Discovery of Coding Genetic Variants Influencing Diabetes-Related Serum Biomarkers and Their Impact on Risk of Type 2 Diabetes

Ahluwalia, Tarunveer S.; Allin, Kristine H.; Sandholt, Camilla H.; Sparsø, Thomas; Jørgensen, Marit E.; Rowe, Michael W.; Christensen, Cramer; Brandslund, Ivan; Lauritzen, Torsten; Linneberg, Allan; Husemoen, Lise Lotte Nystrup; Jørgensen, Torben; Hansen, Torben; Grarup, Niels; Pedersen, Oluf

doi:10.1210/jc.2014-3677

Cited by 26 publications

(24 citation statements)

References 36 publications

(29 reference statements)

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“…9p21 in CDKN2A, CDKN2B, and 1p13 near CELSR2-PSRC1-SORT1 also showed association with other disease. Ahluwalia et al [31] tested the 11 biomarker-associated SNPs for association with T2D in Danish samples and found significant statistical associations for CELSR2 SNPs [OR=1.11 (1.05-1.18), P=1.2×10 -3 ], respectively. rs646776 near CELSR2 was associated with an increased fasting serum insulin like growth factor binding protein 1 (IGFBP1) level and a decreased risk of T2D [31].…”

Section: Discussionmentioning

confidence: 99%

“…Ahluwalia et al [31] tested the 11 biomarker-associated SNPs for association with T2D in Danish samples and found significant statistical associations for CELSR2 SNPs [OR=1.11 (1.05-1.18), P=1.2×10 -3 ], respectively. rs646776 near CELSR2 was associated with an increased fasting serum insulin like growth factor binding protein 1 (IGFBP1) level and a decreased risk of T2D [31]. Gaulton KJ et al [32] observed four loci that each had two distinct association signals, CDKN2A-CDKN2B, diacylglycerol kinase beta (DGKB), melanocortin 4 receptor, (MC4R) and gastric inhibitory polypeptide receptor, (GIPR), with each locus represented by noncoding index variants.…”

Section: Discussionmentioning

confidence: 99%

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Association Study of Single-Nucleotide Polymorphisms on Chromosome 1p13, 1p32, 9p21 and 19p13 with Cardiovascular Diseases in Chinese Han Population: A Case-Control Study

Guo¹,

Feng²,

Li³

2016

J Hypertens

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Objectives: Previous research discovered single nucleotide polymorphism (rs2383206 and rs2383207) on chromosome 9p21 that is associated with coronary heart disease in a Chinese population. However, few data are available on the association of other single nucleotide polymorphism with cardiovascular disease in a Chinese population. This study aimed to determine whether the single nucleotide polymorphisms on chromosome 1p13, 1p32, 9p21 and 19p13 were associated with coronary artery disease in a Chinese population. Methods:We conducted a case-control study. Cases were coronary artery disease (n=670) between 2010 and 2015. Controls (n=1340) were randomly selected and frequency matched to cases on age and gender. All of the participants were selected to study 18 single nucleotides using allele-specific real-time polymerase chain reaction method.Results: Four single nucleotides in 9p21, two single nucleotides in 1p13 and one single nucleotide in 1p32 were associated with cardiovascular disease risk in Chinese population (Global P value for multiple logistic regression, <0.0001, respectively). rs10757274 showing the strongest association with cardiovascular disease. GG carriers of four SNPs (rs10757274, rs2383206, rs10757278 and rs1333049) in 9p21 had higher risk (Odds ratio=1.40, 95% Confidence interval: 1.10-1.79; Odds ratio=1.33, 95% Confidence interval: 1.04-1.69; Odds ratio=1.35, 95% Confidence interval: 1.07-1.72; Odds ratio=1.34, 95% Confidence interval: 1.06-1.71).Conclusion: rs10757274, rs2383206, rs10757278 in 9p21, rs562556 in 1p32, and rs646776 in 1p13 may serve as a novel genetic marker for the risk of significant cardiovascular disease in Chinese Han population.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association Study of Single-Nucleotide Polymorphisms on Chromosome 1p13, 1p32, 9p21 and 19p13 with Cardiovascular Diseases in Chinese Han Population: A Case-Control Study

Guo¹,

Feng²,

Li³

2016

J Hypertens

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“…Informed written consent was obtained from all subjects before participation. The genetic association analyses were performed in three Danish study cohorts (Inter99, Health2006 and Health2008) that have been described previously elsewhere:21 (1) Inter99 (ClinicalTrials.gov ID-no: NCT00289237) is a population-based study for ischaemic heart disease;22 (2) Health2006 (Ethical Committee approval number: KA20060011) is a population-based study comprising individuals aged between 18 and 69 years from the South Western part of greater Copenhagen area 23. This study was designed to address chronic health issues; (3) Health2008 (Ethical Committee approval number: KA20060011) is a cross-sectional population-based study 24…”

Section: Methodsmentioning

confidence: 99%

“…DNA extraction, genotyping and genotype call processing has been described previously 21 25. A total of 8445 individuals (n Inter99 : 5420, n Health2006 : 2442, n Health2008 : 583) with complete phenotype and genotype data participated for the serum TSH association analyses.…”

Section: Methodsmentioning

confidence: 99%

“…A total of 8445 individuals (n Inter99 : 5420, n Health2006 : 2442, n Health2008 : 583) with complete phenotype and genotype data participated for the serum TSH association analyses. The genotyping platform was Illumina Human Exome 12V.1.0 containing 263.894 SNPs (including 16.024 custom SNPs identified from a recent exome sequencing study in Danes21 25) post quality control.…”

Section: Methodsmentioning

confidence: 99%

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Carriers of aVEGFAenhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone

et al. 2016

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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

et al. 2018

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Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6).Conclusions/interpretationThe current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4783-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Discovery of Coding Genetic Variants Influencing Diabetes-Related Serum Biomarkers and Their Impact on Risk of Type 2 Diabetes

Abstract: The identified loci influence processes related to insulin signaling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.

Cited by 26 publications

References 36 publications

Association Study of Single-Nucleotide Polymorphisms on Chromosome 1p13, 1p32, 9p21 and 19p13 with Cardiovascular Diseases in Chinese Han Population: A Case-Control Study

Association Study of Single-Nucleotide Polymorphisms on Chromosome 1p13, 1p32, 9p21 and 19p13 with Cardiovascular Diseases in Chinese Han Population: A Case-Control Study

Carriers of aVEGFAenhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

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