| 1. |
- Sandholm, Niina, et al.
(författare)
-
New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
-
Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
-
Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
|
|
| 2. |
|
|
| 3. |
- Ahlqvist, Emma, et al.
(författare)
-
A common variant upstream of the PAX6 gene influences islet function in man.
- 2012
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55, s. 94-104
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. METHODS: A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. RESULTS: rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. CONCLUSIONS/INTERPRETATION: A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
|
|
| 4. |
- Ahlqvist, Emma, et al.
(författare)
-
A link between GIP and osteopontin in adipose tissue and insulin resistance.
- 2013
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:6, s. 2088-2094
-
Tidskriftsartikel (refereegranskat)abstract
- Low grade inflammation in obesity is associated with accumulation of the macrophagederived cytokine osteopontin in adipose tissue and induction of local as well as systemic insulin resistance. Since GIP (glucose-dependent insulinotropic polypeptide) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate osteopontin (OPN) expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13±}0.04 vs 0.04±}0.01, P<0.05) and correlated inversely with measures of insulin sensitivity (r=-0.24, P=0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with lower amount of the exon 9 containing isoform required for transmembrane activity. Carriers of the A-allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone, but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of GIPR rs10423928 A-allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.
|
|
| 5. |
- Ahlqvist, Emma, et al.
(författare)
-
Genetics of type 2 diabetes
- 2011
-
Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 57:2, s. 241-254
-
Forskningsöversikt (refereegranskat)abstract
- Background: Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease.Content: Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci.Summary: Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.
|
|
| 6. |
- Ahlqvist, Emma, et al.
(författare)
-
High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice
- 2011
-
Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 20:15, s. 3031-3041
-
Tidskriftsartikel (refereegranskat)abstract
- Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F(2) crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2(q) mice were then selected to set up an F(3) generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci. © The Author 2011. Published by Oxford University Press. All rights reserved.
|
|
| 7. |
- Alkayyali, Sami, et al.
(författare)
-
Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes.
- 2012
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X.
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmö Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, β ± SEM, -3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, β ± SEM, -0.008 ± 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.
|
|
| 8. |
- Fagerholm, E., et al.
(författare)
-
SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes
- 2012
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55:9, s. 2386-2393
-
Tidskriftsartikel (refereegranskat)abstract
- Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.
|
|
| 9. |
- Forster, M., et al.
(författare)
-
Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice
- 2012
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 71
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. METHODS: We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. RESULTS: We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. CONCLUSION: This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.
|
|
| 10. |
- Jönsen, Andreas, et al.
(författare)
-
Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
- 2011
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 13, s. R206-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). METHODS: The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523). RESULTS: We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS. CONCLUSION: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
|
|
