Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

Hansen, S. K.; Gjesing, Anette P.; Rasmussen, Søren K.; Glümer, Charlotte; Urhammer, Søren A.; Andersen, Gitte; Rose, Christian Schack; Drivsholm, Thomas; Torekov, Signe S.; Jensen, D. P.; Ekstrøm, Claus Thorn; Borch‐Johnsen, Knut; Jørgensen, Torben; McCarthy, Mark; Hansen, Torben; Pedersen, Oluf

doi:10.1007/s00125-004-1418-3

Cited by 44 publications

(38 citation statements)

References 38 publications

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“…The existence of noncanonical transcripts in transfected cells (Figs. 1B and 2A and C) and in EST libraries (online appendix Table 2) would be consistent with this concept, which appears to be further supported by the observed genetic linkage and allelic association of INS with type 1 diabetes (1) but not type 2 diabetes or other metabolic traits (24), except in childhood obesity (6). Subsequent studies should therefore examine each of these possibilities in greater detail, since alternative splicing and associated pathways might become suitable targets for therapeutic approaches in the future.…”

supporting

confidence: 69%

Variants in the Human Insulin Gene That Affect Pre-mRNA Splicing

et al. 2006

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Predisposition to type 1 diabetes and juvenile obesity is influenced by the susceptibility locus IDDM2 that includes the insulin gene (INS). Although the risk conferred byIDDM2 has been attributed to a minisatellite upstream of INS, intragenic variants have not been ruled out. We examined whether INS polymorphisms affect pre-mRNA splicing and proinsulin secretion using minigene reporter assays. We show that IVS1-6A/T (؊23HphI؉/؊) is a key INS variant that influences alternative splicing of intron 1 through differential recognition of its 3 splice site. The A allele resulted in an increased production of mature transcripts with a long 5 leader in several cell lines, and the extended mRNAs generated more proinsulin in culture supernatants than natural transcripts. The longer mRNAs were significantly overrepresented among ␤-cell-expressed sequenced tags containing the A allele as compared with those with T alleles. In addition, we show that a rare insertion/deletion polymorphism IVS1؉5insTTGC T ype 1 diabetes results from the autoimmune destruction of the insulin-producing pancreatic ␤-cells. In addition to a major susceptibility locus in the HLA region, termed IDDM1, genetic predisposition to this disease is conferred by a locus on chromosome 11, designated IDDM2 (1). The genetic risk at IDDM2 has been attributed to the INS minisatellite (2-6), which is composed of a variable number of tandem repeat sequences. However, reanalysis of allelic association data in type 1 diabetes did not rule out intragenic variants, including a single nucleotide polymorphism (SNP) Ϫ23HphI (7), which is located in position Ϫ6 relative to the 3Ј splice site of intron 1 (IVS1-6A/T). This SNP has been used as a surrogate marker for INS genotyping in a large number of studies to infer minisatellite haplotypes (class I/III) in disease susceptibility (2,3,6 and refs. therein). IVS1-6A/T is located in the polypyrimidine tract (PPT), a splicing signal of central importance for vertebrate 3Ј splice site recognition, and in a position exhibiting a great depletion of purine residues in the PPT (8). Since uridine is the preferred PPT nucleotide in pre-mRNA (9), the A allele, which reduces the ShapiroSenapathy matrix score and other splicing prediction scores for the acceptor splice site of intron 1 (online appendix Table 1, available at http://diabetes.diabetesjour nals.org), is likely to weaken efficient splicing of this intron. As intron 1 separates noncoding and coding exons, differential utilization of its 3Ј splice site by the uridineand adenosine-containing pre-mRNAs would be predicted to result in distinct representation of mature transcripts with short and long 5Ј untranslated regions (UTRs) with potential effects on translation.To test whether the IVS1-6A3 T base change promotes PPT recognition and splicing of intron 1, we transiently transfected the wild-type and mutated INS minigenes (Fig. 1A) into several cell lines and examined their splicing pattern. Nucleotide sequencing of the resulting mRNAs identified six alternatively spliced ...

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confidence: 69%

Variants in the Human Insulin Gene That Affect Pre-mRNA Splicing

et al. 2006

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“…In a general population, other authors also did not support associations between INS VNTR and body composition in childhood [25][26][27][28].…”

Section: Discussionmentioning

confidence: 85%

“…On the other hand, class III is protective against diabetes mellitus type 1 (T1DM) and leads to an overexpression of insulin [19][20][21]. Thus, it may be responsible for obesity, IR, T2DM, and polycystic ovary syndrome (PCOS); however, the results regarding the influence of INS VNTR polymorphism on these disorders, both in the general population and in SGA individuals, are divergent [10,13,15,17,[22][23][24][25][26][27][28][29]. The aim of the study was to verify whether INS VNTR class III allele is associated with low birth weight in the Polish population and to assess the influence of this variant on the current body mass index (BMI) as well as on the metabolic and hormonal profile in prepubertal SGA children.…”

Section: Introductionmentioning

confidence: 99%

Wpływ występowania allelu klasy III VNTR genu INS na parametry auksologiczne, stężenie glukozy, insuliny, lipidów i adipocytokin u przeddojrzewaniowych dzieci urodzonych z niską masą ciała

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Borowiec

et al. 2016

Endokrynologia Polska

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Introduction:The insulin gene variable number of tandem repeats (INS VNTR) class III allele has been implicated in lower birth weight, obesity, and insulin resistance. We assessed its influence on birth weight in the Polish population and on the current body mass and metabolic profile in prepubertal children born small for gestational age (SGA). Material and methods: DNA for genotyping of INS VNTR was available for 123 subjects born SGA and 132 born appropriate for gestational age (AGA). We identified two alleles: class I and class III. Next, in 112 prepubertal (aged: 6.8 ± 1.38 years) SGA children, the auxological measurements, fasting serum C-peptide, triglycerides, cholesterol, ghrelin, leptin, adiponectin, resistin, cortisol, and insulin-like growth factor type I (IGF-I) concentrations, as well as glucose and insulin during oral glucose tolerance test (OGTT), were assessed and insulin resistance indices were calculated. The results were analysed depending on INS VNTR variants. Results: The occurrence of individual INS VNTR variants were similar in the SGA and AGA groups. In prepubertal SGA children, we did not observe any statistical differences as regards birth weight, body mass, lipids, or adipocytokine concentrations among I/I, I/III, and III/III class groups. The concentration of insulin in 120' of OGTT was significantly higher in class III homozygous than in class I homozygous individuals. Conclusions: Variant INS VNTR class III was shown not to be associated in any essential way with birth weight in the Polish population. Among prepubertal SGA children, the presence of INS VNTR class III is related to higher insulin secretion during OGTT. (Endokrynol Pol 2016; 67 (6): 585-591)

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“…In three British cohorts, Mitchell et al 48 did not find an association between INS VNTR size classes or evidence for parent-of-origin effects in the transmission of VNTR alleles. Similarly, Hansen et al 37 found that in a study of Danish Caucasians there was no association between genotype for INS VNTR alleles or for paternal or maternal transmission of class III alleles and birth weight. However, they did not compare average birth weights between class I and class III alleles according to parental origin.…”

Section: Discussionmentioning

confidence: 94%

“…34 Class III (4140 repeats) alleles exhibit a controversial association with type 2 diabetes predisposition, with some data supporting association with paternally transmitted alleles, 35 III/III homozygosity, 36 or no association at all. 37 Owing to a very high level of linkage disequilibrium (X94% concordance across populations 38,39 ) between the A/T single nucleotide poly- In this study, we investigated the association between small for gestational age birth (defined as o2540 g at term) and SNP variation at six sites in the INS and IGF2 genes in African-American subjects. We tested for association with SNP and haplotype genotypes in both the newborns and mothers and with the parental transmission of insulin haplotypes.…”

mentioning

confidence: 99%

Association between small for gestational age and paternally inherited 5′ insulin haplotypes

et al. 2007

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Objective: To test the association between small for gestational age and polymorphisms in the insulin gene in newborns and their mothers, as well as the effect of the parental transmission of haplotypes. Subjects: Pairs of healthy African-American full-term newborns (N ¼ 207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g. Methods: Six single nucleotide polymorphisms (SNPs) located in the insulin (INS) and insulin-like growth factor 2 (IGF2)genes were genotyped in mothers and newborns. Haplotypes composed of three SNPs in the 5 0 region of the INS-IGF2 locus were computationally inferred. Odds ratios for risk of small for gestational age (SGA) birth were calculated for individual SNPs and inferred haplotypes in the newborns and in the mothers using logistic regression. For 162 mother -newborn pairs the parental transmission of the haplotypes could be inferred, and the risks for SGA birth were calculated for the three common haplotypes in this sample. Results: Three INS SNPs exhibited significant association with risk for SGA birth. The SNP alleles associated with increased risk for SGA were opposite in the maternal and newborn genomes, implying opposing influences on the rate of fetal growth. Consistent with these results, haplotypes composed of complementary nucleotide sequences (CAC at rs3842738, rs689 and rs3842748, respectively, in the newborn versus GTG in the mother) were significantly associated with risk for SGA birth. In analyses of haplotypes according to parental transmission, the same trend in risk for SGA was observed for both maternally and paternally transmitted haplotypes, although a significant difference in risk was observed only for paternally transmitted haplotypes. Conclusion: Polymorphisms near the 5 0 end of the INS-IGF2 locus are significantly associated with risk for SGA birth with a major effect due to the paternally transmitted haplotype, which is preferentially expressed due to imprinting.

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Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release

Cited by 44 publications

References 38 publications

Variants in the Human Insulin Gene That Affect Pre-mRNA Splicing

Variants in the Human Insulin Gene That Affect Pre-mRNA Splicing

Wpływ występowania allelu klasy III VNTR genu INS na parametry auksologiczne, stężenie glukozy, insuliny, lipidów i adipocytokin u przeddojrzewaniowych dzieci urodzonych z niską masą ciała

Association between small for gestational age and paternally inherited 5′ insulin haplotypes

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