Biomedical subjects

Donna M Lehman

Publications and source records attributed to Donna M Lehman.

9 recordsLinked to original sources

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2005

Bivariate linkage analysis of the insulin resistance syndrome phenotypes on chromosome 7q.

Metabolic abnormalities of the insulin resistance syndrome (IRS) have been shown to aggregate in families and to exhibit trait-pair correlations, suggesting a common genetic component. A broad region on chromosome 7q has been implicated in several studies to contain loci that cosegregate with IRS-related traits. However, it is not clear whether such loci have any common genetic (pleiotropic) influences on the correlated traits. Also, it is not clear whether the chromosomal regions contain more than one locus influencing the IRS-related phenotypes. In this study we present evidence for linkage of five IRS-related traits [body mass index (BMI), waist circumference (WC), In split proinsulin (LSPI), In triglycerides (LTG), and high-density lipoprotein cholesterol (HDLC)] to a region at 7q11.23. Subsequently, to gain further insight into the genetic component(s) mapping to this region, we explored whether linkage of these traits is due to pleiotropic effects using a bivariate linkage analytical technique, which has been shown to localize susceptibility regions with precision. Four hundred forty individuals from 27 Mexican American families living in Texas were genotyped for 19 highly polymorphic markers on chromosome 7. Multipoint variance component linkage analysis was used to identify genetic location(s) influencing IRS-related traits of obesity (BMI and WC), dyslipidemia (LTG and HDLC), and insulin levels (LSPI); the analysis identified a broad chromosomal region spanning approximately 24 cM. To gain more precision in localization, we used a bivariate linkage approach for each trait pair. These analyses suggest localization of most of these bivariate traits to an approximately 6-cM region near marker D7S653 [7q11.23, 103-109 cM; a maximum bivariate LOD of 4.51 was found for the trait pair HDLC and LSPI (the LODeq score is 3.94)]. We observed evidence of pleiotropic effects in this region on obesity and insulin-related trait pairs.

Adult↗

PubMed2005

A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-D glucosaminidase is associated with type 2 diabetes in Mexican Americans.

Excess O-glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) may be involved in the pathogenesis of type 2 diabetes. The enzyme O-GlcNAc-selective N-acetyl-beta-d glucosaminidase (O-GlcNAcase) encoded by MGEA5 on 10q24.1-q24.3 reverses this modification by catalyzing the removal of O-GlcNAc. We have previously reported the linkage of type 2 diabetes and age at diabetes onset to an overlapping region on chromosome 10q in the San Antonio Family Diabetes Study (SAFADS). In this study, we investigated menangioma-expressed antigen-5 (MGEA5) as a positional candidate gene. Twenty-four single nucleotide polymorphisms (SNPs), identified by sequencing 44 SAFADS subjects, were genotyped in 436 individuals from 27 families whose data were used in the original linkage report. Association tests indicated significant association of a novel SNP with the traits diabetes (P = 0.0128, relative risk = 2.77) and age at diabetes onset (P = 0.0017). The associated SNP is located in intron 10, which contains an alternate stop codon and may lead to decreased expression of the 130-kDa isoform, the isoform predicted to contain the O-GlcNAcase activity. We investigated whether this variant was responsible for the original linkage signal. The variance attributed to this SNP accounted for approximately 25% of the logarithm of odds. These results suggest that this variant within the MGEA5 gene may increase diabetes risk in Mexican Americans.

Acetylglucosaminidase↗

PubMed2005

Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study.

The San Antonio Family Diabetes/Gallbladder Study was initiated to identify susceptibility genes for type 2 diabetes. Evidence was previously reported of linkage to diabetes on 10q with suggestive evidence on 3p and 9p in a genome-wide scan of 440 individuals from 27 pedigrees ascertained through a single diabetic proband. Subsequently, the study was expanded to include 906 individuals from 39 extended Mexican-American pedigrees, two additional examination cycles approximately 5.3 and 7.6 years after baseline, and genotypes for a new set of genome-wide markers. Therefore, we completed a second genome-wide linkage scan. Using information from a participant's most recent exam, the prevalence of diabetes in nonprobands was 21.8%. We performed genome-wide variance components-based genetic analysis on the discrete trait diabetes using a liability model and on the quantitative Martingale residual obtained from modeling age of diabetes diagnosis using Cox proportional hazard models. Controlling for age and age(2), our strongest evidence for linkage to the trait diabetes and the quantitative Martingale residual was on chromosome 3p at marker D3S2406 with multipoint empirical logarithm of odds scores of 1.87 and 3.76, respectively. In summary, we report evidence for linkage to diabetes on chromosome 3p in a region previously identified in at least three independent populations.

Adolescent↗

PubMed2002

Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model.

Gene therapy represents an attractive approach for the treatment of eye diseases such as glaucoma. Ocular administration of viral vectors produces localized retinal gene expression with reduced risks of side effects reported with systemic administration of viral vectors. Recombinant adeno-associated viral (AAV) vectors have proven effective in producing long-term retinal gene expression, due to stable integration of DNA into the genome and lack of host immune response to the virus. Recently developed AAV constructs using the chicken beta-actin (CBA) promoter drive highly efficient transgene expression in retinal ganglion cells (RGCs), photoreceptors, and pigment epithelium. Rats were given unilateral intravitreal injections of AAV-CBA vector coding for human baculoviral IAP repeat-containing protein-4 (BIRC4), a potent caspase inhibitor. Ocular hypertension was induced in the same eye by sclerosis of aqueous humor outflow channels. After chronic exposure to elevated intraocular pressure, we performed optic nerve axon counts to determine the neuroprotective effects of retinal BIRC4 expression, and compared axon survival with vector and balanced salt solution control groups. Gene therapy delivering BIRC4 significantly promoted optic nerve axon survival in a chronic ocular hypertensive model of rat glaucoma. Blocking RGC apoptosis with caspase inhibitors represents a promising approach for treatment of human glaucoma.

Animals↗

PubMed2002

Flash visual evoked potentials in the hypomyelinated mutant mouse shiverer.

Myelin basic protein (MBP) is an essential component of central nervous system (CNS) myelin, as demonstrated by shiverer mutant mice that have deletions of most of the Mbp structural gene. These mutants do not produce detectable MBP protein, and their CNS is hypomyelinated. Although the function of the visual pathway is presumed to be adversely affected by hypomyelination of the optic nerve, it has never been studied. We compared flash visual evoked potentials (FVEPs) of shiverer homozygotes with those of their wild-type littermates in order to characterize any dysfunction. There was a statistically significant delay in the implicit times of a negative component peaking at 85 ms and a large positive component peaking at 170 ms in the FVEPs of the shiverer mice. The amplitudes of the two components did not differ significantly in the shiverers and wild-type controls. Barring a retinal pathology, which cannot be excluded by these data, the delayed FVEP of the shiverer can likely be attributed to effects of hypomyelination of the optic nerve, optic tract and visual radiations on conduction time in the visual pathway and subsequent further post-synaptic delays.

Animals↗

PubMed2002

Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension.

PURPOSE: Retinal ganglion cell (RGC) death in glaucoma involves apoptosis. Activation of caspases and abnormal processing of amyloid precursor protein (APP) are important events in other chronic neurodegenerations, such as Alzheimer's disease (AD). The retinal expression and activation of caspases and the patterns of caspase-3-mediated APP processing in ocular hypertensive models of rat glaucoma were investigated. METHODS: RGC death was produced in one eye by chronic exposure to increased intraocular pressure (IOP) or by optic nerve transection. Elevated IOP was produced by obstruction of aqueous humor outflow with laser coagulation or limbal hypertonic saline injection. Caspase activity and APP processing in the retina were examined by RNase protection assay (RPA), immunocytochemistry, immunoblot assay, and colorimetric assay. RESULTS: RPA revealed elevations of caspase-3 mRNA, as well as other apoptosis-related mRNAs. Immunocytochemistry showed caspase-3 activation in RGCs damaged by ocular hypertension. The generation of the caspase-3-mediated APP cleavage product (DeltaC-APP) was also increased in ocular hypertensive RGCs. Western immunoblot assay and colorimetry revealed significantly more activated caspase-3 in ocular hypertensive retinas than in control retinas. The activated form of caspase-8, an initiator caspase, and amyloid-beta, a product of APP proteolysis and a component of senile plaques in AD, were detected in RGCs by immunohistochemistry significantly more often in ocular hypertensive than in control retinas. The amounts of full-length APP were reduced and amyloid-beta-containing fragments were increased in ocular hypertensive retinas by Western immunoblot assay. CONCLUSIONS: Rat RGCs subjected to chronic ocular hypertension demonstrate caspase activation and abnormal processing of APP, which may contribute to the pathophysiology of glaucoma.

Amyloid beta-Peptides↗

PubMedDate not supplied

A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family.

BACKGROUND: The human beta3-adrenergic receptor gene (ADRB3) has been investigated as a candidate gene for diabetes-related traits in many studies. However, the results have been inconsistent so it is unclear whether variation in ADRB3 is a risk factor for type 2 diabetes. We have identified a novel missense mutation of ADRB3 in a single large pedigree of the San Antonio Family Diabetes/Gallbladder Study (SAFDGS) that is located in the first transmembrane domain at amino acid 62 (Ile62Met). The aim of this study was to investigate the association of this mutation in the SAFDGS with risk for diabetes. METHODS: Variance components-based statistical methods were used to determine association of this mutation with diabetes traits in the SAFDGS. The ADRB3 gene was also resequenced to identify all variants present in this pedigree. RESULTS: Significant association was observed for the Ile62Met mutation and type 2 diabetes (p = 0.01, relative risk 2.3), an earlier age of onset (p = 0.01) and 2-h glucose measures (p = 0.006) in the single pedigree. Average age and body mass index do not differ between the two genotypic groups. In a recent genome-wide linkage analysis of SAFDGS, we observed suggestive linkage of diabetes to this region at marker D8S1477 (2pt LOD of 2.55). The variance attributed to Ile62Met accounted for nearly all of the family-specific LOD score. CONCLUSIONS: These results suggest that this variant in ADRB3 is influencing diabetes risk in this Mexican American family and supports a role for alterations of the beta3-adrenergic receptor in the pathogenesis of type 2 diabetes.

3' Untranslated Regions↗

PubMedDate not supplied

Genetic basis of diabetic nephropathy.

Diabetes mellitus is the leading cause of end-stage renal disease. Development and progression of diabetic nephropathy result from a combination of genetic susceptibility and metabolic and hemodynamic abnormalities. In America, some racial and ethnic minorities have a significant burden of diabetic nephropathy, and, although genetic studies suggest that inherited factors play a major role in the pathogenesis of diabetic nephropathy, little information has been gained on the genes and molecular mechanisms involved. The genetic background of diabetic nephropathy is believed to be polygenic, and the genes predisposing to the development and progression of diabetic nephropathy are actively being investigated. New knowledge in identifying and understanding the role of susceptibility gene(s) will provide valuable information that could help develop new preventive and therapeutic strategies.

Albuminuria↗