Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele

We fine-mapped 76 rheumatoid arthritis (RA) and type 1 diabetes (T1D) loci outside of the MHC. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We fine-mapped1,2 these loci in RA (11,475 cases, 15,870 controls)3, T1D (9,334 cases and 11,111 controls) 4 and combined datasets. We reduced the number of potential causal variants to ≤5 in 8 RA and 11 T1D loci. We identified causal missense variants in five loci (DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non-coding variants in six loci (MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). Functional analysis confirmed allele specific binding and differential enhancer activity for three variants: the CD28/CTLA4 rs117701653 SNP, the TNFAIP3 rs35926684 indel, and the MEG3 rs34552516 indel. This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.

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Identifying the lungs as a susceptible site for allele-specific regulatory changes associated with type 1 diabetes risk

Communications Biology ◽

10.1038/s42003-021-02594-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Daniel Ho ◽

Denis M. Nyaga ◽

William Schierding ◽

Richard Saffery ◽

Jo K. Perry ◽

...

Keyword(s):

Type 1 Diabetes ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Luciferase Reporter ◽

Islet Autoantibody ◽

Specific Expression ◽

Enhancer Activity ◽

Tissue Specific ◽

Allele Specific

AbstractType 1 diabetes (T1D) etiology is complex. We developed a machine learning approach that ranked the tissue-specific transcription regulatory effects for T1D SNPs and estimated their relative contributions to conversion to T1D by integrating case and control genotypes (Wellcome Trust Case Control Consortium and UK Biobank) with tissue-specific expression quantitative trait loci (eQTL) data. Here we show an eQTL (rs6679677) associated with changes to AP4B1-AS1 transcript levels in lung tissue makes the largest gene regulatory contribution to the risk of T1D development. Luciferase reporter assays confirmed allele-specific enhancer activity for the rs6679677 tagged locus in lung epithelial cells (i.e. A549 cells; C > A reduces expression, p = 0.005). Our results identify tissue-specific eQTLs for SNPs associated with T1D. The strongest tissue-specific eQTL effects were in the lung and may help explain associations between respiratory infections and risk of islet autoantibody seroconversion in young children.

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Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations

Acta Endocrinologica ◽

10.1530/eje-07-0354 ◽

2007 ◽

Vol 157 (5) ◽

pp. 641-645 ◽

Cited By ~ 10

Author(s):

Jun Ma ◽

Sofia Nordman ◽

Anna Möllsten ◽

Henrik Falhammar ◽

Kerstin Brismar ◽

...

Keyword(s):

Coronary Heart Disease ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Neuropeptide Y ◽

Causal Variant ◽

Specific Hybridization ◽

Allele Specific ◽

Different Populations ◽

Sample Set

AbstractObjectiveThe distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations.DesignOne sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study.MethodsGenotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization.ResultsThe C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249–5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD.ConclusionsThe present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

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Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species

Biochemical Society Transactions ◽

10.1042/bst0360312 ◽

2008 ◽

Vol 36 (3) ◽

pp. 312-315 ◽

Cited By ~ 19

Author(s):

Dan B. Rainbow ◽

Laura Esposito ◽

Sarah K. Howlett ◽

Kara M. Hunter ◽

John A. Todd ◽

...

Keyword(s):

Type 1 Diabetes ◽

Disease Susceptibility ◽

Autoimmune Diabetes ◽

Interleukin 2 ◽

Nod Mice ◽

Common Disease ◽

Gene Products ◽

Specific Expression ◽

Allele Specific

Variants within the IL-2 (interleukin 2) and CD25 genes are associated with T1DM (Type 1 diabetes mellitus) in mice and humans respectively. Both gene products are essential for optimal immune tolerance and a partial failure to tolerize is linked to the autoimmune responses to insulin and other β-cell proteins that precede T1DM onset. Gene variants that contribute to common disease susceptibility often alter gene expression only modestly. Small expression changes can be technically challenging to measure robustly, especially since biological variation usually contributes negatively to this goal. The present review focuses on allele-specific expression assays that can be used to quantify genotype-determined expression differences such as those observed for IL-2, where the susceptibility allele is transcribed 2-fold less than the resistance allele.

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Allele-specific methylation of type 1 diabetes susceptibility genes

Journal of Autoimmunity ◽

10.1016/j.jaut.2017.11.008 ◽

2018 ◽

Vol 89 ◽

pp. 63-74 ◽

Cited By ~ 11

Author(s):

Alida S.D. Kindt ◽

Rainer W. Fuerst ◽

Jan Knoop ◽

Michael Laimighofer ◽

Tanja Telieps ◽

...

Keyword(s):

Type 1 Diabetes ◽

Susceptibility Genes ◽

Diabetes Susceptibility ◽

Allele Specific ◽

Allele Specific Methylation

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Association of Vitamin D Receptor Ggene Ppolymorphisms and Type 1 diabetes in Egyptian Population.

Journal of Biotechnology Research Center ◽

10.24126/jobrc.2015.9.2.429 ◽

2015 ◽

Vol 9 (2) ◽

pp. 23-28

Author(s):

Ali Salim Al-shehmany Al-shehmany ◽

*Ahmad A. El- Kafoury El- Kafoury ◽

*Ahmad A. El- Kafoury * El- Kafoury ◽

Amira M. Embaby Embaby

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Vitamin D Receptor ◽

Chi Square ◽

Vdr Gene ◽

Egyptian Population ◽

Specific Pcr ◽

Increased Risk ◽

Allele Specific

The human vitamin D receptor (VDR) gene is located on chromosome 12q12–q14, and four commonnucleotide polymorphisms have been identified. Several studies have found a relationship betweenpolymorphisms of the (VDR) gene and development of type 1 diabetes (T1DM). The association ofVDR polymorphisms and susceptibility to T1DM in the Egyptian population were examined in 60individuals with type 1 diabetes and compared with healthy 60 persons. Single nucleotidepolymorphisms (SNP) genotyping was performed using PCR and BsmI and FokI, by using twotechniques, allele specific PCR technique and restriction fragment length polymorphism – PCR(RFLP-PCR). Data were analyzed using the chi square. The result approved that the genotype TA inSNP FokI was risk factor among type 1 diabetes mellitus patients combination which conferredstrongest susceptibility to T1DM (P=0.004) while the SNP BsmI did not showed any significancebetween cases as compared with control (P=0.493). The results of the current study indicated that VDRpolymorphisms are associated with increased risk of T1DM in the Egyptian population. The differencein the association of the aforementioned SNPs variants with T1DM among different populations maybe attributed to the presence of multiple susceptibility alleles.

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Association of HLA-DQ trans-heterodimers with prevalence of type 1 diabetes mellitus in Buryat ethnic group

Diabetes Mellitus ◽

10.14341/2072-0351-6080 ◽

2012 ◽

Vol 15 (3) ◽

pp. 11-18

Author(s):

Olga Nikolaevna Ivanova ◽

Sergey Alexandrovich Prokof'ev ◽

Tatiana Prokop'evna Bardymova

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Ethnic Group ◽

Specific Marker ◽

Software Applications ◽

Specific Pcr ◽

Hla Dq ◽

Allele Specific

Aims. Search for the most pronounced HLA II markers of type 1 diabetes mellitus (T1DM) in Buryat ethnic group and analysis ofHLA-DQ trans-heterodimers. Materials and methods. Case control design was applied for assessment of 74 patients with T1DM and 61 healthy individuals. Alleleidentification was performed with multi-primer allele-specific PCR technique. Association of genetic markers with pathology wasevaluated according to odds ratio (OR) index. All calculations were performed with StatSoft and STATISTICA 6 software applications. Results. We show that regarding race-specific highly diabetogenic HLA class II haplotypes Buryat ethnic group holds intermediateposition between Mongoloids and Caucasians and none of those haplotypes are associated with T1DM. We revealed a statisticallysignificant association of T1DM with DQA1*0301+DQB1*0201+ phenotype represented by trans-coding alleles in 77% of cases. Onpopulation level DQA1*0301+DQB1*0302+ or *0201+ phenotype is found to be the most sensitive marker. It was registered in 43%of patients with T1DM against 11.5% of controls (OR 5.9; рс=0.0094). DQA1*0301+/DQВ1*0201 and DQВ1*0302 phenotype is themost specific marker, registered in 16% of patients, but not found in controls (OR 11.8; рс=0.047).Conclusions. HLA-mediated risk for development of T1DM in Buryat ethnic group is determined by HLA-DQ trans-heterodimers.

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