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B D Mitchell

Publications and source records attributed to B D Mitchell.

At least 37 records · Page 2Linked to original sources
PubMed2000

Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans.

Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genome-wide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p approximately 109 cM from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from pter. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include GBE1 and ACOX2, which encode enzymes involved in glycogen and fatty acid metabolism, respectively.

Adult↗
PubMed2000

Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

Adult↗
PubMed1999

Diabetes and hypertension in Mexican American families: relation to cardiovascular risk.

There is a strong familial predisposition to type 2 diabetes, hypertension, and cardiovascular disease. The authors evaluated the association between a family history of these diseases and a large panel of cardiovascular risk factors in 1,431 Mexican American subjects who were enrolled in the San Antonio Family Heart Study in San Antonio, Texas. The baseline phase of the study covered 1992-1996. Diabetes and hypertension were diagnosed according to standard clinical criteria, while cardiovascular disease was defined as a history of heart attack or heart surgery. The prevalence of diabetes, hypertension, and cardiovascular disease in this population was 15%, 12%, and 3%, respectively. For each unaffected subject, the authors computed a family history score based on the presence or absence of disease in parents and older siblings, and correlations between cardiovascular risk factors and family history scores were estimated by using likelihood-based variance component methods. Diabetes family history score was significantly correlated with a broad panel of cardiovascular risk factors, including glucose and insulin, obesity, blood pressure, triglycerides, and total cholesterol. Hypertension family history score was significantly correlated with glucose, blood pressure, body mass index, waist circumference, total cholesterol, and triglycerides. These results support the idea that genes that confer a risk for diabetes, and to a lesser extent hypertension, adversely alter the cardiovascular risk profile long before the manifestation of clinical disease.

Adult↗
PubMed1999

Genetic determinants of variation in gallbladder disease in the Mexican-American population.

Since there have not been any studies that quantify the influence of genetic factors on gallbladder disease (GBD) in humans using information from families, we utilized pedigree data to explore the genetic control of variation in liability to GBD. Using an extension of a variance components approach, we performed genetic analyses of GBD using information from 32 low-income Mexican-American families with two slightly different general models incorporating several sex-specific GBD risk factors. After evaluating the relative magnitudes of the covariate effects from these two models, we identified a parsimonious model including only significant predictors of GBD. According to this model, heritability for GBD was high (h2 = 0.44+/-0.18), after accounting for the significant effects of age, leptin in both sexes, total cholesterol, and HDL cholesterol in males only. We have shown quantitatively that variation in GBD is under strong genetic control. However, there are two major limitations to our findings: (1) since GBD was defined by a self-reported clinical history rather than an ultrasound examination, the prevalence of GBD could have been underestimated; and (2) since our design did not allow for shared environmental effects, our estimate of heritability may have been inflated.

Adult↗
PubMed1999

The effect of phenotype variation on detection of linkage in the COGA data.

Error in phenotypic measurement can significantly compromise ability to detect linkage. We assessed the impact of introducing phenotypic measurement error on our ability to detect a quantitative trait locus in the Collaborative Study on the Genetics of Alcoholism (COGA) data. The impact of introducing three different types of errors was evaluated: 1) errors generated by sampling from a normal distribution; 2) errors generated by permuting phenotype values between subjects; and 3) errors generated by sampling from a uniform error distribution.

Alcoholism↗
PubMed1999

Identifying influential individuals in linkage analysis: application to a quantitative trait locus detected in the COGA data.

Once linkage is detected to a quantitative trait locus (QTL), the next step towards localizing the gene involved may be to identify those families, or individuals, in whom the putative mutations are segregating. In this paper, we describe a jackknife procedure for identifying individuals (and families) who contribute disproportionately to the linkage. Following initial detection of linkage to a QTL, the strategy involves sequentially removing each individual (or each family) from the analysis and recomputing the lod score associated with the linked region using data from all remaining subjects (or families). This procedure can be used to determine if particular observations have substantial impact on evidence for linkage. Identification of such observations may provide insights for further efforts to localize the QTL.

Alcoholism↗
PubMed1999

Application of an ordered subset analysis approach to the genetics of alcoholism.

For complex diseases, underlying etiologic heterogeneity may reduce power to detect linkage. Thus, methods to identify more homogeneous subgroups within a given sample in a linkage study may improve detection of putative susceptibility loci. In this study we describe an ordered subsetting approach that utilizes disease-related quantitative trait data to complement traditional linkage analysis. This approach uses family-based lod scores derived from the initial genome screen and a family-based descriptor of the trait of interest. The goal of the approach is to identify more homogeneous subgroups of the data by ranking families based on their quantitative trait data. Permutation testing is used to assess statistical significance. This approach can be adapted to a variety of linkage methods and may provide a means to dissect some of the underlying heterogeneity in complex disease genetics.

Alcoholism↗
PubMed1999

Relationship of low-density lipoprotein particle size and measures of adiposity.

OBJECTIVE: To determine if obesity measures are related to measures of low-density lipoprotein (LDL) size and LDL subfractions in a population of Mexican-Americans with high prevalence of obesity. METHODS: LDL size phenotypes, based on nondenaturing gradient gel electrophoresis and staining for cholesterol (using Sudan black B), were determined for 313 unrelated Mexican-American participants in the San Antonio Family Heart Study. LDL size measures included predominant particle diameter, median diameter (particle diameter, where half the LDL absorbance is on larger and half on smaller LDLs) and cholesterol level in various LDL subfractions. Adiposity traits included two measures of general body fatness (body-mass index (BMI) and fat mass determined with bioimpedance) and three measures of regional fat deposition (waist-to-hip ratio (WHR), waist circumference and subscapular-triceps skinfold ratio (STR)). RESULTS: Gender and diabetes were significantly associated with most LDL size measures. In addition, BMI, WHR, waist circumference and STR were significantly (P<0.05) associated with several LDL size measures. Stepwise regression analysis (including adjustment for age, gender and diabetes status) showed that in every case, the strongest adiposity correlate of LDL size, was WHR, which reflects deposition of visceral fat. If triglyceride (TG) concentration was also included in the models, no fat measure was independently correlated with LDL size, suggesting that elevation of TG, associated with increased adiposity, was more directly correlated with LDL size. Supporting this interpretation, we found that WHR was also the strongest correlate of TG among adiposity measures. Regression analysis of the LDL particle size cholesterol profile expressed in 0.1 nm increments revealed a positive correlation of WHR and LDLs in the interval 25.9-26.3 nm (P < 0.05) and a negative correlation of BMI with LDLs in the interval 27.3-28.1 nm (P < 0.05). CONCLUSION: These results suggest that different adiposity measures, reflecting different aspects of fat deposition, are related to specific LDL size intervals. We speculate that increased deposition of fat, particularly visceral fat, is associated with increased TG, which in turn is associated with decreases in LDL particle size.

Adipose Tissue↗
PubMed1999

Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC.

We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.

Chromosome Mapping↗
PubMed1999

A quantitative trait locus influencing BMI maps to the region of the beta-3 adrenergic receptor.

The beta-3 adrenergic receptor (ADRB3) has been implicated as a regulator of energy expenditure, and a polymorphism in codon 64 of this gene (Trp64Arg) has been associated in some studies with obesity and insulin resistance. However, many studies have failed to detect an effect of this variant, and the importance of the Trp64Arg variant in human obesity remains controversial. We performed a quantitative linkage analysis of the ADRB3 and obesity, using 12 markers (including the intragenic Trp64Arg polymorphism) spanning a 57-cM region of chromosome 8. The study population consisted of 470 individuals from 10 large multigenerational families of Mexican-American ancestry residing in San Antonio, TX. In two-point analysis, logarithm of odds (LOD) scores >1.0 were observed for six markers surrounding ADRB3 in a 33-cM region spanned by markers D8S1477 and D8S1136. The multipoint LOD score was 3.21, occurring between markers D8S1121 and ADRB3, approximately 2-3 cM from ADRB3. Adjusting for the presence of the Arg64 allele or excluding from the analysis the 11 individuals homozygous for the Arg64 allele did not reduce the evidence for linkage. A genome scan was conducted at 10 cM map density to detect other loci influencing variation in BMI. Multipoint LOD scores >1.0 were observed in four other regions, including two on chromosome 17, one on chromosome 6q, and one on chromosome 2p. These data suggest that the ADRB3 should continue to be regarded as a strong candidate gene for obesity even though evidence for an effect of the Trp64Arg polymorphism could not be established. It is also possible that a gene closely linked to ADRB3 may influence susceptibility to obesity.

Adult↗
PubMed1999

Excess maternal transmission of type 2 diabetes. The Northern California Kaiser Permanente Diabetes Registry.

OBJECTIVE: To assess excess maternal transmission of type 2 diabetes in a multiethnic cohort. Previous studies have reported higher prevalence of diabetes among mothers of probands with type 2 diabetes than among fathers. This analysis is vulnerable to biases, and this pattern has not been observed in all populations or races. RESEARCH DESIGN AND METHODS: We assessed evidence for excess maternal transmission among 42,533 survey respondents with type 2 diabetes (probands) by calculating the prevalence of diabetes in their siblings and offspring. To assess data quality, we evaluated completeness of family history data provided. Accuracy of family information reported by probands was also evaluated by comparing survey responses in a subsample of 206 probands with family histories modified after further interviews with relatives. RESULTS: Siblings (n = 60,532) of probands with affected mothers had a greater prevalence of diabetes (20%) than those with affected fathers (17%) (P < 0.001 for adjusted odds ratios). Prevalence of diabetes was higher among the offspring (n = 72,087) of female (3.4%) versus male (2.2%) probands (P < 0.001 for adjusted odds ratios). These patterns were evident in all races and both sexes; however, the effect size was clinically insignificant in African-Americans and male offspring. In general, probands provided more complete data about diabetes status for the maternal arm of the pedigree than the paternal arm. Completeness of knowledge was not related to proband sex, but was related to education and race, and inversely to age. Accuracy of proband-reported family history was consistently good (kappa statistics generally > 0.70). CONCLUSIONS: Excess maternal transmission was observed in all races and both sexes, although the size of the excess was negligible in African-Americans and male offspring. Potential reporting and censoring biases are discussed.

Adolescent↗
PubMed1998

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Adult↗
PubMed1998

Variant in sulfonylurea receptor-1 gene is associated with high insulin concentrations in non-diabetic Mexican Americans: SUR-1 gene variant and hyperinsulinemia.

The high-affinity sulfonylurea receptor (SUR1) gene regulates insulin secretion and may play a role in type 2 diabetes. A silent variant in exon 31 of SUR1 (AGG-->AGA) was detected by single-strand conformational polymorphism and genotypes were determined for 396 Mexican American subjects (289 non-diabetic). The normal and mutant alleles were designated G and A, respectively. Among non-diabetics, those with the AA genotype had higher fasting insulin values than those with the AG and GG genotypes (113.4 pmol/l for AA vs 82.8 pmol/l for AG/GG, P=0.043). Similar results were observed for 2-h insulin (849.6 pmol/l for AA vs 498.6 pmol/l for AG/GG, P=0.0003) and for the proinsulin to specific insulin ratio (0.068 for AA vs 0.056 for AG/GG, P=0.030). Specific insulin levels also differed significantly across the three genotypic classes (P=0.021). No differences in fasting glucose, body mass index, or waist circumference according to genotype were noted. Two-hour glucose was modestly higher in individuals with the AA genotype. Since we have previously reported linkage between SUR1 and hyperglycemia, the present association between a SUR1 variant and hyperinsulinemia in normal individuals from a high diabetes risk ethnic group raises the possibility of primary insulin hypersecretion as an antecedent of type 2 diabetes in at least some individuals from this population.

ATP-Binding Cassette Transporters↗
PubMed1997

Power of variance component linkage analysis to detect epistasis.

Variance component methods are now being used in linkage analysis to detect genes influencing complex diseases. These methods are easily extended to allow for simultaneous estimation of both the additive effects of multiple loci on phenotypic variation (conditional oligogenic analysis) and the additive interaction (epistatic) effects among loci. We performed linkage analyses on 200 of the simulated replicates in order to evaluate the power to detect the main effects of MG1 and MG2 on Q1 as well as their interaction effects. The power to detect the main effect of MG1 was moderately good, although the power to detect MG2 and the MG1 x MG2 interaction was poor.

Analysis of Variance↗
PubMed1997

TRP64ARG beta 3-adrenergic receptor and obesity in Mexican Americans.

The beta 3-adrenergic receptor (beta 3AR) is expressed in visceral fat and is a regulator of resting metabolic rate, thermogenesis, and lipolysis. We genotyped 61 unrelated Mexican Americans for a variant in the beta 3AR gene (codon 64 TGGTrp-->CGGArg; TRP64ARG). The allele frequency was 0.13. The TRP64ARG variant was significantly associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (41.3 +/- 4.6 years vs 55.6 +/- 2.6 years; P < 0.02) and in non-diabetics, with elevated 2-h insulin levels during an oral glucose tolerance test (810 +/- 120 pmol/l vs 384 +/- 6 pmol/l; P < 0.005). Non-diabetic subjects with the variant allele tended to have higher body mass indices (BMI), waist-to-hip ratios, and diastolic blood pressures. The study group was expanded to include 421 related subjects from 31 families in the San Antonio Family Diabetes Study. Using a measured genotype analysis approach to estimate genotype-specific means for each trait, those who were homozygous for the TRP64ARG variant had significantly higher 2-h insulin levels (P = 0.036) and trends towards higher BMI compared to the other two genotypes. We detected no associations of these traits in the TRP64ARG heterozygotes in the larger group. We conclude that the TRP64ARG beta 3AR variant is a susceptibility gene for several features of the insulin resistance syndrome in Mexican Americans. Since its effects are modest, study design (e.g., subject selection, genetic background, and statistical analyses) may influence which traits are associated with this variant and whether or not the effect is detectable in heterozygotes.

Arginine↗
PubMed1997

Familial aggregation of age-related maculopathy.

PURPOSE: To determine whether age-related maculopathy aggregates in families by evaluating whether its prevalence is higher among relatives of case subjects with age-related maculopathy compared with relatives of control subjects without age-related maculopathy. METHODS: Individuals with (n = 119) and without (n = 72) age-related maculopathy were identified. First-degree relatives of case and control probands (parents, siblings, or offspring) 40 years of age or older were asked whether they had ever been diagnosed with macular degeneration. Medical records of 177 case and 146 control relatives confirmed the presence or absence of age-related maculopathy. RESULTS: The prevalence of medical-record confirmed age-related maculopathy was significantly higher among first-degree relatives of case probands (23.7%) compared with first-degree relatives of control probands (11.6%) with an age- and sex-adjusted odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.7; P = .013. Relatives of 78 case probands with exudative disease had a significantly higher prevalence of maculopathy (26.9%) compared with relatives of the 72 unaffected control probands (11.6%) (adjusted OR, 3.1; 95% CI, 1.5 to 6.7; P = .003), whereas the prevalence of age-related maculopathy among relatives of 41 probands with dry maculopathy (19.2%) was slightly but not significantly higher (adjusted OR, 1.5; 95% CI, 0.6 to 3.7; P = .36). CONCLUSIONS: The prevalence of age-related maculopathy among first-degree relatives of subjects with age-related maculopathy, particularly with exudative disease, is greater than among first-degree relatives of subjects without this disease. Results suggest that macular degeneration has a familial component and that genetic or shared environmental factors, or both, contribute to its development.

Adult↗
PubMed1997

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Adipose Tissue↗