The HFE Gene Is Associated to an Earlier Age of Onset and to the Presence of Diabetic Nephropathy in Diabetes Mellitus Type 2 (original) (raw)

The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2

Endocrine, 2004

We initiated the present work to determine whether the presence of the HFE C282Y or H63D mutations could be related to the clinical expression of diabetes mellitus type 2. Two hundred and twenty five type 2 consecutive diabetic patients were included and the HFE genotypes were determined. Younger ages of onset of diabetes as well as a longer duration of the disease were detected in patients carrying at least one C282Y allele (p = 0.007). An increased prevalence of retinopathy (p = 0.014) and of nephropathy (p = 0.04) were also detected in individuals carrying at least one C282Y allele in comparison with patients carrying the other alleles. The increased prevalence of retinopathy in C282Y carriers is related to the increased duration of the disease, but we not have detected that the prevalence of nephropathy is associated with the duration of the disease. However, multivariate logistic regression confirms that the prevalence of nephropathy is higher in the group of patients carrying at least one C282Y allele or the H63D/H63D genotype as compared to the group of patients with the wild-type (N/N) or the N/H63D genotype. To our knowledge our study is the first one to report an earlier age of onset in type 2 diabetic patients carrying HFE mutations.

Role of Hemochromatosis C282Y and H63D Mutations in HFE Gene in Development of Type 2 Diabetes and Diabetic Nephropathy

Diabetes Care, 2001

OBJECTIVE—In patients with clinical hemochromatosis, the frequency of diabetes ranges from 20 to 50%, and the heterozygosity for the C282Y mutation in the HFE gene might be associated with an increased risk for diabetes. There are also some reports that suggest that iron overload might cause diabetic nephropathy. RESEARCH DESIGN AND METHODS—We performed an association study to assess the role of the C282Y and H63D mutations in the HFE gene as a risk factor for type 2 diabetes and diabetic nephropathy. Altogether, 563 patients with type 2 diabetes were included in the study. In the analyzed group, 108 patients had overt proteinuria, 154 had microalbuminuria, and 301 had normoalbuminuria. Among the patients with normoalbuminuria, only those with known diabetes duration ≥10 years were considered normoalbuminuric (n = 162). A total of 196 unrelated healthy subjects were used as a control group. All subjects were genotyped for C282Y and H63D using the polymerase chain reaction–based prot...

Undiagnosed diabetes and impaired fasting glucose in HFE C282Y homozygotes and HFE wild-type controls in the HEIRS Study

BMJ open diabetes research & care, 2016

To determine prevalences and predictors of undiagnosed diabetes mellitus (UDM) and impaired fasting glucose (IFG) in non-Hispanic whites with HFE p.C282Y homozygosity and controls without common HFE mutations identified in population screening. We analyzed these observations in a postscreening examination: age; sex; body mass index; systolic/diastolic blood pressure; metacarpophalangeal joint hypertrophy; hepatomegaly; blood neutrophils; alanine and aspartate aminotransferase; elevated C reactive protein; transferrin saturation; serum ferritin; and Field Center. There were 223 p.C282Y homozygotes and 449 controls without diagnosed diabetes (43.9% men). Mean age of p.C282Y homozygotes was 52±13 years (controls 57±14 years; p<0.0001). Mean transferrin saturation in p.C282Y homozygotes was 67±26% (controls 34±14%; p<0.0001). Mean serum ferritin in p.C282Y homozygotes was 607 pmol/L (95% CI 497 to 517; controls 274 pmol/L (247 to 301); p<0.0001). Overall prevalences of UDM (4.0...

Investigation of the relationship between MTHFR, IRS and CALCA gene polymorphisms and development of diabetic nephropathy in patients with type 2 diabetes mellitus

Biotechnology & Biotechnological Equipment, 2018

The aim of this study was to investigate the relationship between MTHFR, IRS and CALCA gene polymorphisms and development of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (DM). Our study included 93 patients with type 2 DM diagnosed as having nephropathy and 95 controls diagnosed with type 2 DM without development of DN. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to determine the genotype distributions of MTHFR, IRS and CALCA gene polymorphisms. The results showed no statistically significant difference between DN patients and type 2 DM controls in terms of genotype distributions of MTHFR (C677T, A1298C), IRS (IRS-1 Gly972Arg, IRS-2 Gly1057Asp) and CALCA T692C gene polymorphisms (p > 0.05). However, in terms of allele frequencies for the MTHFR A1298C gene, the frequency of the C allele was significantly higher in the DN patients compared to the controls (p < 0.05). In the IRS-2 Gly1057Asp gene polymorphism, the G allele frequency was significantly higher in the DN patients than in the type 2 DM controls (p < 0.05). In the DN group, the individuals with one or less mutant alleles were significantly more than in the control group in terms of the IRS-2 Gly1057Asp gene polymorphism (p < 0.05). The C allele frequency for the MTHFR A1298C gene polymorphism and the G allele frequency for the IRS-2 Gly1057Asp gene polymorphism were indicated to be potential a genetic risk factor for the development of DN in patients with type 2 DM who developed DN.

Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23

Kidney International, 2002

Gene for susceptibility to diabetic nephropathy in type 2 diabethy, the diabetes-related loss of kidney function, is one tes maps to 18q22.3-23. of the major complications of diabetes. Diabetic nephrop-Background. Diabetic nephropathy is the major cause of athy is characterized by persistent proteinuria, that is, end-stage renal failure in patients with diabetes mellitus types 1 the presence of protein in the urine. The incidence of and 2. Epidemiological studies have suggested a genetic susceptithis complication peaks during the second decade of bility to diabetic nephropathy. The aim of this study was to localize the gene(s) responsible for susceptibility to diabetic nephropathy. diabetes mellitus type 1 and declines thereafter [2, 3]. Methods. A genetic linkage analysis was performed in 18 Diabetic nephropathy is the major cause of end-stage large Turkish families with type 2 diabetes mellitus and diabetic renal failure in the Western world. nephropathy. The result was checked in 101 affected sibling pairs Despite often poorly controlled blood glucose concenof Pima Indians. Results. A highly significant LOD score of 6.1 on chromotrations, a major subgroup of patients with type 1 [2, 4-6] some 18q22.3-23 between the markers D18S469 and D18S58 or type 2 diabetes mellitus never develops nephropathy was obtained in multipoint analysis. There was no indication [6, 7]. This observation and the clustering of diabetic for locus heterogeneity. In Pima Indians, linkage to the markers nephropathy in families with type 1 [8, 9] and type 2 D18S469 and D18S58 was confirmed (P ϭ 0.033), using the [10, 11] diabetes suggest that only a subset of diabetic affected sib-pair method. The genetic model that fit best was a dominant mode of inheritance with an almost complete penepatients is susceptible to the development of diabetic tration in the Turkish population. nephropathy. Besides a genetic susceptibility to diabetes Conclusions. There is strong evidence for the localization mellitus there may be one or more other (modifier) genes of a gene responsible for diabetic nephropathy in Turkish type 2 for the susceptibility to diabetic nephropathy. Seaquist diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between D18S43 and D18S50, an interval of 8.5 cM.

Genetic Variation in the Hypoxia-Inducible Factor-1α Gene Is Associated with Type 2 Diabetes in Japanese

The Journal of Clinical Endocrinology & Metabolism, 2005

Context and Objective: Vascular endothelial growth factor plays a critical role both in neovascularization of proliferative diabetic retinopathy and in angiogenesis of islets in the pancreatic developmental stage in determining ␤-cell mass and properties. Vascular endothelial growth factor mRNA levels increase as a result of increased transcriptional activation, mediated predominantly by hypoxia-inducible factor-1 ␣ (HIF-1␣) in response to hypoxia.

Genetic determinants of diabetic nephropathy

Clinical Science, 1999

Diabetic nephropathy is the most serious complication of diabetes mellitus. Progression of the condition leads to end-stage renal failure, and other complications of diabetes are also common in this group of patients. The onset of overt albuminuria in a patient with diabetes heralds an increased risk of death, particularly from cardiovascular disease. There is considerable evidence to show that nephropathy is influenced by genetic factors. Epidemiological studies show that only a minority of patients with diabetes develop nephropathy irrespective of glycaemic control, suggesting that a subgroup of patients are at higher risk of nephropathy. Marked ethnic variation is observed, with nephropathy being more common in certain ethnic groups. Familial clustering of nephropathy is also observed. Parental history of hypertension, diabetes or cardiovascular disease appears to predispose to nephropathy in patients with diabetes. A number of methods are available to dissect polygenic disease : animal models, genetic association studies (casecontrol studies), affected sib-pair studies, discordant sib-pair studies and transmission distortion analysis. Most published work has been based on association studies. Association studies have shown conflicting results often due to small numbers of cases and controls, and poor phenotypic characterization. The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism has been studied in detail, but does not appear to be a strong risk marker for nephropathy. It does, however, appear to have a role in response to angiotensin-converting enzyme inhibition, with II homozygotes being the most responsive and DD homozygotes the least. A number of other genetic loci have also shown positive associations with nephropathy, including apolipoprotein E, heparan sulphate and aldose reductase. More recently, affected sibpair analysis and discordant sib-pair analysis have suggested possible genetic loci on chromosomes 3, 7, 9, 12 and 20. These have yet to be reproduced in larger numbers of families, and the specific gene regions on these chromosomes remain elusive. The evidence presented in this review strongly supports the role of genetic factors in nephropathy. Detection of strong genetic risk markers for nephropathy will allow further insights into the pathogenesis of nephropathy, and possibly the development of novel therapeutic agents for its treatment. It will also allow preventive therapy to be directed at those patients with the greatest risk for development of diabetic nephropathy.

Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach

Diabetologia, 2007

Aims/hypothesis In the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits: single-and multi-locus analyses. Materials and methods The study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCRbased methodology (PCR only, PCR plus RFLP, or allelespecific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis. Results After correction for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p=0.0006) in single-locus analysis. In multilocus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER-429T/C) and two SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p=0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p= 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184A/ G and NOS3 774C/T, together with diabetes duration and HbA 1c , as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction. Conclusions/interpretation Using the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single-and multi-locus analyses represent complementary methods.

Genetics of Type 2 Diabetes- A Review Article

Iranian Journal of Diabetes and Obesity, 2015

ype 2 diabetes (T2D) is a worldwide concern. Based on International Diabetes Federation, 285 million adults aged 20–79 years suffered from diabetes in 2010. About 60% of them located in Asia. Almost 80% of people with diabetes live in developing countries. Around 95% of diabetic patients suffer from T2D (1-3).Worryingly, new findings show decrease in the onset age of T2D. The disease is more frequently reported among young Africans and Pima Indians (4). T2D in Asia differs from the other world regions; since it has developed in younger age group, and in people with much lower bodyT 1. Department of Genetics, Faculty of Medicine, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 2. Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 3. Clinical and Research center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran 4. Diabetes Research Center, Shahid ...