Biomedical subjects

Shirng-Wern Tsaih

Publications and source records attributed to Shirng-Wern Tsaih.

11 recordsLinked to original sources

PubMed2006

Complex genetic architecture revealed by analysis of high-density lipoprotein cholesterol in chromosome substitution strains and F2 crosses.

Intercrosses between inbred lines provide a traditional approach to analysis of polygenic inheritance in model organisms. Chromosome substitution strains (CSSs) have been developed as an alternative to accelerate the pace of gene identification in quantitative trait mapping. We compared a classical intercross and three CSS intercrosses to examine the genetic architecture underlying plasma high-density lipoprotein cholesterol (HDL) levels in the C57BL/6J (B) and A/J (A) mouse strains. The B x A intercross revealed significant quantitative trait loci (QTL) for HDL on chromosomes 1, 4, 8, 15, 17, 18, and 19. A CSS survey revealed that many have significantly different HDL levels compared to the background strain B, including chromosomes with no significant QTL in the intercross and, in some cases (CSS-1, CSS-17), effects that are opposite to those observed in the B x A intercross population. Intercrosses between B and three CSSs (CSS-3, CSS-11, and CSS-8) revealed significant QTL but with some unexpected differences from the B x A intercross. Our inability to predict the results of CSS intercrosses suggests that additional complexity will be revealed by further crosses and that the CSS mapping strategy should be viewed as a complement to, rather than a replacement for, classical intercross mapping.

Animals↗

PubMed2006

Structural model analysis of multiple quantitative traits.

We introduce a method for the analysis of multilocus, multitrait genetic data that provides an intuitive and precise characterization of genetic architecture. We show that it is possible to infer the magnitude and direction of causal relationships among multiple correlated phenotypes and illustrate the technique using body composition and bone density data from mouse intercross populations. Using these techniques we are able to distinguish genetic loci that affect adiposity from those that affect overall body size and thus reveal a shortcoming of standardized measures such as body mass index that are widely used in obesity research. The identification of causal networks sheds light on the nature of genetic heterogeneity and pleiotropy in complex genetic systems.

Adipose Tissue↗

PubMed2006

Femur mechanical properties in the F2 progeny of an NZB/B1NJ x RF/J cross are regulated predominantly by genetic loci that regulate bone geometry.

UNLABELLED: Genetic analysis of an NZB/B1NJ x RF/J cross has identified QTLs for femur mechanical, geometric, and densitometric phenotypes. Most mechanical QTLs were associated with geometric QTLs, strongly suggesting common genetic regulation. INTRODUCTION: Previous studies have shown that bone architecture and BMD are important factors affecting bone strength, and both are genetically regulated. We conducted genetic analyses for loci regulating femur mechanical properties, geometric properties, and BMD in a cohort of F2 mice derived from intercross matings of (NZB/B1NJ x RF/J)F1 parents. MATERIALS AND METHODS: Femurs were isolated from 662 10-week-old females. Mechanical properties were determined for a femur from each animal by three-point bending. Geometric properties and volumetric BMD (vBMD) were determined by pQCT. Genotype data were obtained by PCR assays for polymorphic markers carried in the genomic DNA of each mouse. Genome-wide scans were carried out for co-segregation of genetic marker data with values from 23 different phenotypes. Quantitative trait loci (QTLs) were identified for mechanical, geometric, and mineral density phenotypes. RESULTS: QTLs for many phenotypes were significantly refined by covariate analyses using body weight and femur length. Major QTLs for mechanical and geometric phenotypes were found on chromosomes 5, 7, 9, 11, and 12. Nine chromosomal locations were identified with mechanical QTLs and 17 locations with one or more geometric QTLs. The significance of five mechanical and nine geometric QTLs was affected by the inclusion of covariates. These changes included both decreases and increases in significance. The QTLs on chromosomes 5 and 12 were decreased by inclusion of the covariates in the analysis, but QTLs on 7 and 11 were unaffected. Mechanical QTLs were almost always associated with geometric QTLs and less commonly (two of six) with vBMD QTLs. CONCLUSIONS: Genetic regulation of mechanical properties in the F(2) mice of this NZB/B1NJ x RF/J cross seems to be caused by genes regulating femur geometry.

Animals↗

PubMed2005

Quantitative trait mapping in a diallel cross of recombinant inbred lines.

A recombinant inbred intercross (RIX) is created by generating diallel F1 progeny from one or more panels of recombinant inbred (RI) strains. This design was originally introduced to extend the power of small RI panels for the confirmation of quantitative trait loci (QTL) provisionally detected in a parental RI set. For example, the set of 13 C x B (C57BL/6ByJ x BALB/cByJ) RI strains can, in principle, be supplemented with 156 isogenic F1s. We describe and test a method of analysis, based on a linear mixed model, that accounts for the correlation structure of RIX populations. This model suggests a novel permutation algorithm that is needed to obtain appropriate threshold values for genome-wide scans of an RIX population. Despite the combinational multiplication of unique genotypes that can be generated using an RIX design, the effective sample size of the RIX population is limited by the number of progenitor RI genomes that are combined. When using small RI panels such as the C x B there appears to be only modest advantage of the RIX design when compared with the original RI panel for detecting QTLs with additive effects. The RIX, however, does have an inherent ability to detect dominance effects, and, unlike RI strains, the RIX progeny are genetically reproducible but are not fully inbred, providing somewhat more natural genetic context. We suggest a breeding strategy, the balanced partial RIX, that balances the advantage of RI and RIX designs. This involves the use of a partial RIX population derived from a large RI panel in which the available information is maximized by minimizing correlations among RIX progeny.

Animals↗

PubMed2004

Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice.

Hypertension is a complex phenotype induced by multiple environmental and genetic factors. Quantitative trait locus (QTL) analysis is a powerful method for identifying genomic regions underlying complex diseases. We conducted a QTL analysis of blood pressure in mice using 217 F(2) progeny (males and females) from a cross between the normotensive C3H/HeJ and hypertensive SWR/J inbred strains. Our analysis identified significant QTL controlling blood pressure on chromosome 1 [Chr 1; Bpq8; peak 78 cM; 95% confidence interval 64-106 cM; logarithm of the odds ratio (LOD) 3.5; peak marker D1Mit105] and on Chr 16 (Bpq9; peak 56 cM; 95% confidence interval 46-58 cM; LOD 3.6; peak marker D16Mit158). Bpq8 was previously identified in a cross between C57BL/6J and A/J mice, and we narrowed this QTL from 42 to 18 cM (95% confidence interval 68-86 cM) by combining the data from these crosses. By examining Bpq8 for regions where ancestral alleles were conserved among the high allele strains (C57BL/6J, SWR/J) and different from the low allele strains (A/J, C3H/HeJ), we identified a 2.3-cM region where the high allele strains shared a common haplotype. Bpq8 is concordant with known QTL in both rat and human, suggesting that the causal gene underlying Bpq8 may be conserved as a disease gene in human hypertension.

Animals↗

PubMed2004

Determinants of bone and blood lead levels among minorities living in the Boston area.

We measured blood and bone lead levels among minority individuals who live in some of Boston's neighborhoods with high minority representation. Compared with samples of predominantly white subjects we had studied before, the 84 volunteers in this study (33:67 male:female ratio; 31-72 years of age) had similar educational, occupational, and smoking profiles and mean blood, tibia, and patella lead levels (3 microg/dL, 11.9 microg/g, and 14.2 microg/g, respectively) that were also similar. The slopes of the univariate regressions of blood, tibia, and patella lead versus age were 0.10 microg/dL/year (p < 0.001), 0.45 microg/g/year (p < 0.001), and 0.73 microg/g/year (p < 0.001), respectively. Analyses of smoothing curves and regression lines for tibia and patella lead suggested an inflection point at 55 years of age, with slopes for subjects greater than or equal to 55 years of age that were not only steeper than those of younger subjects but also substantially steeper than those observed for individuals > 55 years of age in studies of predominantly white participants. This apparent racial disparity at older ages may be related to differences in historic occupational and/or environmental exposures, or possibly the lower rates of bone turnover that are known to occur in postmenopausal black women. The higher levels of lead accumulation seen in this age group are of concern because such levels have been shown in other studies to predict elevated risks of chronic disease such as hypertension and cognitive dysfunction. Additional research on bone lead levels in minorities and their socioeconomic and racial determinants is needed.

Adult↗

PubMed2004

Lead, diabetes, hypertension, and renal function: the normative aging study.

In this prospective study, we examined changes in renal function during 6 years of follow-up in relation to baseline lead levels, diabetes, and hypertension among 448 middle-age and elderly men, a subsample of the Normative Aging Study. Lead levels were generally low at baseline, with mean blood lead, patella lead, and tibia lead values of 6.5 microg/dL, 32.4 microg/g, and 21.5 microg/g, respectively. Six percent and 26% of subjects had diabetes and hypertension at baseline, respectively. In multivariate-adjusted regression analyses, longitudinal increases in serum creatinine (SCr) were associated with higher baseline lead levels but these associations were not statistically significant. However, we observed significant interactions of blood lead and tibia lead with diabetes in predicting annual change in SCr. For example, increasing the tibia lead level from the midpoints of the lowest to the highest quartiles (9-34 microg/g) was associated with an increase in the rate of rise in SCr that was 17.6-fold greater in diabetics than in nondiabetics (1.08 mg/dL/10 years vs. 0.062 mg/dL/10 years; p < 0.01). We also observed significant interactions of blood lead and tibia lead with diabetes in relation to baseline SCr levels (tibia lead only) and follow-up SCr levels. A significant interaction of tibia lead with hypertensive status in predicting annual change in SCr was also observed. We conclude that longitudinal decline of renal function among middle-age and elderly individuals appears to depend on both long-term lead stores and circulating lead, with an effect that is most pronounced among diabetics and hypertensives, subjects who likely represent particularly susceptible groups.

Adult↗

PubMed2003

Association between iron deficiency and blood lead level in a longitudinal analysis of children followed in an urban primary care clinic.

OBJECTIVE: To determine if iron deficiency (ID) is longitudinally associated with lead poisoning. STUDY DESIGN: Blood lead levels, hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), insurance status, and age were determined for 1,275 children. ID was defined as MCV <70 fl and RDW >14.5 if age was <2 years and MCV <73 fl and RDW >14.5 if age was >/=2 years. Logistic regression models were constructed by using the second-visit blood lead levels dichotomized at >/=0.48 microm/L (10 microg/dL) as the outcome. RESULTS: The odds ratio (OR) for baseline ID predicting lead poisoning at the second visit was 4.12 (95% CI, 1.96-8.65). In the second model, using children who were iron-replete at both visits as the referent group, for children with ID at both visits, the OR for predicting lead poisoning at the second visit was 5.54 (95% CI, 2.25-13.62). For children with ID at the first visit and iron-replete at the second visit, the OR was 2.73 (95% CI, 0.90-8.27), and for children iron-replete at the first visit and ID at the second visit, the OR was 0.81 (95% CI, 0.10-6.30). CONCLUSIONS: ID is associated with subsequent lead poisoning. These data are consistent with a biological mechanism of increased lead absorption among iron deficient children.

Anemia, Iron-Deficiency↗

PubMed2002

Correlates of bone and blood lead levels among middle-aged and elderly women.

In 1993-1995, the authors evaluated risk factors for elevated blood and bone lead levels in 264 Boston, Massachusetts, area women previously selected for a case-control study of lead and hypertension. Bone lead was measured at the tibia and patella with K x-ray fluorescence. Blood lead was analyzed by graphite furnace atomic absorption. Participants were aged 46-74 years and had mean lead levels of 3 (standard deviation, 2) micro g/dl (blood), 13 (standard deviation, 9) micro g/g (tibia), and 17 (standard deviation, 11) micro g/g (patella). In multivariate linear regression models, use of postmenopausal estrogen (inverse) and alcohol intake (positive) were significantly associated with blood lead levels. Both bone lead measures were significantly and positively associated with blood lead but only among postmenopausal women not using estrogen; for example, an increase from the first to the fifth quintile of tibia lead level (19 micro g/g) was associated with a 1.7- micro g/dl increase in blood lead (p = 0.0001) in this group. Older age and lower parity were associated with higher tibia lead; only age was associated with patella lead. The observed interaction of bone lead with estrogen status in determining blood lead supports the hypothesis that increased bone resorption, as occurs postmenopausally because of decreased estrogen production, results in heightened release of bone lead stores into blood.

Aged↗

PubMed2002

Occupational determinants of bone and blood lead levels in middle aged and elderly men from the general community: the Normative Aging Study.

BACKGROUND: Few studies of the general population have investigated risk factors for elevated levels of lead in bone in relation to occupation. METHODS: Six hundred and fifty six community-exposed men had their bone and blood lead levels measured (by K-X-ray fluorescence). Based on their occupational histories, participants were categorized into those who worked in white-collar (WC) occupations (59%) or blue-collar (BC) occupations (41%). No subjects had worked in a primary lead industry (e.g., smelting). RESULTS: In multivariate regression models that adjusted for age, race, education, smoking, alcohol ingestion and retirement status, BC subjects had tibia and patella lead concentrations that were 5.5 (95% CI: 3.2-7.8) and 6.5 (95% CI: 3.1-9.8) microg/g higher than WC subjects, respectively. Interaction terms pairing race with occupational status indicated that in non-white BC subjects, tibia and patella lead levels were higher still by 11.3 (95% CI: -2 to 24.5) and 20.5 (95% CI: 1.2-39.8) microg/g, respectively. Blood lead levels were low for these mostly retired men (mean [SD]: 6.1 [3.9] microg/g) and in multivariate regression models, occupational status was not a significant predictor of blood lead levels; however, an interaction between race and occupational status was also suggested, with non-white BC subjects having blood lead levels that were predicted to be higher by 4.5 (95% CI: 0.3-8.7) microg/dl. CONCLUSIONS: Bone lead levels are higher in the men who worked in BC occupations even if they have not worked in primary lead-exposed occupations. This effect is markedly stronger in non-white BC workers and suggests an interaction between occupational exposures and race/ethnicity with respect to cumulative exposure to lead. A similar interaction was suggested by models of blood lead levels.

Adult↗

PubMed2002

Maternal bone lead as an independent risk factor for fetal neurotoxicity: a prospective study.

OBJECTIVE: A number of prospective studies have examined lead levels in umbilical cord blood at birth as predictors of infant mental development. Although several have found significant inverse associations, others have not. Measurement of lead levels in maternal bone, now recognized as the source of much fetal exposure, has the potential to serve as a better or complementary predictor of lead's effect on the fetus. Our objective was to compare lead levels in umbilical cord blood and maternal bone as independent predictors of infant mental development using a prospective design. METHODS: We recruited women who were giving birth at 3 maternity hospitals in Mexico City that serve a homogeneous middle-class community. Umbilical cord blood lead levels were measured by graphite furnace atomic absorption spectroscopy, and maternal lead levels in cortical (tibial) and trabecular (patellar) bone were measured within 4 weeks of giving birth using a 109-Cd K-x-ray fluorescence instrument. At 24 months of age, each infant was assessed using the Bayley Scales of Infant Development-II (Spanish Version). RESULTS: A total of 197 mother-infant pairs completed this portion of the study and had data on all variables of interest. After adjustment for other well-known determinants of infant neurodevelopment, including maternal age, IQ, and education; paternal education; marital status; breastfeeding duration; infant gender; and infant illness, lead levels in umbilical cord blood and trabecular bone were significantly, independently, and inversely associated with the Mental Development Index (MDI) scores of the Bayley Scale. In relation to the lowest quartile of trabecular bone lead, the second, third, and fourth quartiles were associated with 5.4-, 7.2-, and 6.5-point decrements in adjusted MDI scores. A 2-fold increase in cord blood lead level (eg, from 5 to 10 micro g/dL) was associated with a 3.1-point decrement in MDI score, which is comparable to the magnitude of effect seen in previous studies. CONCLUSION: Higher maternal trabecular bone lead levels constitute an independent risk factor for impaired mental development in infants at 24 months of age. This effect is probably attributable to mobilization of maternal bone lead stores, a phenomenon that may constitute a significant public health problem in view of the long residence time of lead in bone.

Bone and Bones↗