Richard L. Bauer

Quantitative Trait Loci on Chromosomes 2p, 4p, and 13q Influence Bone Mineral Density of the Forearm and Hip in Mexican Americans

We performed a genome scan using BMD data of the forearm and hip on 664 individuals in 29 Mexican‐American families. We obtained evidence for QTL on chromosome 4p, affecting forearm BMD overall, and on chromosomes 2p and 13q, affecting hip BMD in men.

The Association of Obesity and Glucose and Insulin Concentrations With Bone Density in Premenopausal and Postmenopausal Women

Obese subjects have increased bone density relative to non-obese subjects, yet this relationship is not fully understood. We examined whether alterations in glucose or insulin concentrations might explain the effect of obesity on bone density in 317 women from the San Antonio Heart Study, a population-based study of diabetes. We measured fasting and 2-hour plasma glucose and fasting and 2-hour serum insulin levels. Bone density was assessed by a Hologic dual-photon absorptiometer. Lumbar spine and femoral neck density were positively correlated with body mass index (BMI). Femoral neck density also was positively correlated with fasting insulin level in younger women after adjustment for age (r = .214, P < .01). After further adjustment for BMI, femoral neck density was not significantly correlated with fasting insulin level (P = .08). The magnitude of the estimated femoral neck density difference for a 32.2-microU/mL decrease in fasting insulin level (the difference in insulin concentrations between nondiabetics and diabetics) was 0.13 g/cm2. Adjustment for glucose and insulin concentrations does not explain the association between bone density and obesity.

Genetic and environmental determinants of bone mineral density in Mexican Americans: results from the San Antonio Family Osteoporosis Study.

Osteoporosis is a major cause of disability in the United States. Numerous factors contribute to the decline in bone mineral density (BMD) that characterizes this disease, and the importance of heredity is now widely appreciated. We evaluated the joint contributions of genes and environmental factors on variation in BMD in 895 participants of the San Antonio Family Osteoporosis Study (SAFOS). Participants of the SAFOS ranged in age from 18 to 96 years and were members of 34 large families of Mexican American ancestry. BMD was measured at the spine, hip, and forearm by dual-energy X-ray absorptiometry. Information about medical history, lifestyle habits, dietary intake, and physical activity patterns was obtained by questionnaire. Age and body mass index were strongly associated with BMD at nearly every site; these and other measured risk factors accounted in aggregate for up to 46% of the total variation in BMD. In general, the environmental risk factors accounted for proportionately more of the total variation in BMD in men than in women. Genes accounted for 65-80% of the residual variation in spine and hip BMD, and 25-55% of the residual variability in forearm BMD. Although residual heritabilities were generally comparable between men and women across all ages combined, heritabilities at all sites tended to be higher in premenopausal women than in men younger than 50 years of age. Identifying the individual genes involved will shed insights into the processes that govern bone remodeling and may suggest strategies for the prevention of osteoporosis.

Genome Scan for Determinants of Serum Uric Acid Variability

Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.

Bone Mineral Density, Carotid Artery Intimal Medial Thickness, and the Vitamin D Receptor BsmI Polymorphism in Mexican American Women

Low bone mineral density (BMD) is a predictor of cardiovascular mortality, suggesting that osteoporosis and cardiovascular disease may share common risk factors. We assessed the relationship between BMD and intimal medial thickening (IMT) of the common carotid artery, a marker of sub-clinical atherosclerosis, in 471 women examined as part of the San Antonio Family Osteoporosis Study, a population-based study of osteoporosis risk conducted in Mexican American families. Because of the documented role of vitamin D metabolism in bone metabolism and its possible role in cardiovascular function, we further evaluated whether allelic variation at the vitamin D receptor locus (VDR) influenced joint variation in BMD and IMT. The association of BMD with IMT depended on age, with low BMD being correlated with high IMT in older women, but with low IMT in younger women [age by IMT interaction effects significant at the spine (P = 0.042), radius ultradistal (P = 0.010), and hip (P = 0.006)]. In all women, the VDR BsmI BB genotype was associated with significantly higher forearm BMD (P = 0.005 for both radius ultradistal and midpoint), higher IMT (P = 0.05), and higher spine BMD in older women (P = 0.06), but not with hip BMD. The association of the VDR genotype with IMT was independent of its association with BMD. Although a functional consequence of the BsmI polymorphism on vitamin D metabolism has not been established, these findings support a possible biological relationship among VDR, bone metabolism, and atherosclerosis. We conclude that VDR polymorphisms may be one of multiple factors influencing the joint risk of atherosclerosis and osteoporosis.

A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS

BACKGROUND Chronic kidney disease (CKD) phenotypes such as albuminuria measured by urinary albumin creatinine ratio (ACR), elevated serum creatinine (SrCr) and/or decreased creatinine clearance (CrCl) and glomerular filtration rate (eGFR) are major risk factors for renal and cardiovascular diseases. Epidemiological studies have reported that CKD phenotypes cluster in families suggesting a genetic predisposition. However, studies reporting chromosomal regions influencing CKD are very limited. Therefore, the purpose of this study is to identify susceptible chromosomal regions for CKD phenotypes in Mexican American families enrolled in the San Antonio Family Heart Study (SAFHS). METHODS We used the variance components decomposition approach (implemented in the software package SOLAR) to perform linkage analysis on 848 participants from 26 families. A total of 417 microsatellite markers were genotyped at an average interval of 10 cM spanning 22 autosomal chromosomes. RESULTS All phenotypes were measured by standard procedures. Mean +/- SD values of ACR, SrCr, CrCl and eGFR were 0.06 +/- 0.38, 0.85 +/- 0.72 mg/dl, 129.85 +/- 50.37 ml/min and 99.18 +/- 25.69 ml/min/1.73 m(2) body surface area, respectively. All four CKD phenotypes exhibited significant heritabilities (P < 0.0001). A genome-wide scan showed linkage on chromosome 2p25 for SrCr, CrCl and eGFR. Significant linkage was also detected on chromosome 9q21 for eGFR [logarithm of the odds (LOD) score = 3.87, P = 0.00005] and SrCr (LOD score = 2.6, P = 0.00026). ACR revealed suggestive evidence for linkage to a region on chromosome 20q12 (LOD score = 2.93, P = 0.00020). CONCLUSION Findings indicate that chromosomal regions 2p25, 9q21 and 20q12 may have functional relevance to CKD phenotypes in Mexican Americans.

Genetics of variation in serum uric acid and cardiovascular risk factors in Mexican Americans

BACKGROUND Elevated serum uric acid is associated with several cardiovascular disease (CVD) risk factors such as hypertension, inflammation, endothelial dysfunction, insulin resistance, dyslipidemia, and obesity. However, the role of uric acid as an independent risk factor for CVD is not yet clear. OBJECTIVE The aim of the study was to localize quantitative trait loci regulating variation in serum uric acid and also establish the relationship between serum uric acid and other CVD risk factors in Mexican Americans (n = 848; men = 310, women = 538) participating in the San Antonio Family Heart Study. METHODS Quantitative genetic analysis was conducted using variance components decomposition method, implemented in the software program SOLAR. RESULTS Mean +/- SD of serum uric acid was 5.35 +/- 1.38 mg/dl. Univariate genetic analysis showed serum uric acid and other CVD risk markers to be significantly heritable (P < 0.005). Bivariate analysis showed significant correlation of serum uric acid with body mass index, waist circumference, waist/hip ratio, total body fat, plasma insulin, serum triglycerides, high-density lipoprotein cholesterol, C-reactive protein, and granulocyte macrophage-colony stimulating factor (P < 0.05). A genome-wide scan for detecting quantitative trait loci regulating serum uric acid variation showed a significant logarithm of odds (LOD) score of 4.72 (empirical LOD score = 4.62; P < 0.00001) on chromosome 3p26. One LOD support interval contains 25 genes, of which an interesting candidate gene is chemokine receptor 2. SUMMARY There is a significant genetic component in the variation in serum uric acid and evidence of pleiotropy between serum uric acid and other cardiovascular risk factors.

Genetics of variation in HOMA-IR and cardiovascular risk factors in Mexican-Americans

Insulin resistance is a major biochemical defect underlying the pathogenesis of cardiovascular disease (CVD). Mexican-Americans are known to have an unfavorable cardiovascular profile. Thus, the aim of this study was to investigate the genetic effect on variation in HOMA-IR and to evaluate its genetic correlations with other phenotypes related to risk of CVD in Mexican-Americans. The homeostatic model assessment method (HOMA-IR) is one of several approaches that are used to measure insulin resistance and was used here to generate a quantitative phenotype for genetic analysis. For 644 adults who had participated in the San Antonio Family Heart Study (SAFHS), estimates of genetic contribution were computed using a variance components method implemented in SOLAR. Traits that exhibited significant heritabilities were body mass index (BMI) (h2 = 0.43), waist circumference (h2 = 0.48), systolic blood pressure (h2 = 0.30), diastolic blood pressure (h2 = 0.21), pulse pressure (h2 = 0.32), triglycerides (h2 = 0.51), LDL cholesterol (h2 = 0.31), HDL cholesterol (h2 = 0.24), C-reactive protein (h2 = 0.17), and HOMA-IR (h2 = 0.33). A genome-wide scan for HOMA-IR revealed significant evidence of linkage on chromosome 12q24 (close to PAH (phenylalanine hydroxylase), LOD = 3.01, p < 0.001). Bivariate analyses demonstrated significant genetic correlations (p < 0.05) of HOMA-IR with BMI (ρG = 0.36), waist circumference (ρG = 0.47), pulse pressure (ρG = 0.39), and HDL cholesterol (ρG = -0.18). Identification of significant linkage for HOMA-IR on chromosome 12q replicates previous family-based studies reporting linkage of phenotypes associated with type 2 diabetes in the same chromosomal region. Significant genetic correlations between HOMA-IR and phenotypes related to CVD risk factors suggest that a common set of gene(s) influence the regulation of these phenotypes.

Episodic secretion of parathyroid hormone in postmenopausal women: Assessment by deconvolution analysis and approximate entropy

In healthy young subjects, parathyroid hormone (PTH) is secreted presumptively in a dual fashion, with low amplitude pulses apparently superimposed on tonic secretion. In contrast, PTH secretion has not been as well characterized in postmenopausal women, and relationships among bone density, estrogen status, and PTH release have not been explored. It is possible that a pulsatile pattern of PTH secretion is important for bone remodeling, since exogenous PTH administered in a pulsatile manner stimulates bone formation. To assess the importance of pulsatile PTH secretion as a determinant of bone mass, we measured PTH in blood sampled every 2 minutes for 6 h in four groups of older women: (1) high bone density receiving estrogen (n = 6), (2) high bone density not receiving estrogen (n = 5), (3) low bone density receiving estrogen (n = 6), and (4) low bone density not receiving estrogen (n = 8). The plasma PTH release profiles were subjected to deconvolution analysis, which resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In postmenopausal subjects, PTH was secreted in a fashion similar to that observed in young adults, with significant tonic secretion and PTH pulse occurrences averaging every 18–19 minutes. Pulsatile PTH secretion accounted for approximately 25% of the total secreted PTH. There were no differences in the amplitude or frequency of pulsatile PTH secretory parameters or in ApEn values among the four groups or compared with young controls. We conclude that in postmenopausal women, PTH secretory patterns and temporal organization are similar to those in healthy young subjects and are not altered in states of low bone density or estrogen deficiency. This suggests that abnormalities in orderly pulsatile PTH secretion are unlikely to play a major role in established postmenopausal osteoporosis.

Risk of postmenopausal hip fracture in Mexican American women

To assess the risk of hip fracture in Mexican Americans, the ethnicity of 80 women aged 50 years and over admitted with hip fractures to a Texas hospital was compared with that of age-matched women hospitalized for other reasons. The risk of fracture for Mexican Americans was only 35 per cent that of Whites (95% CI = 19 per cent, 65 per cent). This finding was confirmed in a chart survey performed in a second hospital population. These results suggest that Mexican American women may receive less potential benefit from preventive measures for hip fracture than Whites.