VNTR Genotype Research Articles

Role of serotonergic polymorphisms in the clinical severity of the panic disorder

Introduction and objectivesTo investigate the association between three serotonergic polymorphisms (A-1438G [rs6311] of the HTR2A gene, STin2 VNTR and 5-HTTLPR of the SLC6A4 gene) and the severity of panic and depression symptomatology among mental health outpatients with diagnosis of panic disorder (PD). Methods92 unrelated PD outpatients (DSM-IV criteria) from a homogeneous Spanish Caucasian population (mean age±SD, 35.9±12.4 years; 28 [30.4%] males) were assessed using the Panic and Agoraphobia Scale (PAS), and the Hamilton Depression Rating Scale (HDRS), and genotyped using standard methods. ResultsAge of onset of PD varied by STin2 VNTR genotype (F=3.21; p=0.045). On average, onset of PD occurred earlier for those with the 10/10 than for those with the 12/12 genotype (25.1 versus 33.3; p=0.043). No relationship was found between A-1438G, 5-HTTLPR, and STin2 VNTR genotypes and PAS or HDRS total scores. Variation in scores on the HDRS Anxiety subscale by A-1438G genotype almost reached statistical significance (F=3.03; p=0.053). Post hoc pairwise comparisons showed higher anxiety levels among A/G than among A/A carriers (4.1 versus 2.9; p=0.043). Finally, variation in scores on the Preoccupied with Health subscale of the PAS by 5-HTTLPR genotype approached statistical significance (F=2.56; p=0.083). Post hoc pairwise comparisons showed higher scores among L/S than among L/L carriers (2.4 versus 1.4; p=0.078). ConclusionsOur data provide support of an involvement of the serotonin system, particularly, the HTR2A gene in the severity of PD.

Dopamine transporter 3'UTR VNTR genotype is a marker of performance on executive function tasks in children with ADHD

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder from both clinical and pathogenic viewpoints. Executive function deficits are considered among the most important pathogenic pathways leading to ADHD and may index part of the heterogeneity in this disorder.MethodsTo investigate the relationship between the dopamine transporter gene (SLC6A3) 3'-UTR VNTR genotypes and executive function in children with ADHD, 196 children diagnosed with ADHD were sequentially recruited, genotyped, and tested using a battery of three neuropsychological tests aimed at assessing the different aspects of executive functioning.ResultsTaking into account a correction for multiple comparisons, the main finding of this study is a significant genotype effect on performances on the Tower of London (F = 6.902, p = 0.009) and on the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) Freedom From Distractibility Index (F = 7.125, p = 0.008), as well as strong trends on Self Ordered Pointing Task error scores (F = 4,996 p = 0.026) and WISC-III Digit Span performance (F = 6.28, p = 0.023). Children with the 9/10 genotype exhibited, on average, a poorer performance on all four measures compared to children with the 10/10 genotype. No effect of genotype on Wisconsin Card Sorting Test measures of performance was detected.ConclusionResults are compatible with the view that SLC6A3 genotype may modulate components of executive function performance in children with ADHD.

INS VNTR Is Not Associated With Childhood Obesity in 1,023 Families: A Family‐based Study

Previous studies have described genetic associations of the insulin gene variable number tandem repeat (INS VNTR) variant with childhood obesity and associated phenotypes. We aimed to assess the contribution of INS VNTR genotypes to childhood obesity and variance of insulin resistance, insulin secretion, and birth weight using family-based design. Participants were either French or German whites. We used transmission disequilibrium tests (TDTs) for assessing binary traits and quantitative pedigree disequilibrium tests for assessing continuous traits. In contrast to previous findings, we did not observe any familial association with childhood obesity (T = 50%, P = 0.77) in the 1,023 families tested. In French obese children, INS VNTR did not associate with fasting insulin levels (P = 0.23) and class I allele showed only borderline association with increased insulin secretion index at 30 min (P = 0.03). INS VNTR did not associate with birth weight in obese children (P = 0.98) and TDT analyses in 350 French families with history of low birth weight (LBW) showed no association with this condition (P = 0.92). In summary, our study, the largest performed so far, does not support the previously reported associations between INS VNTR and childhood obesity, insulin resistance, or birth weight, and does not suggest any major role for this variant in modulating these traits.

Variation of DAT1 VNTR Alleles and Genotypes Among Old Ethnic Groups in Mesopotamia to the Oxus Region

Variation of a VNTR in the DAT1 gene in seven ethnic groups of the Middle East was used to infer the history and affinities of these groups. The populations consisted of Assyrian, Jewish, Zoroastrian, Armenian, Turkmen, and Arab peoples of Iran, Iraq, and Kuwait. Three hundred forty subjects from these seven ethnic groups were screened for DAT1. DAT1 VNTR genotyping showed 3, 6, 7, 8, 9, 10, 11, and 12 alleles in the samples. Analysis of these data revealed differentiation and relationship among the populations. In this region, which covers an area of 2-2.5 million km2, the influence of geography and especially of linguistic characteristics has had potentially major effects on differentiation. Religion also has played a major role in imposing restrictions on some ethnic groups, who as a consequence have maintained their community. Overall, these ethnic groups showed greater heterogeneity compared to other populations.

Variation of DAT1 VNTR Alleles and Genotypes Among Old Ethnic Groups in Mesopotamia to the Oxus Region

Variation of a VNTR in the DAT1 gene in seven ethnic groups of the Middle Eastwas used to infer the history and affinities of these groups. The populations consisted of Assyrian, Jewish, Zoroastrian, Armenian, Turkmen, and Arab peoples of Iran, Iraq, and Kuwait. Three hundred forty subjects from these seven ethnic groups were screened for DAT1. DAT1 VNTR genotyping showed 3, 6, 7, 8, 9, 10, 11, and 12 alleles in the samples. Analysis of these data revealed differentiation and relationship among the populations. In this region, which covers an area of 2–2.5 million km2, the influence of geography and especially of linguistic characteristics has had potentially major effects on differentiation. Religion also has played a major role in imposing restrictions on some ethnic groups, who as a consequence have maintained their community. Overall, these ethnic groups showed greater heterogeneity compared to other populations.

VNTR I/I genotype of insulin gene is associated with the increase of follicle number independent from polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is accompanied by selective insulin resistance and enhanced ovarian steroidogenic effects of insulin. We analysed the minisatellite variations of the insulin gene (INS VNTR) with regard to the clinical features of PCOS. Retrospective, adjusted association study. Infertile patients with PCOS (n=30) and tubal factor (n=75) were screened for anthropometrical, clinical and ovarian morphology parameters, as well as hormonal values. INS VNTR was genotyped by its surrogate marker at -23 HphI locus. INS VNTR genotype distribution was similar in PCOS and tubal infertility group. The mean ovarian follicle number was higher in VNTR I/I individuals compared to VNTR I/III and III/III individuals (adjusted OR=1.28, p=0.03), independent from the cause of infertility, the age, the follicle stimulating hormone level on day 3-5 of menstrual cycle, BMI and the previous surgical ovarian tissue removal. In addition, higher level of the luteinising hormone in VNTR I/I individuals was associated with the increase in follicle number. We suggest that INS VNTR genotypes are not associated with PCOS in general, but could have a certain influence on the phenotypic spectrum of the syndrome.

Effects of craving and DRD4 VNTR genotype on the relative value of alcohol: an initial human laboratory study

BackgroundCraving for alcohol is a highly controversial subjective construct and may be clarified by Loewenstein's visceral theory, which emphasizes craving's behavioral effects on the relative value of alcohol. Based on the visceral theory, this study examined the effects of a craving induction on the relative value of alcohol as measured by a behavioral choice task. In addition, based on previous evidence of its role in the expression of craving, the influence of DRD4 VNTR genotype (DRD4-L vs. DRD4-S) was also examined.MethodsThirty-five heavy drinkers (54% male; 31% DRD4-L) were randomly assigned to receive either a craving induction (exposure to personally relevant alcohol cues) or a control induction (exposure to neutral cues), which was followed by an alcohol-money choice task. Participants were assessed for craving and positive/negative affect throughout the procedure, and relative value of alcohol was derived from participant choices for alcohol versus money. DRD4 VNTR status was assessed retrospectively via buccal samples using previously established protocols.ResultsFactorial analysis of the craving induction revealed that it was associated with significant increase in craving (p < .001), but not greater relative value of alcohol. Factorial analyses including DRD4 VNTR genotype of did not suggest an influence on reactivity to the craving induction, although this analysis was substantially compromised by small cell sample sizes. Continuous analyses revealed that craving was significantly associated with the relative value of alcohol (p < .05) and possession of the DRD4-L allele further amplified this relationship (p < .001).ConclusionThese results are interpreted as generally supporting Loewenstein's visceral theory of craving and evidence of a functional role of DRD4 VNTR genotype in the expression of craving for alcohol. Methodological limitations, mechanisms underlying these findings, and future directions are discussed.

Two Insulin Gene Single Nucleotide Polymorphisms Associated with Type 1 Diabetes Risk in the Finnish and Swedish Populations

We have developed high-throughput tests for the detection of the insulin gene region SNPs −23HphI and −2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p = 0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both −23HphI and −2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.

5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism

The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism. The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3-19 years old) met diagnostic criteria for autistic disorder based on both measures. Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain "failure to use nonverbal communication to regulate social interaction," and the long group (L/L genotype) being more severe on the subdomain "stereotyped and repetitive motor mannerisms" and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.

5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism

Objective: The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism. Method: The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3–19 years old) met diagnostic criteria for autistic disorder based on both measures. Results: Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain “failure to use nonverbal communication to regulate social interaction,” and the long group (L/L genotype) being more severe on the subdomain “stereotyped and repetitive motor mannerisms” and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. Conclusions: These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.

Number of risk genotypes is a risk factor for major depressive disorder: a case control study

BackgroundThe objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects.MethodsA candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies.ResultsA statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group.ConclusionAn association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.

VNTR polymorphism of C6orf37 in Chinese population

To identify a novel VNTR in C6orf37 and to detect the C6orf37 VNTR polymorphism distribution in Chinese population. RT-PCR and sequencing were conducted to identify VNTR alleles in the variable region of C6orf37.SSLP and DHPLC were applied in detecting the VNTR genotypes in 166 Chinese individuals. A novel VNTR sequence was found in the second exon of C6orf37, which was composed of 15 base pairs encoding 5-amino-acid (G-G-D-F-G). The repeat times ranged from 3 to 5. There were three common alleles containing three repeats (a), four repeats (b) and five repeats (c), respectively, which produced three homozygotes (a/a, b/b and c/c) and three heterozygotes (a/b, a/c and b/c). The frequency of a, b, c alleles were 0.145, 0.304, 0.551, respectively in Chinese population. Heterozygosity (H) was 0.583. Polymorphism information content (PIC) was 0.510. The screened result of DHPLC was consistent with that of SSLP. A novel highly polymorphic VNTR in C6orf37 exists in Chinese population. DHPLC is the most efficient technique for screening VNTR polymorphism.

Serotonin Transporter Protein Polymorphism and Harm Avoidance Personality in Migraine without Aura

To investigate polymorphisms in the serotonin transporter protein gene and harm avoidance personality dimension in patients with migraine without aura (MWOA). The serotonin transporter protein is a key modulator of serotonergic synaptic neurotransmission. Two polymorphic regions of the gene for serotonin transporter protein have been found, and are associated with variations in the functional activity of serotonin caused by differing transcriptional efficiency. The harm avoidance (HA) personality trait may also be heritable and associated with altered serotonergic neurotransmitter activity. We amplified the polymorphism in the promoter of serotonin transporter protein (5-HTTLPR) and the variable number of tandem repeats polymorphism within intron 2 (VNTR) using the polymerase chain reaction and performed genotype polymorphism analyses in 97 patients with MWOA and 100 healthy controls. We investigated serotonin-related personality traits by evaluating the HA personality dimension using a tridimensional questionnaire. The genotype frequencies and allele distributions of 5-HTTLPR did not differ between patients with MWOA and controls. The VNTR genotype STin2.12/STin2.12 was significantly more common in patients with MWOA (90%) than in controls (77%; P= .017). Patients with MWOA also had HA scores (21.9 +/- 6.4) significantly higher than those of controls (16.3 +/- 6.1; P < .001). Serotonergic activity might be involved in the development of MWOA and VNTR of serotonin transporter gene might be one of the genetically contributing factors.

Identification of a novel VNTR polymorphism in C6orf37 and its association with colorectal cancer risk in Chinese population

Background C6orf37 was a gene up-regulated in colorectal adenoma in our previous study. A variable region of C6orf37 sequence was found when we blasted its full sequence with NCBI nucleotide database. Methods RT-PCR and sequencing were conducted to identify the variable region of C6orf37 as VNTR. DHPLC was applied to detect the VNTR genotypes in 122 colorectal carcinoma patients and 166 healthy controls. Results A novel VNTR sequence found in C6orf37 second exon was composed of 15 base pair consensus sequence encoding 5-amino-acid (G–G–D–F–G). The repeat timePOST http://ees.elsevier.com/cca/upload.aspx alleles contain three repeats (a), 4 repeats (b) and 5 repeats (c), respectively, which produced 3 homozygotes (a/a, b/b and c/c) and 3 heterozygotes (a/b, a/c and b/c). a, b, c allele frequencies were 0.145, 0.304, 0.551, respectively in Chinese population. Heterozygosity ( H) was 0.583. Polymorphism information content (PIC) was 0.510. The distribution of genotypes and allele frequencies of the VNTR reached no significant difference between patients and healthy controls and there was no correlation between VNTR polymorphism and colorectal cancer clincopathological features. Conclusion A novel VNTR polymorphism in C6orf37 exists in Chinese population and is not associated with colorectal cancer risk.

Association of Kir6.2 and INS VNTR variants with glucose homeostasis in young obese

Although insulin secretion is commonly increased and glucose tolerance decreased in young obese patients, there is a wide individual variability of these parameters. We investigated whether common variants at the Kir6.2 (KCNJ11) and insulin variable number of tandem repeat (INS VNTR) loci are associated with insulin or glucose levels in 388 obese children. The E23K and INS VNTR alleles showed no significant association when each locus was examined individually but a clear effect when the two loci were combined for analysis. In obese children with Kir6.2 KK and class III VNTR alleles, fasting glucose was slightly but consistently greater (4.76 +/- 0.05 mM) than in those with Kir6.2 EE and class I/I VNTR alleles (4.63 +/- 0.06 mM, P = 6.10(-4)) or other genotypes (4.64 +/- 0.03 mM, P = 1.10(-3)). Obese children with KK and class III VNTR genotypes also had an early response to oral glucose diminished by approximately 36% [insulinogenic index (IGI) = 50 +/- 4] compared with Kir6.2 EE and class I/I (IGI = 78 +/- 7, P = 0.026) or other genotypes (IGI = 69 +/- 3, P = 0.001). In young European obese, the polymorphisms of Kir6.2 and INS VNTR are thus associated with a trend for lower insulin and higher glucose levels, which may reveal a possible epistatic genetic effect that may influence a prediabetic trait in young obese children.

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Maternal-fetal interactions and birth order influence insulin variable number of tandem repeats allele class associations with head size at birth and childhood weight gain.

Polymorphism of the insulin gene (INS) variable number of tandem repeats (VNTR; class I or class III alleles) locus has been associated with adult diseases and with birth size. Therefore, this variant is a potential contributory factor to the reported fetal origins of adult disease. In the population-based Avon Longitudinal Study of Pregnancy and Childhood birth cohort, we have confirmed in the present study the association between the INS VNTR III/III genotype and larger head circumference at birth (odds ratio [OR] 1.92, 95% CI 1.23-3.07; P = 0.004) and identified an association with higher cord blood IGF-II levels (P = 0.05 to 0.0001). The genotype association with head circumference was influenced by maternal parity (birth order): the III/III OR for larger head circumference was stronger in second and subsequent pregnancies (OR 5.0, 95% CI 2.2-11.5; P = 0.00003) than in first pregnancies (1.2, 0.6-2.2; P = 0.8; interaction with birth order, P = 0.02). During childhood, the III/III genotype remained associated with larger head circumference (P = 0.004) and was also associated with greater BMI (P = 0.03), waist circumference (P = 0.03), and higher fasting insulin levels in girls (P = 0.02). In addition, there were interactions between INS VNTR genotype and early postnatal weight gain in determining childhood BMI (P = 0.001 for interaction), weight (P = 0.005), and waist circumference (P = 0.0005), such that in the approximately 25% of children (n = 286) with rapid early postnatal weight gain, class III genotype-negative children among this group gained weight more rapidly. Our results indicate that complex prenatal and postnatal gene-maternal/fetal interactions influence size at birth and childhood risk factors for adult disease.

INS VNTR is a QTL for the insulin response to oral glucose in obese children.

We performed a genotype-phenotype association study to examine whether the insulin VNTR (INS VNTR) polymorphism located in the insulin gene promoter was associated with changes in insulin response to oral glucose. Two classes of INS VNTR alleles are observed in Caucasians, the "short" class I and the "long" class III. Plasma insulin and glucose concentrations and indices of insulin secretion (IGI) and sensitivity (ISI) were measured using an oral glucose tolerance test (OGTT) in 387 obese children aged 12 +/- 0.1 yr with a mean body mass index (BMI) of 30.6 kg/m(2) (161% of the normal mean). During OGTT, plasma insulin and IGI were 20-30% higher in I/I obese children vs. III carriers (P < 0.01). A general linear model adjusting for age, sex, and puberty was also used to evaluate the influence of the VNTR genotype on the BMI-IGI (P = 0.07) and the BMI-ISI (P < 0.006) relationships. The INS VNTR can therefore be considered a quantitative trait locus influencing glucose-stimulated insulin physiology in obese juveniles.

Insulin gene VNTR genotype is associated with insulin sensitivity and secretion in infancy.

We have previously demonstrated that insulin sensitivity and secretion at age 1 year was in part related to variation in weight and height gain during infancy. In order to determine whether genetic variation at the insulin gene could also influence these associations, we have studied the relationship between insulin gene variable number of tandem repeat (INS VNTR) genotypes, insulin secretion and early postnatal growth. We assessed fasting and dynamic insulin secretion in 99 healthy infants at age 1 year, using a short intravenous glucose tolerance test (sIVGTT). Infants were genotyped at the -23 HphI locus, as a surrogate marker for INS VNTR allele classes I and III. Anthropometric data were recorded at birth and at 1 year. Data are shown as median (interquartile range). Fasting insulin levels were higher in III/III infants (n = 9) than in I/I infants [n = 55; 27.4 (17.6-75.6) pmol/l vs. 18.1 (10.3-25.2) pmol/l; P < 0.05]. Insulin secretion during the sIVGTT, as estimated by the serum insulin area under the curve, was also higher in III/III infants [2417 (891-4041) pmol min/l vs. 1208 (592-2284) pmol min/l; P < 0.05]. Fasting and postload plasma glucose levels were similar in both groups. Analysis of covariance showed that genotype differences in fasting insulin sensitivity and insulin secretion were independent of size at birth, postnatal growth velocity and current body mass index. Significant associations between INS VNTR genotype and both insulin sensitivity and secretion were apparent in infancy; these might interact with childhood appetite and nutrition to impact the development of childhood obesity and insulin resistance.

IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity.

Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/ insulin( INS) 5' variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk.