria, and macroalbuminuria showed that there was no obvious evidence of association between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels.ConclusionsThe rs1800450 and rs11003125 SNPs of the MBL2 gene have strong linkage disequilibrium and are associated with type 2 diabetes in the North Chinese Han population. No association was observed between the MBL2 gene and diabetic nephropathy. Subjects with the GG genotype of rs1800450 and the CC genotype of rs11003125 had much higher serum MBL levels. An association between elevated serum MBL and diabetic nephropathy was also observed.

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Section: Discussionmentioning

confidence: 94%

“…Most studies focused on the association of the MBL2 gene with type 1 diabetes and the conclusions were controversial [2], [23], [24]. Few studies have discussed the association between the MBL2 gene and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy

Zhang

Zhuang

et al. 2013

PLoS ONE

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“…Higher MBL concentrations early after the onset of type 1 diabetes may predict the development of nephropathy many years later [48] . Serum MBL concentrations are higher in type 1 diabetics with albuminuria and overt nephropathy [49,50] although this does not appear to relate to genotype. The effect of MBL on the development of diabetic nephropathy has been studied in MBL deficient mice with streptozotocin induced diabetes.…”

Section: Complement Function In Diabetic Nephropathymentioning

confidence: 90%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

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“…However, MBL concentrations are higher in patients with diabetes than in healthy subjects, despite similar MBL2 genotype distribution (2,6,12,13). Animal studies suggest this to be explained by a secondary increase in MBL concentration after diabetes induction (14).…”

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confidence: 84%

Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

et al. 2015

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OBJECTIVEMannan-binding lectin (MBL) is a complement-activating carbohydrate-recognizing molecule associated with diabetic nephropathy. MBL is associated with all-cause mortality in type 2 diabetes, but whether MBL is associated with mortality in type 1 diabetes remains unknown. We therefore aimed to investigate this. RESEARCH DESIGN AND METHODSWe studied an existing 12-year prospective cohort with RESULTSNinety-eight patients died during follow-up. The unadjusted hazard ratio (HR) for all-cause mortality was 1.61 (95% CI 1.07-2.43) for patients with high MBL expression genotypes versus patients with low MBL expression genotypes (P = 0.023). All-cause mortality was higher in patients with MBL concentrations above the median than in patients with MBL concentrations below the median (unadjusted HR 1.90 [95% CI 1.26-2.87], P = 0.002). CONCLUSIONSHigh MBL expression genotypes and high MBL concentrations are both associated with increased mortality rates in type 1 diabetes compared with low MBL expression genotypes and low MBL concentrations.Late diabetes complications contribute to excess morbidity and mortality in diabetes. The complement cascade of the immune system is most likely implicated in the development of these complications (1). Diabetes may induce the formation of complement-activating ligands by two mechanisms: altered enzymatic protein glycosylation and increased nonenzymatic advanced glycation end product formation. Both products are hypothesized to be adversely recognized by complement-activating

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Elevated MBL Concentrations Are Not an Indication of Association Between the MBL2 Gene and Type 1 Diabetes or Diabetic Nephropathy

Cited by 33 publications

References 24 publications

Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy

Association of Levels of Mannose-Binding Lectin and the MBL2 Gene with Type 2 Diabetes and Diabetic Nephropathy

Complement activation in progressive renal disease

Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

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