Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

Igo, Robert P.; Iyengar, Sudha K.; Nicholas, Susanne B.; Goddard, Katrina A.B.; Langefeld, Carl D.; Hanson, Robert L.; Duggirala, Ravindranath; Divers, Jasmin; Abboud, Hanna E.; Adler, Sharon G.; Arar, Nedal H.; Horvath, Amanda; Elston, Robert C.; Bowden, Donald W.; Guo, Xiuqing; Ipp, Eli; Kao, W. H. Linda; Kimmel, Paul L.; Knowler, William C.; Meoni, Lucy A.; Molineros, Julio E.; Nelson, Robert G.; Pahl, M. V.; Parekh, Rulan S.; Rasooly, Rebekah S.; Schelling, Jeffrey R.; Shah, Vallabh O.; Smith, Michael W.; Winkler, Cheryl A.; Zager, Philip G.; Sedor, John R.; Freedman, Barry I.

doi:10.1159/000326763

Cited by 52 publications

(31 citation statements)

References 53 publications

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“…After fine-mapping the region around the 22q11 locus the best linkage signal was detected at 3 cM (D22S420) and this locus does not overlap with any previously reported DN locus detected in patients with T1D. On the other hand, a locus approximately 20 Mb apart from our susceptibility region has in the FIND Study recently been linked to urinary albumin∶creatinine ratio in Mexican-Americans with diabetes [31]. This region contains the MYH9 (myosin, heavy polypeptide 9, non-muscle) and APOL1 (Apolipoprotein L1) genes associated in African-Americans with diabetic or nondiabetic nephropathy [32]–[34].…”

Section: Discussionsupporting

confidence: 47%

Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

et al. 2011

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BackgroundDiabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21–q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.Methods and ResultsWe performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPLpairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.ConclusionsThis study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21–q25 and 19q13.

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Section: Discussionsupporting

confidence: 47%

Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

et al. 2011

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“…A finer mapping of genes susceptible for T2DN in AAs by a GWAS from the same group also revealed the association of MHY9/APOL1 locus [19]. The MYH9 / APOL1 locus was also linked to T2DN in a family linkage study [20]. The function of MYH9/APOL1 in DN is rapidly evolving and remains a hot topic of debate.…”

Section: Geneticsmentioning

confidence: 99%

Genetics and Epigenetics of Diabetic Nephropathy

Liu

Lee

2015

Kidney Dis

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Background: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in the USA and worldwide, contributing to significant morbidity and mortality in diabetic patients. A genetic factor for the development of DN is strongly implicated, as only one third of diabetic patients eventually develop kidney disease. Growing evidence also supports an important role of epigenetic modifications in DN. Summary: Multiple studies have been performed to identify risk genes and loci associated with DN. So far, only several genes and loci have been identified, none of which showed a strong association with DN. Therefore, a better study design with a larger sample size to identify rare variants and a clinically defined patient population to identify genes and loci associated with progressive DN are still needed. In addition to genetic factors, epigenetic modifications, such as DNA methylation, histone modifications and microRNAs, also play a major role in the pathogenesis of DN through a second layer of gene regulation. Although a major progress has been made in this field, epigenetic studies in DN are still in the early phase and have been limited mostly due to the heterogeneity of kidney tissue samples with multiple cells. However, rapid development of high-throughput genome-wide techniques will help us to better identify genetic variants and epigenetic changes in DN. Key Message: Understanding of genetic and epigenetic changes in DN is needed for the development of new biomarkers and better drug targets against DN. Summarized in this review are important recent findings on genetic and epigenetic studies in the field of DN.

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“…However, linkage scan only in MA participants failed to identify a genetic region significantly linked to DN. Subsequently, Igo et al, [20] performed a genome-wide linkage scan for DN susceptibility loci in the FIND study using the genotypic data of 5,500 SNPs (Illumina panel IV) on 1623 subjects from 1,235 nuclear and extended pedigrees that included 632 subjects from 478 pedigrees of MA participants. DN trait was adjusted for sex.…”

Section: Genome-wide Linkage Scan For Dn In Mamentioning

confidence: 99%

“…However, linkage analysis failed to identify a chromosomal region significantly linked to ACR only in MA participants examined. Subsequently, using the genotypic data of 5,500 SNPs and the ACR data of 1316 MA participants of the FIND study, Igo et al, [20] identified a suggestive evidence for linkage of ACR with a LOD score of 2.29 (P = 0.00058) occurring on chromosome 22q12 near the nonmuscle myosin heavy chain 9 ( MYH9) / apolipoprotein L1 (APOL1) gene region. Age and sex were used as covariates.…”

Section: Genome-wide Linkage Scan For Albuminuria In Mamentioning

confidence: 99%

Susceptibility gene search for nephropathy and related traits in Mexican–Americans

et al. 2013

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The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican Americans. Mexican Americans with type 2 diabetes (T2DM) are three times more likely to develop microalbuminuria, and four times more likely to develop clinical proteinuria compared to non-Hispanic whites. Furthermore, Mexican Americans have a six fold increased risk of developing renal failure secondary to T2DM compared to Caucasians. Prevention and better treatment of DN should be a high priority for both health-care organizations and society at large. Pathogenesis of DN is multi-factorial. Familial clustering of DN-related traits in MAs show that DN and related traits are heritable and that genes play a susceptibility role. While, there has been some progress in identifying genes which when mutated influence an individual’s risk, major gene(s) responsible for DN are yet to be identified. Knowledge of the genetic causes of DN is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Self-identification and collaboration among researchers with suitable genomic and clinical data for meta-analyses in Mexican Americans is critical for progress in replicating/identifying DN risk genes in this population. This paper reviews the approaches and recent efforts made to identify genetic variants contributing to risk for DN and related phenotypes in the Mexican American population.

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Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

Cited by 52 publications

References 53 publications

Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

Genetics and Epigenetics of Diabetic Nephropathy

Susceptibility gene search for nephropathy and related traits in Mexican–Americans

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