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Joseph A Murray,
Stela McLachlan,
Paul C Adams, John H Eckfeldt,
Chad P Garner,
Chris D Vulpe,
Victor R Gordeuk,
Tricia Brantner,
Catherine Leiendecker-Foster,
Anthony A Killeen,
Ronald T Acton,
Lisa F Barcellos,
Debbie A Nickerson,
Kenneth B Beckman,
Gordon D McLaren,
Christine E McLaren
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ABSTRACT: BACKGROUND & AIMS: Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease. METHODS: We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency. RESULTS: Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher's exact test, P=1.92 10(-6)). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7-212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype. CONCLUSIONS: Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians-even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 02/2013; · 5.64 Impact Factor
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Stacey Gabriel,
Christopher O'Donnell,
Esteban Gonzalez Burchard,
Rebecca K F Sze,
George Church,
Francine Gachupin,
Ellen Wright Clayton,
Leslie G Biesecker,
Joseph V Thakuria,
P Pearl O'Rourke, [......],
Laura M Beskow,
Wylie Burke,
Rebecca Fisher,
Gail P Jarvik,
Mona Puggal,
Stephanie M Fullerton,
Rick Kittles,
Sheri D Schully,
Jennifer R Leib,
Alan R Shuldiner
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Victor R Gordeuk,
Laura Lovato,
James Barton,
Mara Vitolins,
Gordon McLaren,
Ronald Acton,
Christine McLaren,
Emily Harris,
Mark Speechley, John H Eckfeldt,
Sharmin Diaz,
Phyliss Sholinsky,
Paul Adams
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ABSTRACT: HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.
To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration.
Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada.
No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 06/2012; 26(6):345-9. · 1.21 Impact Factor
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ABSTRACT: To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of individuals on the basis of their genetic profile who benefit most from a particular treatment.
Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score.
For each treatment group, we identified a panel of genetic variants that collectively improved the prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3 rs3918226; SELE rs5361; ICAM1 rs1799969; AGT rs5051; GNAS rs7121; ROC comparison, P=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09).
Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.
Pharmacogenetics and Genomics 02/2012; 22(5):355-66. · 3.48 Impact Factor
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Christine E McLaren,
Stela McLachlan,
Chad P Garner,
Chris D Vulpe,
Victor R Gordeuk, John H Eckfeldt,
Paul C Adams,
Ronald T Acton,
Joseph A Murray,
Catherine Leiendecker-Foster,
Beverly M Snively,
Lisa F Barcellos,
James D Cook,
Gordon D McLaren
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ABSTRACT: The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and controls (SF >100 µg/L in men, SF >50 µg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7 × 10(-6)) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4 × 10(-5)); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0 × 10(-5)). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.
PLoS ONE 01/2012; 7(6):e38339. · 4.09 Impact Factor
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ABSTRACT: Nitric oxide synthase 3 (NOS3) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease (CVD). We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes. Hypertensive subjects (n = 30,280) from a multi-center, double-blind clinical trial were randomized to chlorthalidone, amlodipine, or lisinopril treatment (mean follow up, 4.9 years). Outcomes included coronary heart disease (CHD: fatal CHD and nonfatal myocardial infarction); stroke; heart failure (fatal, requiring hospitalization, or outpatient treatment); all-cause mortality; and end-stage renal disease (ESRD). Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested. For NOS3 -690 C>T (rs3918226), a higher hazard ratio (HR) was found in minor allele carriers for CHD (CC = 1.00, CT+TT = 1.12 (95% confidence interval (CI) = 1.00-1.26), P = 0.048). For NOS3 -922 A>G (rs1800779), a higher HR was found in minor allele carriers for heart failure (AA = 1.00, AG+GG = 1.10 (CI = 1.00-1.21), P = 0.046). Significant pharmacogenetic findings were observed for stroke and all-cause mortality. For -690 C>T, a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril (CC = 0.85 (CI = 0.73-0.99), CT+TT = 0.49 (CI = 0.31-0.80), P = 0.04). For glu298asp G>T (rs1799983), a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril (GG = 1.01 (CI = 0.91-1.13), GT+TT = 0.85 (CI = 0.75-0.97), P = 0.04). We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality. This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future.
PLoS ONE 01/2012; 7(3):e34217. · 4.09 Impact Factor
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ABSTRACT: Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE (High Iron) 282 Cys → Tyr (C282Y) homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload resulting from hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99,711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were compared between 162 C282Y homozygotes and 1,367 nonhomozygotes with serum ferritin levels >300 μg/L in men and >200 μg/L in women and transferrin saturation >45% in women and 50% in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges. Mean ALT and AST activities were significantly lower in C282Y homozygotes than nonhomozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased. CONCLUSION: Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.
Hepatology 12/2011; 55(6):1722-6. · 11.66 Impact Factor
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ABSTRACT: Population studies such as NHANES analyze large numbers of laboratory measurements and are often performed in different laboratories using different measurement procedures and over an extended period of time. Correct clinical and epidemiologic interpretations of the results depend on the accuracy of those measurements. Unfortunately, considerable variability has been observed among assays for folate, vitamin B-12, and related biomarkers. In the past few decades, the science of metrology has advanced considerably, with the development of improved primary reference measurement procedures and high-level reference materials, which can serve as the basis for accurate measurement. A rigorous approach has been established for making field methods traceable to the highest-level reference measurement procedures and reference materials. This article reviews some basic principles of metrology and describes their recent application to measurements of folate and vitamin B-12.
American Journal of Clinical Nutrition 07/2011; 94(1):332S-336S. · 6.67 Impact Factor
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Elizabeth A Yetley,
Christine M Pfeiffer,
Karen W Phinney,
Regan L Bailey,
Sheena Blackmore,
Jay L Bock,
Lawrence C Brody,
Ralph Carmel,
L Randy Curtin,
Ramón A Durazo-Arvizu, [......],
Christopher Sempos,
Barry Shane,
Sally Stabler,
Patrick Stover,
Tsunenobu Tamura,
Alison Tedstone,
Susan J Thorpe,
Paul M Coates,
Clifford L Johnson,
Mary Frances Picciano
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ABSTRACT: A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12-related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES--serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)--and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12-related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.
American Journal of Clinical Nutrition 07/2011; 94(1):313S-321S. · 6.67 Impact Factor
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Elizabeth A Yetley,
Christine M Pfeiffer,
Karen W Phinney,
Zia Fazili,
David A Lacher,
Regan L Bailey,
Sheena Blackmore,
Jay L Bock,
Lawrence C Brody,
Ralph Carmel, [......],
Christopher Sempos,
Barry Shane,
Sally Stabler,
Patrick Stover,
Tsunenobu Tamura,
Alison Tedstone,
Susan J Thorpe,
Paul M Coates,
Clifford L Johnson,
Mary Frances Picciano
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ABSTRACT: A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999-2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991-1994 and NHANES 1999-2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007-2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA.
American Journal of Clinical Nutrition 07/2011; 94(1):303S-312S. · 6.67 Impact Factor
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Ebony B Bookman,
Aleisha A Langehorne, John H Eckfeldt,
Kathleen C Glass,
Gail P Jarvik,
Michael Klag,
Greg Koski,
Arno Motulsky,
Benjamin Wilfond,
Teri A Manolio,
Richard R Fabsitz,
Russell V Luepker
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ABSTRACT: Bookman et al. write to correct the impression given in the Commentary by Kohane and Taylor that the recommendations of the National Heart, Lung, and Blood Institute (NHLBI) Working Group "Reporting Genetic Results in Research Studies" included advice to return genetic information to research subjects only in cases where there is a proven or preventative intervention for the identified disorder. In fact, the report does recommend that genetic information be returned to subjects when there is an intervention available, but it does not recommend against giving this kind of information to subjects if there is no available intervention.
Science translational medicine 02/2011; 3(70):70le1. · 7.80 Impact Factor
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ABSTRACT: Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure-lowering drugs.
The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class.
Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61; P=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio(interaction)=0.74; 95% CI, 0.53 to 1.04; P(interaction)=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio(interaction)=0.51; 95% CI, 0.31 to 0.85; P(interaction)=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone.
The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00563901.
Stroke 02/2011; 42(2):330-5. · 5.73 Impact Factor
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Richard R. Fabsitz,
Amy L. McGuire,
Richard R. Sharp,
Mona Puggal,
Laura M. Beskow,
Leslie G. Biesecker,
Ebony Bookman,
Wylie Burke,
Esteban Gonzalez Burchard,
George Church, [......],
Jennifer R. Leib,
Christopher O'Donnell,
P. Pearl O'Rourke,
Laura Lyman Rodriguez,
Sheri D. Schully,
Alan R. Shuldiner,
Rebecca K.F. Sze,
Joseph V. Thakuria,
Susan M. Wolf,
Gregory L. Burke
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ABSTRACT: Tremendous controversy surrounds return of individual research results and incidental findings in genetic and genomic research on human participants. Researchers traditionally have not offered individual research results back to human participants. However, with increasing recognition of the potential health importance of those results (which may indeed be life-saving), scholars, researchers, and policy makers have begun considering under what circumstances results should be offered back to participants, what results would warrant this effort, and how it should be done. This article is a significant new consensus statement growing out of a workshop convened by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). Thirty top researchers, scholars, and participants in the policy debate worked for over a year to reach agreement on 5 core recommendations. The group offers two recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of investigators' obligation to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators working with identifiable research participant communities to engage those communities on the return of aggregate and individual research results.
Vanderbilt University Law School, Public Law & Legal Theory Research Paper Series. 01/2011;
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ABSTRACT: MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.
Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested.
There were 38,698 participants genotyped for at least one of the polymorphisms included here. For MMP9 R668Q (rs2274756), lower hazard ratios (HRs) were found for AA subjects for most outcomes when treated with chlorthalidone versus amlodipine (eg., CCHD: GG = 1.00, GA = 1.01, AA = 0.64; P = 0.038). For MMP9 R279Q (rs17576), modest pharmacogenetic findings were observed for combined CHD and the composite CVD outcome. For MMP12 N122S (rs652438), lower HRs were observed for CHD in subjects carrying at least one G allele and being treated with chlorthalidone versus lisinopril (CHD: AA = 1.07, AG = 0.80, GG = 0.49; P = 0.005). In the lisinopril-amlodipine comparison, higher HRs were observed for participants having at least one G allele at the MMP12 N122S locus (CHD: AA = 0.94, AG = 1.19, GG = 1.93; P = 0.041). For MMP12 -82A>G (rs2276109), no pharmacogenetic effect was found for the primary outcome, although lower HRs were observed for AA homozygotes in the chlorthalidone-amlodipine comparison for HF (P = 0.015).
We observed interactions between antihypertensive drugs and MMP9 and MMP12 for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions.
PLoS ONE 01/2011; 6(8):e23609. · 4.09 Impact Factor
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Christine E McLaren,
Chad P Garner,
Clare C Constantine,
Stela McLachlan,
Chris D Vulpe,
Beverly M Snively,
Victor R Gordeuk,
Debbie A Nickerson,
James D Cook,
Catherine Leiendecker-Foster,
Kenneth B Beckman, John H Eckfeldt,
Lisa F Barcellos,
Joseph A Murray,
Paul C Adams,
Ronald T Acton,
Anthony A Killeen,
Gordon D McLaren
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ABSTRACT: The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF)≤12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7) for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9), corrected P=0.012) was replicated within the VA samples (observed P=0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification.
PLoS ONE 01/2011; 6(3):e17390. · 4.09 Impact Factor
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Richard R Fabsitz,
Amy McGuire,
Richard R Sharp,
Mona Puggal,
Laura M Beskow,
Leslie G Biesecker,
Ebony Bookman,
Wylie Burke,
Esteban Gonzalez Burchard,
George Church, [......],
Jennifer R Leib,
Christopher O'Donnell,
P Pearl O'Rourke,
Laura Lyman Rodriguez,
Sheri D Schully,
Alan R Shuldiner,
Rebecca K F Sze,
Joseph V Thakuria,
Susan M Wolf,
Gregory L Burke
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ABSTRACT: In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago. Although unable to reach consensus on a number of issues, the working group produced 5 recommendations. The working group offers 2 recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to institutional review boards, investigators, research institutions, and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.
Circulation Cardiovascular Genetics 12/2010; 3(6):574-80. · 6.11 Impact Factor
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ABSTRACT: Several clinical studies report increased risk of diabetes mellitus with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment.
The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N = 9309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or angiotensin-converting enzyme (ACE) inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up.
Fasting glucose at year 2 increased on average 6.8, 4.8 and 3.0 mg/dl from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the ACE I/D polymorphism was associated with lower fasting glucose levels (P = 0.02). Additionally, an ACE promoter polymorphism (-262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT, which remained significant after correction for multiple testing (P = 0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine vs. chlorthalidone treatment with fasting glucose (P < 0.001).
Further examination of these genes and their relationships with cardiometabolic disease could foster development of pharmacogenetic guidelines aimed to prevent increases in fasting glucose during antihypertensive treatment.
Journal of hypertension 10/2010; 28(10):2076-83. · 4.02 Impact Factor
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Elizabeth A Yetley,
Christine M Pfeiffer,
Rosemary L Schleicher,
Karen W Phinney,
David A Lacher,
Sylvia Christakos, John H Eckfeldt,
James C Fleet,
George Howard,
Andrew N Hoofnagle, [......],
Joseph Massaro,
Munro Peacock,
Bernard Rosner,
Donald Wiebe,
Regan L Bailey,
Paul M Coates,
Anne C Looker,
Christopher Sempos,
Clifford L Johnson,
Mary Frances Picciano
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ABSTRACT: A roundtable to discuss monitoring of serum 25-hydroxyvitamin D [25(OH)D] in the NHANES was held in late July 2009. Topics included the following: 1) options for dealing with assay fluctuations in serum 25(OH)D in the NHANES conducted between 1988 and 2006; 2) approaches for transitioning between the RIA used in the NHANES between 1988 and 2006 to the liquid chromatography tandem MS (LC-MS/MS) measurement procedure to be used in NHANES 2007 and later; 3) approaches for integrating the recently available standard reference material for vitamin D in human serum (SRM 972) from the National Institute of Standards and Technology (NIST) into the NHANES; 4) questions regarding whether the C-3 epimer of 25-hydroxyvitamin D3 [3-epi-25(OH)D3] should be measured in NHANES 2007 and later; and 5) identification of research and educational needs. The roundtable experts agreed that the NHANES data needed to be adjusted to control for assay fluctuations and offered several options for addressing this issue. The experts suggested that the LC-MS/MS measurement procedure developed by NIST could serve as a higher order reference measurement procedure. They noted the need for a commutability study for the recently released NIST SRM 972 across a range of measurement procedures. They suggested that federal agencies and professional organizations work with manufacturers to improve the quality and comparability of measurement procedures across all laboratories. The experts noted the preliminary nature of the evidence of the 3-epi-25(OH)D3 but felt that it should be measured in 2007 NHANES and later.
Journal of Nutrition 09/2010; 140(11):2030S-45S. · 3.92 Impact Factor
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ABSTRACT: We sought to determine if TNF promoter variants could explain iron phenotype heterogeneity in adults with previous HFE genotyping. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened the TNF promoter region in each participant. We performed multiple regression analyses in C282Y homozygotes using age, sex, HEIRS Study Field Center, and positivity for TNF -308G-->A and -238G-->A to determine if these attributes predicted ln TS or ln SF. DHPLC analyses were successful in 99.3% of 791 participants and detected 9 different variants; TNF -308G-->A and -238G-->A were the most prevalent. Most subjects positive for variants were heterozygous. The phenotype frequencies of each variant did not differ significantly (p<0.05) across subgroups of C282Y homozygotes, or across white, black, Hispanic, and Asian non-C282Y homozygotes subgrouped as high TS/SF phenotypes and controls. TNF -308G-->A positivity was a significant predictor of initial screening ln TS but not ln SF; TNF -238G-->A predicted neither ln TS nor ln SF. We conclude that TNF promoter variants have little, if any, effect on initial screening SF values in adults with or without C282Y homozygosity. We cannot exclude a possible association of homozygosity for TNF promoter variants on TS and SF values.
Blood Cells Molecules and Diseases 02/2010; 44(4):252-6. · 2.35 Impact Factor
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Christine E McLaren,
James C Barton, John H Eckfeldt,
Gordon D McLaren,
Ronald T Acton,
Paul C Adams,
Leora F Henkin,
Victor R Gordeuk,
Chris D Vulpe,
Emily L Harris,
Barbara W Harrison,
Jacob A Reiss,
Beverly M Snively
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ABSTRACT: Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The Hemochromatosis and Iron Overload Screening family study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 microg/L, men; SF > 200 microg/L, women). Heritability (h(2)) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N = 942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) years; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h(2) (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h(2) was significant with a value of 0.64 (0.26) for ln SF (P = 0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and nongenetic sources of variation.
American Journal of Hematology 02/2010; 85(2):101-5. · 4.67 Impact Factor
