Genome-wide association study reveals a complex genetic architecture underpinning-induced CYP3A4 enzyme activity.

Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity-induced and inhibited-is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John's Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3-hydroxyquinine to quinine. We failed to detect any genome-wide significant associations (P < 1 × 10(-8)) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity.

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB.

Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

Genetic epidemiology of induced CYP3A4 activity.

AIM: The cytochrome P450 3A4 (CYP3A4) enzyme is implicated in the metabolism of more than 50% of all prescribed medications and its activity - including induced or inhibited activity - is deemed to be a crucial determinant of interindividual variability in drug disposition, poor therapeutic efficacy, and adverse response to medication. METHODS: We used the classical twin model in conjunction with an induction experiment to uncover the relative contribution of genetic and environmental factors to interindividual variation in induced CYP3A4 activity. A total of 367 healthy twins participated in the study. Each volunteer was administered a potent inducer of CYP3A4 (St John's Wort) for 14 days and the activity of CYP3A4 was quantified through the metabolism of the exogenously administered probe drug quinine sulfate. RESULTS: Baseline and induced CYP3A4 activity were highly variable with a seven-fold and 11-fold difference among our population, respectively. Alcohol consumption, BMI, and smoking were significantly associated with induced CYP3A4 activity, collectively explaining 20% of the variation (P<1×10(-4)). The narrow-sense heritability of induced CYP3A4 activity was estimated at 66%, whereas the remainder of the variation was attributed to unique environmental factors. CONCLUSION: To our knowledge, this is the first genetic epidemiological study of induced CYP3A4 activity. Our results motivate further research to identify common and rarer genetic variants that underpin the heritable component of variation in induced CYP3A4 activity.

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial.

BACKGROUND: Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial. METHODS: Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 microg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA. RESULTS: Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I). Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range. CONCLUSION: Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis. NTR 1029.

The interaction of genes and smoking on forced expiratory volume: a classic twin study.

BACKGROUND: Genetic influences on lung function as measured by FEV1 have been reported from twin and family studies. The aims of this study were to estimate heritability of the ratio of measured FEV1 (mFEV1) to expected FEV(1) (eFEV1) in a white population, and to examine the interaction between genetic factors and smoking on this ratio. METHODS AND SUBJECTS: The sample consisted of unselected monozygotic (MZ) and dizygotic (DZ) twin pairs from the TwinsUK registry. FEV1 was measured with a spirometer, and mFEV1/eFEV1 ratio was calculated. RESULTS: A total of 475 MZ and 1,054 DZ twin pairs participated (mean age, 47 years; range, 18 to 84 years). mFEV1/eFEV1 ratio was 0.057 lower in smokers than nonsmokers (p < 0.0001). The difference in the correlation for mFEV1/eFEV1 ratio between MZ and DZ twin pairs was 0.32 in nonsmokers and 0.19 in current smokers, suggesting a significant genetic influence on lung function that was modified in current smokers. Using structural equation modeling, the heritability estimate for mFEV1/eFEV1 ratio was found to be 66% (95% confidence interval [CI], 59 to 72%) in nonsmokers but significantly reduced to 32% (95% CI, 12 to 53%) in current smokers. However, there was no clear difference in the heritability of mFEV1/eFEV1 ratio between nonsmokers and ex-smokers. CONCLUSION: Genes are the major influence on the variability of mFEV1/eFEV1 ratio in nonsmokers. However, this strong genetic influence is strongly modified by an interaction with cigarettes.

Heritability analyses show visit-to-visit blood pressure variability reflects different pathological phenotypes in younger and older adults: evidence from UK twins.

BACKGROUND: Clinic and long-term average blood pressure (BP) are heritable traits with estimates of heritability ranging from 0.31 to 0.68. Long-term visit-to-visit BP variability (BPV) is emerging as a new cardiovascular risk predictor, though it is unclear if this is completely independent of BP. We hypothesize that BPV should demonstrate the same pattern of additive genetic, shared environmental and unique environmental variance as BP, if both are phenotypic surrogates. METHOD: We studied 2889 twin pairs not on any BP-lowering therapy from the Twins UK cohort, and estimated the additive genetic variance for baseline BP, long-term average BP, BP trajectory (rate of change of BP in mmHg/year) and BPV (coefficient of variation and average real variability over an average of 3.2 visits). Heritability estimates were obtained by structural equation modelling adjusting for age, age, sex and BMI. RESULTS: The heritabilities for baseline SBP and DBP were 0.51 (95% confidence interval 0.49, 0.53) and 0.56 (0.54, 0.58); long-term average SBP and DBP were 0.56 (0.53, 0.59) and 0.61 (0.58, 0.64); and systolic and diastolic trajectories over 10 years were 0.49 (0.46, 0.52) and 0.29 (0.27, 0.32), respectively. Both overall systolic and diastolic BPV showed no additive genetic variance contributing to the phenotypic variation, but after stratification by age, the younger subgroup (<51 years) showed heritability estimates of 0.44 (0.38, 0.50) for coefficient of variation and 0.35 (0.29, 0.41) for average real variability. CONCLUSION: Age is a major factor that influences heritability estimation of BPV and it is likely that BPV in younger and older age groups may reflect different pathological phenotypes.

The basis of differential responses to folic acid supplementation.

BACKGROUND/AIMS: Elevated levels of total homocysteine (tHcy) are associated with an increased risk of many common diseases. Supplementation with folic acid has been shown to significantly reduce tHcy levels. We used the classical twin model to partition the variability in changes in plasma tHcy levels through folic acid supplementation into genetic, environmental, and confounding epidemiological factors. METHODS: We carried out an intervention study of folic acid using 101 healthy, female, identical and non-identical twins aged 50-80 years. Each twin was administered folic acid (0.8 mg/day) for 6 weeks. Total plasma folate, cobalamin and tHcy were measured at both baseline and after dosing. We calculated the heritability and tested for associations between the MTHFR C677T functional variant and response to folic acid supplementation. RESULTS: Supplementation with folic acid led to a significant reduction in tHcy levels. The mean tHcy changed from 12.14 to 10.42 µmol/l after supplementation (p < 10(-5)). Moreover, the change in tHcy levels was highly heritable (64%), not associated with the C677T functional variant at MTHFR and not confounded by age, BMI or diet. CONCLUSIONS: Our results highlight the need to identify genetic factors associated with biomarkers of response to folate supplementation.

A twin study of mitochondrial DNA polymorphisms shows that heteroplasmy at multiple sites is associated with mtDNA variant 16093 but not with zygosity.

The mitochondrial theory of ageing proposes that damage to mitochondria and diminished mitochondrial DNA (mtDNA) repair are major contributors to cellular dysfunction and age-related diseases. We investigate the prevalence of heteroplasmy in the mtDNA control region in buccal swab and blood derived samples for 178 women from the TwinsUK cohort (41 DZ pair 39 MZ pairs, 18 singletons, mean age 57.5 range 28-82) and its relationship to age, BMI and fasting insulin and glucose serum levels. The overall estimated prevalence of heteroplasmy for both tissues in the control region measured for 37 sites was 17%. The prevalence of heteroplasmy was higher among the older half of the study subjects than in the younger half (23% vs 10% p<0.03), primarily reflecting the increase in the prevalence of a heteroplasmic dinucleotide CA repeat in variable region II (VRII) with age. The VRII 523-524 heteroplasmic site (heteroplasmic in 25 subjects) was also associated with a decrease in BMI. In addition, concordance rates for common heteroplasmy were observed to be near complete for both dizygotic (DZ = 94%) and monozygotic twin pairs (MZ = 100%), consistent with previous reports that suggest variation in heteroplasmy rates between generations are determined by bottlenecks in maternal transmission of mitochondria. Differences in the prevalence of heteroplasmy were observed overall between samples derived from buccal swabs (19%) and blood (15%, p<0.04). These were particularly marked at position 16093 of hypervariable region I (HVI, 7% vs 0%, respectively, p<4×10(-11)). The presence of the C allele at position 16093 in blood was associated with the presence of heteroplasmy in buccal swabs at this position (p = 3.5×10(-14)) and also at VRII (p = 2×10(-4)) suggesting a possible predisposing role for this site in the accumulation of heteroplasmy. Our data indicate that BMI is potentially associated with control region heteroplasmy.