Alexander Whitehead - Academia.edu (original) (raw)

Papers by Alexander Whitehead

Atherosclerosis, 2000

This cross-sectional study assessed relationships between plasma homocysteine, 'thermolabile' met... more This cross-sectional study assessed relationships between plasma homocysteine, 'thermolabile' methylenetetrahydrofolatereductase (MTHFR) genotype, B vitamin status and measures of renal function in elderly (70-89 years) and nonagenarian (90 + years) subjects, with the hypothesis that octo/nonagenarian subjects who remain healthy into old age as defined by 'Senieur' status might show reduced genetic or environmental risk factors usually associated with hyperhomocysteinaemia. Plasma homocysteine was 9.1 mmol/l (geometric mean [GM]) for all elderly subjects. Intriguingly, homocysteine was significantly lower in 90 + (GM; 8.2 mmol/l) compared to 70-89-year-old subjects (GM; 9.8 mmol/l) despite significantly lower glomerular filtration rate (GFR) and serum B12 in nonagenarian subjects and comparable MTHFR thermolabile (TT) genotype frequency, folate and B6 status to 70-89-year-olds. For all elderly subjects, the odds ratio and 95% confidence intervals for plasma homocysteine being in the highest versus lowest quartile was 4.27 (2.04-8.92) for age B 90 compared \ 90 years, 3.4 (1.5-7.8) for serum folate B10.7 compared \10.7nmol/l, 3.0 (0.9-10.2) for creatinine \140 compared B140 umol/l and 2.1 (1.0-4.4) for male sex. This study shows that plasma homocysteine does not invariably increase with age. Compared to similarly enlisted 70-89-year-olds, apparently well, mentally alert, community-living 90 + year olds approximating 'Senieur' status, show lower homocysteine, which is unexplained by renal function, TT genotype and B vitamin status, suggesting that lower homocysteine may be associated with survival.

The American Journal of Human Genetics, 2002

There is currently considerable interest in the relationship between variation in genes that are ... more There is currently considerable interest in the relationship between variation in genes that are involved in the folatehomocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis-methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G-provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (, 95% CI R p 2.16 1 0.92-5.06; , 95% CI 0.87-49.67) and MTRR (, 95% CI 1.05-3.99; , 95% CI R p 6.58 R p 2.05 R p 3.15 2 1 2 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci. Maternal genetic effects occur when a genetically mediated maternal phenotype influences the phenotype of offspring. Such effects are independent of the alleles contributed by the mother to her offspring and are, therefore, genetic only with respect to the mother. With respect to offspring, maternal genetic effects behave as environmental risk factors. Studies in animals indicate that maternal genetic effects can contribute to the risk of specific malformations among offspring (see, e.g., Trasler and Trasler 1984; Gilliam et al. 1997). The teratogenic effect of untreated maternal phenylketonuria (MIM 261600) provides a classic example of a maternal genetic effect that influences human development (Mabry et al. 1963).

) and families ( ) n ϭ 271 n ϭ 218 to date, establishing that, in Ireland, the "TT" genotype is f... more ) and families ( ) n ϭ 271 n ϭ 218 to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P ϭ ). The maternal and paternal TT genotypes have .0005 intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P ϭ ) but no evidence of a maternal TT genotypic effect .02 ( ). The log-linear model predicted that the risk P ϭ .83 of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

Objectives: A low folate/high homocysteine phenotype is associated with several pathologies, incl... more Objectives: A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as "total" folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS).

Journal of Toxicology and Environmental Health, Part A, 2007

Ketoconazole is a widely prescribed antifungal drug, which has also been investigated as an antic... more Ketoconazole is a widely prescribed antifungal drug, which has also been investigated as an anticancer therapy in both clinical and pre-clinical settings. However, severe hepatic injuries were reported to be associated with the use of ketoconazole, even in patients routinely monitored for their liver functions. Several questions concerning ketoconazole-induced hepatic injury remain unanswered, including (1) does ketoconazole alter cytochrome P450 expression at the transcriptional level?, (2) what types of gene products responsible for cytotoxicity are induced by ketoconazole?, and (3) what role do the major metabolites of ketoconazole play in this pathophysiologic process? A mouse model was employed to investigate hepatic gene expression following hepatotoxic doses of ketoconazole. Hepatic gene expression was analyzed using a toxicogenomic microarray platform, which is comprised of cDNA probes generated from livers exposed to various hepatoxicants. These hepatoxicants fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Nine genes encoding enzymes involved in Phase I metabolism and one Phase II enzyme (glutathione S-transferase) were found to be upregulated. Serum amyloid A (SAA1/2) and hepcidin were the only genes that were downregulated among the 2364 genes assessed. In vitro cytotoxicity and transcription analyses revealed that SAA and hepcidin are associated with the general toxicity of ketoconazole, and might be usefully explored as generalized surrogate markers of xenobiotic-induced hepatic injury. Finally, it was shown that the primary metabolite of ketoconazole (de-N-acetyl ketoconazole) is largely responsible for the hepatoxicity and the downregulation of SAA and hepcidin.

International Journal for Vitamin and Nutrition Research, 2008

Raised plasma homocysteine is a risk factor for cardiovascular disease (CVD). Cysteine has also b... more Raised plasma homocysteine is a risk factor for cardiovascular disease (CVD). Cysteine has also been associated with CVD risk. In this study, we investigated the association between known CVD risk factors, dietary factors, and total plasma cysteine, cysteinyl-glycine, and homocysteine.

Immunogenetics, 1991

The TNFB genes from two major histocompatibility complex (MHC) ancestral haplotypes have been com... more The TNFB genes from two major histocompatibility complex (MHC) ancestral haplotypes have been compared. The genes carried by the ancestral haplotypes 8.1 (A1,B8,BfS, C4AQO, C4B1,DR3) and 57.1 (A1,B57, BfS,C4A6,C4B1,DR7) were cloned and sequenced to determine the degree of polymorphism. In this report we show that the respective TNF genes are allelic and have unique nucleotide sequences. The data demonstrate the presence of three nucleotide differences between the TNFB alleles of 8.1 and 57.1. Two of the differences occur in untranslated regions of the gene but the third nucleotide change results in an amino acid difference in the mature TNFB protein. These polymorphisms may have implications with respect to differential regulation in disease-and nondisease-associated haplotypes.

Arteriosclerosis, Thrombosis, and Vascular Biology, 2003

Objective-Mild hyperhomocystenemia is an independent, graded risk factor for cardiovascular disea... more Objective-Mild hyperhomocystenemia is an independent, graded risk factor for cardiovascular disease. Genetic determinants of hyperhomocystenemia include functional polymorphisms in several folate/homocysteine metabolic enzymes. Nitric oxide may also modulate plasma homocysteine (tHcy) concentrations, either by direct inhibition of methionine synthase or via an indirect effect on folate catabolism. Methods and Results-The hypothesis that the endothelial nitric oxide synthase (NOS3) G894T polymorphism is a genetic determinant of tHcy concentrations was tested in 2 independent healthy adult populations. In both populations, NOS3 genotype was significantly associated with tHcy concentrations in nonsmokers with low folate (Pϭ0.03 for each). Models were constructed to adjust for known determinants of tHcy concentrations and test for interactions between NOS3 genotype and these determinants in nonsmokers from each population. NOS3 genotype remained a significant determinant of tHcy concentrations after adjustment. Interactions between NOS3 genotype and serum folate were significant in both populations, and the interaction between NOS3 genotype and MTHFR C677T genotype was significant in the larger population. Conclusions-These data indicate that the NOS3 894TT genotype is a risk factor for elevated tHcy in healthy nonsmoking adults with low serum folate and supports the hypothesis that nitric oxide modulates homocysteine through an effect on folate catabolism. (Arterioscler Thromb Vasc Biol. 2003;23:1014-1020.)

Annals of Human Genetics, 2009

Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of... more Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor/marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within this gene may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 (RFC1) c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland.

American Journal of Medical Genetics Part A, 2006

Genetic Epidemiology, 1999