Biomedical subjects

Jose R Fernandez

Publications and source records attributed to Jose R Fernandez.

5 recordsLinked to original sources

PubMed2006

Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women.

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S(i)), acute insulin response to glucose (AIR(g)), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR(g) adjusted for S(i) in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S(i). The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S(i) and higher AIR(g) observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.

Adult↗

PubMed2005

Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation.

Understanding the distribution of human genetic variation is an important foundation for research into the genetics of common diseases. Some of the alleles that modify common disease risk are themselves likely to be common and, thus, amenable to identification using gene-association methods. A problem with this approach is that the large sample sizes required for sufficient statistical power to detect alleles with moderate effect make gene-association studies susceptible to false-positive findings as the result of population stratification. Such type I errors can be eliminated by using either family-based association tests or methods that sufficiently adjust for population stratification. These methods require the availability of genetic markers that can detect and, thus, control for sources of genetic stratification among populations. In an effort to investigate population stratification and identify appropriate marker panels, we have analysed 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations. Individuals in each population cluster to the exclusion of individuals from other populations using two clustering methods. Higher-order branching and clustering of the populations are consistent with the geographic origins of populations and with previously published genetic analyses. These data provide a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies. Using three US resident populations (European-American, African-American and Puerto Rican), we demonstrate how such studies can proceed, quantifying proportional ancestry levels and detecting significant admixture structure in each of these populations.

Chromosomes, Human, X↗

PubMed2004

Rimonabant Sanofi-Synthélabo.

Rimonabant, an antagonist of central cannabinoid type 1 (CB1) receptors, is being developed by Sanofi-Synthélabo for the potential treatment of obesity and as a potential smoking cessation agent. Phase III trials were initiated for obesity in August 2001 and were ongoing in September 2003. By September 2002, the compound had entered phase III trials for smoking cessation, and these trials were ongoing in September 2003.

Animals↗

PubMed2002

Bias in estimates of quantitative-trait-locus effect in genome scans: demonstration of the phenomenon and a method-of-moments procedure for reducing bias.

An attractive feature of variance-components methods (including the Haseman-Elston tests) for the detection of quantitative-trait loci (QTL) is that these methods provide estimates of the QTL effect. However, estimates that are obtained by commonly used methods can be biased for several reasons. Perhaps the largest source of bias is the selection process. Generally, QTL effects are reported only at locations where statistically significant results are obtained. This conditional reporting can lead to a marked upward bias. In this article, we demonstrate this bias and show that its magnitude can be large. We then present a simple method-of-moments (MOM)-based procedure to obtain more-accurate estimates, and we demonstrate its validity via Monte Carlo simulation. Finally, limitations of the MOM approach are noted, and we discuss some alternative procedures that may also reduce bias.

Bias↗

PubMedDate not supplied

Cardiovascular factors explain genetic background differences in VO2max.

The purpose of this study was to further explore factors that may be related to ethnic differences in the maximum rate at which an individual can consume oxygen (VO2max) between 20 African American (AA) and 30 European American (EA) sedentary women who were matched for body weight (kg) and fat-free mass (FFM). VO2max (l/min) was determined during a graded treadmill exercise test. Submaximal steady-state heart rate and submaximal VO2 were determined at a treadmill speed of 1.3 m/sec and a 2.5% grade. Hemoglobin (Hb) was determined by the cyanide method, muscle oxidative capacity by 31P magnetic resonance spectroscopy (ADP time constant), and FFM (kg) by dual-energy x-ray absorptiometry. Genetic classification was self-reported, and in a subset of the sample (N = 32), the determinants of ethnicity were measured by African genetic admixture. AA women had significantly reduced VO2max, Hb levels, and muscle oxidative capacity (longer ADP time constants, P < or = 0.05) than EA women. Submaximal oxygen pulse (O2Psubmax), ADP time constant, Hb, and ethnic background were all significantly related to VO2max (ml/kg/min and ml/kg FFM/min, all P < or = 0.01). By multiple regression modeling, Hb, O2Psubmax, muscle oxidative capacity, and ethnicity were found to explain 61% and 57% of the variance of VO2max in ml/kg/min and ml/kg FFM/min, respectively. Muscle oxidative capacity and O2Psubmax were both significantly and independently related to VO2max in all three models (P < or = 0.05), whereas Hb and ethnicity were not. These results suggest that mitochondrial muscle oxidative capacity and oxygen delivery capabilities, as determined by O2Psubmax, account for most if not all of the ethnic differences in VO2max.

Adenosine Diphosphate↗