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1.  Polymorphisms in LMNA and near a SERPINA gene cluster are associated with cognitive function in older people 
Neurobiology of aging  2008;31(9):1563-1568.
A recent genome-wide association (GWA) study of late-onset Alzheimer's disease (LOAD) identified 15 novel single nucleotide polymorphisms (SNPs) independent of ApoE. We hypothesized that variants associated with LOAD are also associated with poor cognitive function in elderly populations. We measured additive associations between the five most strongly associated LOAD SNPs and grouped Mini Mental State Examination (MMSE) scores. Variants were genotyped in respondents (mean age 79yrs) from the Oxford Healthy Aging project (OHAP) and other sites of the MRC Cognitive Function and Aging Study (MRC-CFAS). In adjusted ordinal logistic models, two variants were associated with poorer cognitive function: rs11622883 (OR=1.14, 95%CI: 1.01 to 1.28, p=0.040) and rs505058 (OR=1.29, 95% CI: 1.02 to 1.64, p=0.036). These SNPs are close to a SERPINA gene cluster and within LMNA respectively. The mechanisms underlying the associations with cognitive impairment and LOAD require further elucidation, but both genes are interesting candidates for involvement in age-related cognitive impairment.
PMCID: PMC2975102  PMID: 18848371
Late-onset Alzheimer's disease; dementia; cognitive function; cognitive impairment; gene; single nucleotide polymorphism; ApoE; LMNA
2.  Circulating β-carotene levels and Type 2 diabetes: Cause or effect? 
Diabetologia  2009;52(10):2117-2121.
Aims and Hypothesis
Circulating β-carotene levels are inversely associated with type 2 diabetes risk, but the causal direction of this association is not certain. In this study we used a Mendelian Randomization approach to provide evidence for or against the causal role of the anti-oxidant vitamin β-carotene in type 2 diabetes.
We used a common polymorphism (rs6564851) near the β-carotene 15,15'-Monooxygenase 1 (BCMO1) gene that is strongly associated with circulating β-carotene levels (P = 2×10−24) - each G allele is associated with a 0.27 standard deviation increase in levels. We used data from the InCHIANTI study and the ULSAM study to estimate the association between β-carotene levels and type 2 diabetes. We next used a triangulation approach to estimate the expected effect of rs6564851 on type 2 diabetes risk, and compared this to the observed effect using data from 4549 type 2 diabetes cases and 5579 controls from the DIAGRAM consortium.
A 0.27 standard deviation increase in β-carotene levels is associated with an odds ratio of 0.90 (0.86–0.95) for type 2 diabetes in the InCHIANTI study. This association is similar to that of the ULSAM study, OR (0.90 (0.84–0.97)). In contrast there was no association between rs6564851 and type 2 diabetes (OR 0.98 (0.93–1.04, P = 0.58), and this effect size was smaller than that expected given the known associations between rs6564851 and β-carotene levels and the associations between β-carotene levels and type 2 diabetes.
Our Mendelian Randomization studies are in keeping with randomized controlled trials that suggest β-carotene is not causally protective against type 2 diabetes.
PMCID: PMC2746424  PMID: 19662379
type 2 diabetes; β-carotene; mendelian randomization
3.  The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or InCHIANTI studies 
Background The human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies.
Methods We used logistic regression models to examine the associations in men and women aged 60–79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression.
Results The PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR) = 1.01 [confidence interval (CI) 0.91–1.13], P = 0.80} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87–1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82–1.30), P = 0.80].
Conclusions We found no evidence of an association between the PON1 Q192R polymorphism and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported.
PMCID: PMC2755129  PMID: 19651761
PON1 Q192R polymorphism; rs662; organophosphates; detoxification; paraoxonase activity; depression; Mendelian randomization
4.  The 9p21 Myocardial Infarction risk allele increases risk of Peripheral Artery Disease in older people 
A common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 SNP) is strongly associated with Myocardial Infarction (MI) and major arterial aneurysms. An association with Peripheral Arterial Disease (PAD) was also reported in a sample aged <75 years, but this disappeared on removal of respondents with a MI history, resulting in an odds ratio for PAD of 1.09 (p=0.075). We aimed to estimate the association of this variant with Ankle Brachial Index (ABI) and PAD in three older populations.
Methods and Results
We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging and Health, Aging and Body Composition studies. In 2,630 Caucasian individuals (mean age 76.4 years) the C allele at rs1333049 was associated with lower mean ABI measures and with increased prevalence of PAD. These associations remained after removal of baseline and incident MI cases over a 6 year follow-up for both ABI (−0.017 ABI units, 95% CI: −0.03- −0.01, p=1.3×10−4) and PAD (per allele OR: 1.29, 95% CI: 1.06–1.56, p=0.012). These associations also remained after adjustment for known atherosclerosis risk factors including Diabetes Mellitus, smoking, hypercholesterolemia and hypertension.
The C allele at rs1333049 is associated with an increased prevalence of Peripheral Arterial Disease and lower mean Ankle Brachial Index. This association was independent of the presence of diagnosed MI and atherosclerotic risk factors in 3 older Caucasian populations.
PMCID: PMC2777723  PMID: 20031606
Genetics; Myocardial Infarction; Peripheral Vascular Disease; 9p21; CDKN2a/2b
5.  Association between Serum Perfluorooctanoic Acid (PFOA) and Thyroid Disease in the U.S. National Health and Nutrition Examination Survey 
Environmental Health Perspectives  2010;118(5):686-692.
Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health.
We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population.
Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999–2000, 2003–2004, and 2005–2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake.
The NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA ≥ 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38–3.65; p = 0.002] compared with PFOA ≤ 4.0 ng/mL (quartiles 1 and 2); we found a near significant similar trend in men (OR = 2.12; 95% CI, 0.93–4.82; p = 0.073). For PFOS, in men we found a similar association for those with PFOS ≥ 36.8 ng/mL (quartile 4) versus ≤ 25.5 ng/mL (quartiles 1 and 2: OR for treated disease = 2.68; 95% CI, 1.03–6.98; p = 0.043); in women this association was not significant.
Higher concentrations of serum PFOA and PFOS are associated with current thyroid disease in the U.S. general adult population. More work is needed to establish the mechanisms involved and to exclude confounding and pharmacokinetic explanations.
PMCID: PMC2866686  PMID: 20089479
C8; human population; PFOA; PFOS; thyroid disease
6.  Association of Urinary Bisphenol A Concentration with Heart Disease: Evidence from NHANES 2003/06 
PLoS ONE  2010;5(1):e8673.
Bisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years.
Methodology and Findings
A cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18–74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.
Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.
PMCID: PMC2800195  PMID: 20084273
8.  A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs) 
PLoS Genetics  2008;4(5):e1000072.
There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.
Author Summary
One of the central dogmas of molecular genetics is that DNA is transcribed to RNA which is translated to protein and alterations to proteins can influence human diseases. Genome-wide association studies have recently revealed many new DNA variants that influence human diseases. To complement these efforts, several genome-wide studies have established that DNA variation influences mRNA expression levels. Loci influencing mRNA levels have been termed “eQTLs”. In this study we have performed the first genome-wide association study of the third piece in this jigsaw – the role of DNA variation in relation to protein levels, or “pQTLs”. We analysed 42 proteins measured in blood fractions from the InCHIANTI study. We identified eight cis effects including common variants in or near the IL6R, CCL4, IL18, LPA, GGT1, SHBG, CRP and IL1RN genes, all associated with blood levels of their respective protein products. Mechanisms implicated included altered transcription (GGT1) but also rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA) and variation in gene copy number (CCL4). Blood levels of many of these proteins are correlated with human diseases and the identification of “pQTLs” may in turn help our understanding of disease.
PMCID: PMC2362067  PMID: 18464913

Results 1-8 (8)