A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Secondary intraocular lenses in eyes with aphakia or dislocated IOL: impact of suture fixation on early and late complications.

BACKGROUND: Secondary intraocular lens (IOL) implantation is exposed to an increased risk of complications, including endophthalmitis and retinal detachment. The present analysis compares the outcomes and complications experienced in our own series of patients. PATIENTS AND METHODS: We retrospectively reviewed a consecutive series of secondary posterior chamber IOL implantations performed in a single centre, two surgeon setting over a period of 8 years and with a follow up-time of at least 4 months. RESULTS: Between 1997 and 2005, 75 patients received a sulcus-supported secondary IOL without suture fixation, whereas suture fixation was required in 137 instances. Visual acuity improved in both groups (group 1: from 0.36 +/- 0.39 (0.01-1.2) to 0.73 +/- 0.33 (0.02-1.0; p = 0.18); group 2: from 0.33 +/- 0.34 (0.02-1.0) to 0.46 +/- 0.33 (0.01-1.0; p = 0.006), but more pronounced in eyes not requiring suture fixation (p = 0.012). IOL placement was more likely to be combined with endophacoemulsification in the not suture-fixed IOLs (12.7 vs. 5.3 %). In contrast, retinal tears (10.6 vs. 8.6 %, respectively) and retinal detachment (5.3 vs. 2.2 %, respectively) were equally distributed. In the early postoperative phase, IOP was lower in suture-fixed eyes, which showed a higher incidence of minor intraocular haemorrhages and cystoid macular edema (5.3 vs. 8.0 %); late complications up to 5 years postoperatively were equally distributed. CONCLUSION: A preoperatively less complicated anterior segment situation and a lower incidence of postoperative macular edema may account for a better visual outcome after placement of a sulcus supported IOLs without suturing. If required, suture fixation may be performed without exposing the eye to an increased risk of late postoperative complications.

Genome scan of schizophrenia families in a large Veterans Affairs Cooperative Study sample: evidence for linkage to 18p11.32 and for racial heterogeneity on chromosomes 6 and 14.

Genome-wide linkage analyses of schizophrenia have identified several regions that may harbor schizophrenia susceptibility genes but, given the complex etiology of the disorder, it is unlikely that all susceptibility regions have been detected. We report results from a genome scan of 166 schizophrenia families collected through the Department of Veterans Affairs Cooperative Studies Program. Our definition of affection status included schizophrenia and schizoaffective disorder, depressed type and we defined families as European American (EA) and African American (AA) based on the probands' and parents' races based on data collected by interviewing the probands. We also assessed evidence for racial heterogeneity in the regions most suggestive of linkage. The maximum LOD score across the genome was 2.96 for chromosome 18, at 0.5 cM in the combined race sample. Both racial groups showed LOD scores greater than 1.0 for chromosome 18. The empirical P-value associated with that LOD score is 0.04 assuming a single genome scan for the combined sample with race narrowly defined, and 0.06 for the combined sample allowing for broad and narrow definitions of race. The empirical P-value of observing a LOD score as large as 2.96 in the combined sample, and of at least 1.0 in each racial group, allowing for narrow and broad racial definitions, is 0.04. Evidence for the second and third largest linkage signals come solely from the AA sample on chromosomes 6 (LOD = 2.11 at 33.2 cM) and 14 (LOD = 2.13 at 51.0). The linkage evidence differed between the AA and EA samples (chromosome 6 P-value = 0.007 and chromosome 14 P-value = 0.004).

Toxic effects of indocyanine green, infracyanine green, and trypan blue on the human retinal pigmented epithelium.

BACKGROUND: Indocyanine green, infracyanine green, and trypan blue are frequently used as aids to visualize structures removed during vitreoretinal surgery. But they may have toxic effects on the retina. We therefore compared the acute and chronic toxicities of these stains on cultured human retinal pigmented epithelial (RPE) cells using clinically relevant concentrations and an identical experimental setup for each agent. METHODS: Monolayers of RPE cells were incubated with various concentrations of indocyanine green, infracyanine green (each at 0.005%, 0.05%, and 0.5%) or trypan blue (0.05%, 0.06%, 0.1%, 0.15%, and 0.5%) for 5 min (acute exposure) or 6 days (chronic exposure). Using the propidium iodide assay, acute cytotoxicity was monitored at 15-min intervals for up to 3 h. Chronic cytotoxicity was assessed by monitoring cell calcein esterase activity, cell proliferation, and cell morphology (viability) after 6 days of exposure. RESULTS: Indocyanine and infracyanine green induced acute and chronic toxicities at a concentration above 0.05%. Trypan blue evoked no acute toxicity, but it was chronically cytotoxic at all tested concentrations. CONCLUSIONS: Despite thorough rinsing after application, significant amounts of the not sufficiently water soluble indocyanine and infracyanine green are retained after surgery by the eye. Trypan blue, being more water-soluble than ICG, is probably retained to the least degree. This circumstance is fortunate given that trypan blue exhibits a chronic cytotoxicity comparable to ICG at all clinically relevant concentrations. During vitrectomy, surgeons should aim to expose retinal tissue to only low concentrations of these stains and for as short a period as possible.

Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects.

AIMS/HYPOTHESIS: Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with type 2 diabetes and related traits in a Finnish sample. METHODS: In 781 cases with type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with type 2 diabetes and related traits. RESULTS: The SNPs were not significantly associated with type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls. CONCLUSIONS/INTERPRETATION: Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance.

Modest evidence for linkage and possible confirmation of association between NOTCH4 and schizophrenia in a large Veterans Affairs Cooperative Study sample.

Wei and Hemmings [2000: Nat Genet 25:376-377], using 80 British parent-offspring trios, identified a number of NOTCH4 variants and haplotypes that showed statistically significant evidence of association to schizophrenia. Specifically, the 10 repeat allele of a (CTG)(n) marker and the 8 repeat allele of a (TAA)(n) marker demonstrated excess transmission to affected individuals; SNP21 and haplotypes SNP2-(CTG)(n) and SNP12-SNP2-(CTG)(n) also showed significant associations. In an attempt to replicate these findings, we tested for linkage and association between the same five markers used by Wei and Hemmings in 166 families collected from a multi-center study conducted by the Department of Veterans Affairs (DVA) Cooperative Study Program (CSP). The families include 392 affected subjects (schizophrenia or schizoaffective disorder, depressed) and 216 affected sibling pairs. The families represent a mix of European Americans (n = 62, 37%), African Americans (n = 60, 36%), and racially mixed or other races (n = 44, 27%). We identified moderate evidence for linkage in the pooled race sample (LOD = 1.25) and found excess transmission of the 8 (P = 0.06) and 13 (P = 0.04) repeat alleles of the (TAA)(n) marker to African American schizophrenic subjects. The 8 and 13 repeat alleles were previously identified to be positively associated with schizophrenia by Wei and Hemmings [2000: Nat Genet 25:376-377] and Sklar et al. [2001: Nat Genet 28:126-128], respectively.

Leber's hereditary optic neuropathy mitochondrial DNA mutations in normal-tension glaucoma.

BACKGROUND: in Leber's hereditary optic neuropathy, increased optic nerve cupping has been reported by several authors. Recently, a mitochondrial DNA (mtDNA) mutation at nucleotide 11778 typically associated with Leber's hereditary optic neuropathy (LHON) was identified in a patient treated for glaucoma but lacking typical signs of LHON. The question arises: should all normal-tension glaucoma patients be further evaluated for LHON? METHODS: we screened 54 unselected patients with normal-tension glaucoma (age range 20-96 years, 16 men and 38 women) for the primary mtDNA LHON mutations at nucleotides 3460, 11778 and 14484. RESULTS: none of the patients harboured the mtDNA mutations at nucleotides 3460, 11778 or 14484 (95% confidence intervals for each mutation ranged from 0% to 5.3%). CONCLUSIONS: primary LHON mtDNA mutations are rare or absent in unselected normal-tension glaucoma patients. Therefore, unselected normal-tension glaucoma patients should not be screened for these mutations. It is probable that only normal-tension glaucoma patients with atypical features (rapid progression, early deep central scotoma, pallor of neuroretinal rim, elevated disc, peripapillary teleangiectasia) or a positive family history of visual loss compatible with a matrilinear transmission should be further evaluated.

Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies.

The study of complex genetic traits in humans is limited by the expense and difficulty of ascertaining populations of sufficient sample size to detect subtle genetic contributions to disease. Here we introduce an application of a somatic cell hybrid construction strategy called conversion that maximizes the genotypic information from each sampled individual. The approach permits direct observation of individual haplotypes, thereby eliminating the need for collecting and genotyping DNA from family members for haplotype-based analyses. We describe experimental data that validate the use of conversion as a whole-genome haplotyping tool and evaluate the theoretical efficiency of using conversion-derived haplotypes instead of conventional genotypes in the context of haplotype-frequency estimation. We show that, particularly when phenotyping is expensive, conversion-based haplotyping can be more efficient and cost-effective than standard genotyping.

Lod scores for gene mapping in the presence of marker map uncertainty.

Multipoint lod scores are typically calculated for a grid of locus positions, moving the putative disease locus across a fixed map of genetic markers. Changing the order of a set of markers and/or the distances between the markers can make a substantial difference in the resulting lod score curve and the location and height of its maximum. The typical approach of using the best maximum likelihood marker map is not easily justified if other marker orders are nearly as likely and give substantially different lod score curves. To deal with this problem, we propose three weighted multipoint lod score statistics that make use of information from all plausible marker orders. In each of these statistics, the information conditional on a particular marker order is included in a weighted sum, with weight equal to the posterior probability of that order. We evaluate the type 1 error rate and power of these three statistics on the basis of results from simulated data, and compare these results to those obtained using the best maximum likelihood map and the map with the true marker order. We find that the lod score based on a weighted sum of maximum likelihoods improves on using only the best maximum likelihood map, having a type 1 error rate and power closest to that of using the true marker order in the simulation scenarios we considered.

Linkage disequilibrium between microsatellite markers extends beyond 1 cM on chromosome 20 in Finns.

Linkage disequilibrium (LD) is a proven tool for evaluating population structure and localizing genes for monogenic disorders. LD-based methods may also help localize genes for complex traits. We evaluated marker-marker LD using 43 microsatellite markers spanning chromosome 20 with an average density of 2.3 cM. We studied 837 individuals affected with type 2 diabetes and 386 mostly unaffected spouse controls. A test of homogeneity between the affected individuals and their spouses showed no difference, allowing the 1223 individuals to be analyzed together. Significant (P < 0.01) LD was observed using a likelihood ratio test in all (11/11) marker pairs within 1 cM, 78% (25/32) of pairs 1-3 cM apart, and 39% (7/18) of pairs 3-4 cM apart, but for only 12 of 842 pairs more than 4 cM apart. We used the human genome project working draft sequence to estimate kilobase (kb) intermarker distances, and observed highly significant LD (P < 10(-10)) for all six marker pairs up to 350 kb apart, although the correlation of LD with cM is slightly better than the correlation with megabases. These data suggest that microsatellites present at 1-cM density are sufficient to observe marker-marker LD in the Finnish population.

The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences.

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.

Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds.

Improved inference of relationship for pairs of individuals.

Linkage analyses of genetic diseases and quantitative traits generally are performed using family data. These studies assume the relationships between individuals within families are known correctly. Misclassification of relationships can lead to reduced or inappropriately increased evidence for linkage. Boehnke and Cox (1997) presented a likelihood-based method to infer the most likely relationship of a pair of putative sibs. Here, we modify this method to consider all possible pairs of individuals in the sample, to test for additional relationships, to allow explicitly for genotyping error, and to include X-linked data. Using autosomal genome scan data, our method has excellent power to differentiate monozygotic twins, full sibs, parent-offspring pairs, second-degree (2 degrees ) relatives, first cousins, and unrelated pairs but is unable to distinguish accurately among the 2 degrees relationships of half sibs, avuncular pairs, and grandparent-grandchild pairs. Inclusion of X-linked data improves our ability to distinguish certain types of 2 degrees relationships. Our method also models genotyping error successfully, to judge by the recovery of MZ twins and parent-offspring pairs that are otherwise misclassified when error exists. We have included these extensions in the latest version of our computer program RELPAIR and have applied the program to data from the Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus (FUSION) study.

Effect of fortified antibiotic solutions on corneal epithelial wound healing.

PURPOSE: To evaluate the influence of fortified antibiotic eyedrops on corneal epithelial wound healing. METHODS: We developed an in vitro epithelial wound-healing model to evaluate the toxicity of antibiotics. An excimer laser was used to create an epithelial defect 1.5 mm in diameter, 70 microm in depth on the central area of porcine cornea. The intact animal globes were maintained in the incubator by a perfusion system. Fortified antibiotics: 10% piperacillin, 5% cefazolin, 0.5% chloramphenicol, 5% vancomycin, 1% amikacin, 2% gentamicin, and 0.1% amphotericin B were applied to the wound in three applications. The wounds were evaluated 24 h after setup with fluorescein stain and a scoring system. RESULTS: The 0.1% amphotericin B and 2% gentamicin disturbed the corneal epithelial healing rate significantly. The remaining antibiotics did not interfere with the epithelial healing rate in our study design. CONCLUSION: Fortified antibiotic eyedrops demonstrated varied degrees of influence on corneal epithelial wound healing. When antibiotic eyedrops are used, both the efficacy and toxicity of the antibiotics should be the major concern. If efficacy is equivalent, less-toxic agents should be given preference.

A multipoint method for detecting genotyping errors and mutations in sibling-pair linkage data.

The identification of genes contributing to complex diseases and quantitative traits requires genetic data of high fidelity, because undetected errors and mutations can profoundly affect linkage information. The recent emphasis on the use of the sibling-pair design eliminates or decreases the likelihood of detection of genotyping errors and marker mutations through apparent Mendelian incompatibilities or close double recombinants. In this article, we describe a hidden Markov method for detecting genotyping errors and mutations in multilocus linkage data. Specifically, we calculate the posterior probability of genotyping error or mutation for each sibling-pair-marker combination, conditional on all marker data and an assumed genotype-error rate. The method is designed for use with sibling-pair data when parental genotypes are unavailable. Through Monte Carlo simulation, we explore the effects of map density, marker-allele frequencies, marker position, and genotype-error rate on the accuracy of our error-detection method. In addition, we examine the impact of genotyping errors and error detection and correction on multipoint linkage information. We illustrate that even moderate error rates can result in substantial loss of linkage information, given efforts to fine-map a putative disease locus. Although simulations suggest that our method detects

Early aqueous humor analysis in patients with human ocular toxoplasmosis.

To evaluate the diagnostic sensitivity of a panel of laboratory tests for ocular toxoplasmosis performed at the time of presentation, paired samples of aqueous humor and serum were collected from 49 consecutive episodes of ocular toxoplasmosis with a clinical course of less than 3 weeks. Total immunoglobulin G (IgG) and Toxoplasma gondii-specific IgG, IgM, and IgA were quantified by enzyme-linked immunosorbent assay. The avidity of T. gondii-specific IgG was determined, and DNA extracted from aqueous humor was amplified for detection of a glycoprotein B gene sequence of T. gondii. The diagnosis was confirmed for 73% (36 of 49) of the patients; this rate rose to 79.5% if data from a later analysis of aqueous humor derived from five of the negative patients were included. The analysis of serum (detection of T. gondii-specific IgM and analysis of consecutive serum samples) alone did not contribute to the diagnosis. Calculation of local antibody production lacked diagnostic sensitivity when it was determined less than 3 weeks after the manifestation of clinical symptoms (28 of 49 patients [57%]), but this rose to 70% after an analysis of a second aqueous humor sample. The antibody avidity index attained diagnostic significance in only 8 of 43 instances (19%), and T. gondii DNA was amplified from no more than 6 of 39 (16%) aqueous humor samples. However, T. gondii-specific IgA was found within the aqueous humors of 11 of 43 patients (26%); measurement of the T. gondii-specific IgA level thus contributed substantially to the diagnostic sensitivity of the laboratory tests.

Point and interval estimates of marker location in radiation hybrid mapping.

Radiation hybrid (RH) mapping is a powerful method for ordering loci on chromosomes and for estimating the distances between them. RH mapping is currently used to construct both framework maps, in which all markers are ordered with high confidence (e.g., 1,000:1 relative maximum likelihood), and comprehensive maps, which include markers with less-confident placement. To deal with uncertainty in the order and location of markers, marker positions may be estimated conditional on the most likely marker order, plausible intervals for nonframework markers may be indicated on a framework map, or bins of markers may be constructed. We propose a statistical method for estimating marker position that combines information from all plausible marker orders, gives a measure of uncertainty in location for each marker, and provides an alternative to the current practice of binning. Assuming that the prior distribution for the retention probabilities is uniform and that the marker loci are distributed independently and uniformly on an interval of specified length, we calculate the posterior distribution of marker position for each marker. The median or mean of this distribution provides a point estimate of marker location. An interval estimate of marker location may be constructed either by using the 100(alpha/2) and 100(1-alpha)/2 percentiles of the distribution to form a 100(1-alpha) % posterior credible interval or by calculating the shortest 100(1-alpha) % posterior credible interval. These point and interval estimates take into account ordering uncertainty and do not depend on the assumption of a particular marker order. We evaluate the performance of the estimates on the basis of results from simulated data and illustrate the method with two examples.

Eyelid, conjunctival, and corneal findings in sleep apnea syndrome.

OBJECTIVE: To determine the prevalence of eyelid, conjunctival, and corneal findings in patients with sleep apnea syndrome (SAS). DESIGN: Case series. PARTICIPANTS: Seventy-two white patients referred for evaluation of suspected SAS. INTERVENTION: Complete examination of eyelids, conjunctiva, and cornea, including videokeratography. MAIN OUTCOME MEASURES: Spearman rank correlations were determined between the respiratory disturbance index (RDI) during night sleep, a value used to diagnose and grade SAS, and tear film break-up time, eyelid distraction distance, presence or absence of ocular irritation symptoms, blepharoptosis, floppy eyelids, lacrimal gland prolapse, keratoconus, and endothelial dystrophy. Each correlation was controlled for age and body mass index. RESULTS: According to the RDI, 44 (61 %) of the 72 patients had SAS. The RDI correlated positively with the eyelid distraction distance (P = 0.05), presence or absence of floppy eyelids (P = 0.01), and lacrimal gland prolapse (P = 0.01), and correlated negatively with tear film break-up time (P = 0.02). None of our patients with floppy eyelids had corneal abnormalities. One patient with SAS had bilateral keratoconus; another had bilateral Fuch endothelial dystrophy. CONCLUSIONS: Sleep apnea syndrome was significantly associated with reduced tear film break-up time, floppy eyelids, and lacrimal gland prolapse. However, ocular irritation symptoms and corneal involvement were rare among patients with SAS. These findings do not confirm previous studies that reported a high prevalence of corneal involvement in floppy eyelid syndrome.

Familiality of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators.

Type 2 diabetes mellitus (NIDDM) is a complex disorder encompassing multiple metabolic defects. There exists strong evidence for a genetic component to NIDDM; however, to date there have been few reports of linkage between genetic markers along the genome and NIDDM or NIDDM-related quantitative traits. We sought to determine whether individual quantitative traits which determine glucose tolerance exhibit familiality in Finnish families with at least one NIDDM-affected sibling pair. Tolbutamide-modified frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on unaffected offspring (n = 431) and spouses (n = 154) of affected sibling pairs sampled for the Finland-United States Investigation of NIDDM Genetics (FUSION) study. FSIGT data were analyzed using the Minimal Model to obtain quantitative measures of insulin sensitivity (SI), glucose effectiveness (SG), and insulin secretion assessed as the acute insulin response to glucose (AIR). The disposition index (DI), a measure of insulin resistance-corrected beta-cell function, was also derived as the product of SI and AIR. Variance components analysis was used to determine for each trait, the heritability (h2), the proportion of the total trait variance accounted for by additive genes. After adjustment for age, gender, and body mass index, h2 estimates were: SG: 18 +/- 9%, SI: 28 +/- 8%, AIR: 35 +/- 8%, and DI: 23 +/- 8%. We conclude that there is strong evidence for modest heritability of Minimal-Model-derived NIDDM-related quantitative traits in unaffected spouses and offspring of Finnish affected sibling pairs.