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S J Hasstedt

Publications and source records attributed to S J Hasstedt.

At least 19 recordsLinked to original sources
PubMed2002

Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q.

Macrovascular disease is a major complication of type 2 diabetes. Epidemiological data suggest that the risk of macrovascular complications may predate the onset of hyperglycemia. Hypertriglyceridemia, low levels of HDL cholesterol, and an atherogenic profile characterize the insulin resistance/metabolic syndrome that is also prevalent among nondiabetic members of familial type 2 diabetic kindreds. To identify the genes for lipid-related traits, we first performed a 10-cM genome scan using 440 markers in 379 members of 19 multiplex families ascertained for two diabetic siblings (screening study). We then extended findings for three regions with initial logarithm of odds (LOD) scores >1.5 to an additional 23 families, for a total of 576 genotyped individuals (extended study). We found heritabilities for all lipid measures in the range of 0.31 to 0.52, similar to those reported by others in unselected families. However, we found the strongest evidence for linkage of triglyceride levels to chromosome 19q13.2, very close to the ApoC2/ApoE/ApoC1/ApoC4 gene cluster (LOD 2.56) in the screening study; the LOD increased to 3.16 in the extended study. Triglyceride-to-HDL cholesterol ratios showed slightly lower LOD scores (2.73, extended family) in this same location. Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the NIDDM1 locus. Neither region showed stronger evidence for linkage in the extended studies, however. Our results suggest that genes in or near the ApoE/ApoC2/ApoC1/ApoC4 cluster on 19q13.2 may contribute to the commonly observed hypertriglyceridemia and low HDL seen in diabetic family members and their offspring, and thus may be a candidate locus for the insulin resistance syndrome.

Adolescent↗
PubMed2001

Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds.

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.

Alanine↗
PubMed2001

Role of common sequence variants in insulin secretion in familial type 2 diabetic kindreds: the sulfonylurea receptor, glucokinase, and hepatocyte nuclear factor 1alpha genes.

OBJECTIVE: We have demonstrated high heritability of insulin secretion measured as acute insulin response to glucose times insulin sensitivity (disposition index). Furthermore, we showed that obese normoglycemic family members of a type 2 diabetic proband failed to compensate for the insulin resistance of obesity by increasing insulin secretion. In this study, we tested the primary hypotheses that previously described variants in the pancreatic sulfonylurea receptor gene (SUR1 or ABCC8), glucokinase (GCK) gene, or hepatocyte nuclear factor 1alpha (TCF1 or HNF1alpha) gene contribute to the inherited deficiencies of insulin secretion and beta-cell compensation to insulin resistance, as well as the secondary hypotheses that these variants altered insulin sensitivity. RESEARCH DESIGN AND METHODS: We typed 124 nondiabetic members of 26 familial type 2 diabetic kindreds who had undergone tolbutamide-modified intravenous glucose tolerance tests for two variants of the ABCC8 (sulfonylurea) gene, two variants of the GCK gene, and one common amino acid variant in the TCF1 (HNF1alpha) gene. All family members were classified as normal or having impaired glucose tolerance based on oral glucose tolerance testing. We used minimal model analysis to calculate the insulin sensitivity index (S1) and glucose effectiveness (SG), and acute insulin response to glucose was calculated as the mean insulin excursion above baseline during the first 10 min after the glucose bolus. Disposition index (DI), a measure of beta-cell compensation for insulin sensitivity, was calculated as insulin sensitivity times acute insulin response. Effects of polymorphisms were determined using mixed effects models that incorporated family membership and by a likelihood analysis that accounted for family structure through polygenic inheritance. RESULTS: An intronic variant of the ABCC8 gene just upstream of exon 16 was a significant determinant of both DI and an analogous index based on acute insulin response to tolbutamide. Surprisingly, heterozygous individuals showed the lowest indexes, whereas the DI in the two homozygous states did not differ significantly. Neither the exon 18 variant nor the variants in the GCK and TCF1 genes were significant in this model. However, combined genotypes of ABCC8 exon 16 and 18 variants again significantly predicted both indexes of glucose and tolbutamide-stimulated insulin secretion. Unexpectedly, a variant in the 3' untranslated region of the GCK gene interacted significantly with BMI to predict insulin sensitivity. CONCLUSIONS: The exon 16 variant of the ABCC8 gene reduced beta-cell compensation to the decreased insulin sensitivity in the heterozygous state. This may explain the observation from several groups of an association of the ABCC8 variants in diabetes and is consistent with other studies showing a role of ABCC8 variants in pancreatic beta-cell function. However, our study focused on individuals from relatively few families. Ascertainment bias, family structure, and other interacting genes might have influenced our unexpected result. Additional studies are needed to replicate our observed deficit in beta-cell compensation in individuals heterozygous for ABCC8 variants. Likewise, the role of the GCK 3' variant in the reduced insulin sensitivity of obesity will require further study.

ATP-Binding Cassette Transporters↗
PubMed2001

Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred.

The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.

Blood Coagulation Factors↗
PubMed2000

The G20210A prothrombin polymorphism is not associated with increased thromboembolic risk in a large protein C deficient kindred.

Likelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 +/- 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 +/- 0.130 NS). Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 +/- 2% to 124 +/- 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (approximately 2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.

Female↗
PubMed1999

Heritability of pancreatic beta-cell function among nondiabetic members of Caucasian familial type 2 diabetic kindreds.

Both defective insulin secretion and insulin resistance have been reported in relatives of type 2 diabetic subjects. We tested 120 members of 26 families with a type 2 diabetic sibling pair with a tolbutamide-modified, frequently sampled i.v. glucose tolerance test to determine the insulin sensitivity index (S(I)) and acute insulin response to glucose (AIRglucose). A measure of beta-cell compensation for insulin sensitivity was calculated as the product S(I) x AIRglucose, based on the demonstrated hyperbolic relationship between insulin sensitivity and insulin secretion. A percentile score for this compensation was assigned based on published values. Of the 120 family members, 26 had previously diagnosed impaired glucose tolerance on oral testing, and 94 had normal glucose tolerance tests. As a group, family members showed a significantly lower S(I) x AIRglucose than a similar, previously reported, control population, even when impaired glucose tolerance members were excluded. We performed a multivariate analysis of diabetes status, S(I), AIRglucose and to estimate the heritability of each trait and the genetic and environmental correlations between traits. We estimated the heritability of S(I) x AIRglucose to be 67 +/- 3% when all members were included and 70 +/- 4% when only normal glucose tolerance members were considered. Both AIRglucose and S(I) were also familial, albeit with lower heritabilities (38 +/- 1% and 38 +/- 2%, respectively, for all family members). Both S(I) x AIRglucose and S(I) showed strong negative genetic correlations with diabetes (-85 +/- 3% and -87 +/- 2%, respectively, all family members), whereas AIRglucose did not correlate with diabetes. We conclude that insulin secretion, as measured by S(I) x AIRglucose, is decreased in nondiabetic members of familial type 2 diabetic kindreds, that S(I) x AIRglucose in these high risk families is highly heritable, and that the same polygenes may determine diabetes status and a low S(I) x AIRglucose. Our data suggest that insulin secretion, when expressed as an index normalized for insulin sensitivity, is more familial than either insulin sensitivity or first phase insulin secretion alone and may be a very useful trait for identifying genetic predisposition to type 2 diabetes.

Adult↗
PubMed1999

A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians.

Considerable evidence supports a major inherited component of type 2 diabetes. We initially conducted a genome-wide scan with 440 microsatellite markers at 10-cM intervals in 19 multigenerational families of Northern European ancestry with at least two diabetic siblings. Initial two-point analyses of these families directed marker typing of 23 additional families. Subsequently, all available marker data on the total of 42 families were analyzed using both parametric and nonparametric multipoint methods to test for linkage to type 2 diabetes. One locus on chromosome 1q21-1q23 met genome-wide criteria for significant linkage under a model of recessive inheritance with a common diabetes allele (logarithm of odds [LOD] = 4.295). Both pedigree-based nonparametric linkage (NPL) analysis and affected sib pair (MAPMAKER/SIBS) nonparametric methods also showed the highest genome-wide scores at this region, near markers CRP and APOA2, but failed to meet levels of genome-wide significance. The risk of type 2 diabetes to siblings of a diabetic person when compared with the population (lambdaS) was estimated from MAPMAKER/SIBS to be 2.8 in these 42 families. Simulation studies using study data confirmed a genome-wide significance level of P<0.05 (95% CI 0.005-0.0466). However, analysis of 20 similarly ascertained but smaller families failed to confirm this linkage. The LOD score with 50% heterogeneity for all 62 families considered together was only 2.25, with an estimated lambdaS of 1.87. Our data suggest a novel diabetes susceptibility locus near APOA2 on chromosome 1 in a region with many transcribed genes.

Adult↗
PubMed1998

Evidence of genetic transmission in African iron overload.

Iron overload in Africa was previously regarded as purely due to excessive iron in traditional beer, but we recently found evidence that transferrin saturation and unsaturated iron binding capacity may be influenced by an interaction between dietary iron content and a gene distinct from any HLA-linked locus. To determine if serum ferritin follows a genetic pattern and to confirm our previous observations, we studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was characterized with repeated morning measurements of serum ferritin, transferrin saturation, and unsaturated iron binding capacity after supplementation with vitamin C. For each measure of iron status, segregation analysis was consistent with an interaction between a postulated iron-loading gene and dietary iron content (P < .01). In the most likely model, transferrin saturation is 75% and serum ferritin is 985 micrograms/L in a 40-year-old male heterozygote with an estimated beer consumption of 10,000 L, whereas the saturation is 36% and serum ferritin is 233 micrograms/L in an unaffected individual with identical age, sex, and beer consumption. This segregation analysis provides further evidence for a genetic influence on iron overload in Africans.

Adult↗
PubMed1998

Is there a link between African iron overload and the described mutations of the hereditary haemochromatosis gene?

Over 80%, of Caucasian patients with hereditary haemochromatosis are homozygotes for a C282Y mutation in the HFE gene on chromosome 6. Recent evidence suggests that a genetic factor may also be involved in the pathogenesis of African iron overload, although the locus has not been described. PCR analysis of DNA from 25 southern Africans, identified by segregation analysis as having a high probability of carrying the putative African iron-loading gene, failed to identify any subjects with the C282Y mutation. The possible genetic defect in African iron overload appears to be different from that described in most cases of hereditary haemochromatosis in Caucasians.

Adult↗
PubMed1998

An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency.

We used two-locus segregation analysis to test whether an unknown genetic defect interacts with protein C deficiency to increase susceptibility to venous thromboembolic disease in a single large pedigree. Sixty-seven pedigree members carry a His107Pro mutation in the protein C gene, which reduces protein C levels to a mean of 46% of normal. Twenty-one carriers of the mutation and five other pedigree members had verified thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficiency, by rejecting the hypothesis that the cases of thromboembolic disease resulted from protein C deficiency alone and by not rejecting Mendelian transmission of the interacting gene. When coinherited with protein C deficiency, the interacting gene conferred a probability of a thrombotic episode of approximately 79% for men and approximately 99% for women, before age 60 years.

Adolescent↗
PubMed1997

Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and lack of linkage to nine candidate genes.

Segregation analysis of body-mass index (BMI) supported recessive inheritance of obesity, in pedigrees ascertained through siblings with non-insulin dependent diabetes mellitus (NIDDM). BMI was estimated as 39 kg/m2 for those subjects homozygous at the inferred locus. Two-locus segregation analysis provided weak support for a second recessive locus, with BMI estimated as 32 kg/m2 for homozygotes. NIDDM prevalence was increased among those subjects presumed to be homozygous at either locus. Using both parametric and nonparametric methods, we found no evidence of linkage of obesity to any of nine candidate genes/regions, including the Prader-Willi chromosomal region (PWS), the human homologue of the mouse agouti gene (ASP), and the genes for leptin (OB), the leptin receptor (OBR/DB), the beta3-adrenergic receptor (ADRB3), lipoprotein lipase (LPL), hepatic lipase (LIPC), glycogen synthase (GYS), and tumor necrosis factor alpha (TNFA).

Adult↗
PubMed1995

Phenotypic assortative mating in segregation analysis.

A model of phenotypic assortative mating was developed for application in segregation analysis. The model assumed a constant spouse correlation across the range of a quantitative trait or the liability to a discrete trait. Four traits were analyzed to evaluate: 1) the feasibility of applying likelihood analysis to pedigree data in order to distinguish between assortative mating and shared environmental effects as the source of spouse correlation; and 2) the impact on segregation analysis of the failure to account for either assortative mating or shared environmental effects, as appropriate. Height ratio (the ratio of sitting to standing height) and eye color comprised the traits for which the observed spouse correlation reflected assortative mating; serum cholesterol and peptic ulcers (with genotypes defined by the ABO blood group) comprised the traits for which the observed spouse correlation reflected shared environmental effects. For all four traits the test statistics agreed with the known cause of spouse correlation; however, significance was not attained for height ratio or serum cholesterol. The ability to distinguish between the causes of spouse correlation in pedigree data presumably depends on trait and sample characteristics which remain to be delineated. Despite significant spouse correlation, its omission from the segregation analysis model did not undermine the inference of major locus inheritance for any of the four traits. However, the lack of an impact for these traits does not preclude an impact for other traits of ignoring the appropriate spouse correlation in segregation analysis.

Environment↗
PubMed1995

Intermediate inheritance of Tourette syndrome, assuming assortative mating.

Segregation analysis incorporating assortative mating was used to test for major locus inheritance of Tourette syndrome in a single large pedigree containing 182 members. The analysis provided evidence of a major locus with an intermediate inheritance pattern for which the penetrance was estimated from the data as 28% in heterozygotes and 98%-99% in homozygotes. A significant assortative mating correlation was estimated from the data as 70%-79%. In contrast, when assortative mating was not included in the model, intermediate inheritance was not inferred. If, in addition, constancy of the allele frequencies across generations was not assumed, Mendelian transmission was rejected. Each subject, affected or unaffected, was assigned a score reflecting the presence and severity of symptoms. Higher means scores in affected homozygotes than in affected heterozygotes suggested greater severity in homozygotes: genotype information was obtained from genotype probabilities computed assuming intermediate inheritance.

Adolescent↗
PubMed1994

Evidence for multiple genes determining sodium transport.

Sodium transport comprises a set of interacting systems. Consequently, a defective sodium transport gene affects multiple sodium transport systems, and a sodium transport variable measured on a sample of individuals reflects genetic variation from a number of different genes, complicating the task of identifying the effect of a single gene. To test for genes which affect sodium transport, we first applied principal components analysis to 14 variables related to sodium transport, thereby defining uncorrelated sources of variation in the variables. The sample consisted of 1,218 members of 68 pedigrees ascertained through probands with early-onset stroke, hypertension, or coronary heart disease. Segregation analysis of the 14 principal components scores provided evidence for 8 genetic variants which alter sodium transport. One of the 8 variants is recessive, has homozygous genotype frequency estimated as 8.8% of the population, and increases sodium-lithium countertransport, the passive sodium leak, body mass index, and triglyceride; the genetic variant may coincide with an insulin resistance gene. A second of the 8 variants is also recessive, has homozygous genotype frequency estimated as 7.4% of the population, and increases intraerythrocytic sodium and the passive sodium leak while decreasing sodium pump number; the genetic variant may reduce pump number. Two of the 8 variants substantially increase sodium-lithium countertransport; frequency estimates for heterozygotes for the dominant variant and homozygotes for the recessive variant equal 1.8% and 3.1%, respectively. Another of the 8 variants is recessive, has homozygous genotype frequency estimated as 1.9%, and increases body mass index. Each of the 3 remaining variants is rare and expressed in less than 1% of the sample.

Cardiovascular Diseases↗
PubMed1994

HLA-linked rheumatoid arthritis.

Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 2.16%, and estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-half of familial RA, although it accounts for only approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically.

Adolescent↗
PubMed1994

Tabulations and expectations regarding the genetics of human hypertension.

Results from family studies suggest several possible single gene traits may be related to essential hypertension in humans. Results of segregation analysis are reviewed for six possibly related traits (high sodium-lithium countertransport, low urinary kallikrein excretion, high fasting plasma insulin level, a fat pattern index, dense LDL subfractions, and body mass index). Eight genetic loci (on chromosomes 1, 6, 8, 17 and 19) are possibly related to essential hypertension in humans and are also reviewed. Two of them (GRA and AGT) are well-established. Glucocorticoid remediable aldosteronism (GRA) is attributable to a well-defined mutation on chromosome 8q21 and leads to the production of high levels of abnormal adrenal steroid hormones with subsequent aldosteronism, early severe hypertension, and strokes. This form of hypertension is unresponsive to ordinary medications but very responsive to glucocorticoid hormone administration. The angiotensinogen (AGT) locus on chromosome 1q4 has been related to hypertension in sibship linkage studies, association studies, and studies of angiotensinogen levels by genotype in three different populations (Utah, France, Japan). This locus seems to be associated with more severe essential hypertension and also with preeclampsia. Genetic heterogeneity, imprecision in measuring specific phenotypes, and variability in sampling methods in populations studied may all contribute to weaknesses and inconsistencies between reported studies. However, growing evidence for several single gene traits promoting susceptibility to hypertension offers opportunities for identifying genetically profiled subsets of patients in whom specific environmental interventions or specific types of medications will achieve more focused prevention and treatment of hypertension and its complications.

Animals↗
PubMed1993

Variance components/major locus likelihood approximation for quantitative, polychotomous, and multivariate data.

Pearson [Philos Trans R Soc Lond [A] 200:1-66, 1903], Mendell and Elston [Biometrics 30:41-57, 1974], and Rice et al. [Biometrics 35:451-459, 1979] approximated the likelihood of the multifactorial model on a dichotomous phenotype by a procedure of successive univariate computation and conditioning. Hasstedt [Pap: Pedigree Analysis Package, Rev. 3. 1989] and Demenais [Am J Hum Genet 49:773-785, 1991] extended the algorithm to include a major locus. Here I extend the algorithm to polychotomous, quantitative, and multivariate phenotypes, add a major locus to the model, and describe and evaluate the accuracy of an approximation of the resulting variance components/major locus model.

Algorithms↗