RESUMO
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 study to identify individuals with iron deficiency and to assess the frequency of celiac disease. METHODS: We analyzed serum samples from white men (≥25 y) and women (≥50 y) who participated in the Hemochromatosis and Iron Overload Screening study; cases were defined as individuals with iron deficiency (serum ferritin level, ≤12 µg/L) and controls were those without (serum ferritin level, >100 µg/L in men and >50 µg/L in women). All samples also were 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 cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher exact test, P = 1.92 × 10(-6)). Celiac disease was more common in Caucasian cases (14 of 363; 4%) than non-Caucasian cases (0 of 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 of 14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype. CONCLUSIONS: Celiac disease is associated with iron deficiency in Caucasians. Celiac disease is rare among non-Caucasians-even among individuals with features of celiac disease, such as iron deficiency. Celiac disease also is rare among individuals without iron deficiency. Men and postmenopausal women with iron deficiency should be tested for celiac disease.
Assuntos
Anemia Ferropriva/epidemiologia , Doença Celíaca/complicações , Deficiências de Ferro , Grupos Raciais , Adulto , Idoso , Autoanticorpos/sangue , Feminino , Ferritinas/sangue , Humanos , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-Idade , Soro/química , Transglutaminases/imunologiaRESUMO
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Assuntos
Anlodipino/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Clortalidona/efeitos adversos , Doxazossina/efeitos adversos , Hipertensão/tratamento farmacológico , Lisinopril/efeitos adversos , Polimorfismo Genético , Idoso , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Clortalidona/administração & dosagem , Doença das Coronárias/induzido quimicamente , Doença das Coronárias/genética , Doxazossina/administração & dosagem , Feminino , Seguimentos , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/complicações , Hipertensão/genética , Lisinopril/administração & dosagem , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do TratamentoRESUMO
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.
Assuntos
Ferritinas/sangue , Hemocromatose/genética , Sobrecarga de Ferro/genética , Ferro/sangue , Regiões Promotoras Genéticas/genética , Transferrina/análise , Fator de Necrose Tumoral alfa/genética , Adulto , Cromatografia Líquida de Alta Pressão , Etnicidade/genética , Feminino , Testes Genéticos , Variação Genética , Genótipo , Hemocromatose/sangue , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Sobrecarga de Ferro/sangue , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Mutação PuntualRESUMO
Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; and 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9).
Assuntos
Hemocromatose/genética , Sobrecarga de Ferro/genética , Proteínas de Membrana Transportadoras/genética , Canadá/epidemiologia , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Análise Mutacional de DNA , Etnicidade/genética , Éxons/genética , Hemocromatose/sangue , Hemocromatose/etnologia , Proteína da Hemocromatose , Heterozigoto , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Íntrons/genética , Ferro/sangue , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etnologia , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/fisiologia , Mutação de Sentido Incorreto , Desnaturação de Ácido Nucleico , Mutação Puntual , Transportador de Folato Acoplado a Próton , Grupos Raciais/genética , Estudos de Amostragem , Transferrina/análise , Estados Unidos/epidemiologiaRESUMO
We sought to identify mutations that could explain iron phenotype heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D. 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 20 regions of HFE, SLC40A1, HAMP, HJV, TFR2, and FTL in each participant. DHPLC analyses were successful in 99.3% of 791 participants and detected 117 different mutations. In C282Y homozygotes, 4.0% of high TS/SF participants had SLC40A1 Q248H, HAMP -72C>T, or HAMP R59G heterozygosity (0% Controls; P = 0.1200). In whites, 4.1% with high TS/SF and 1.3% of controls had HFE S65C or E168Q (P = 0.3049). HJV c.-6C>G and FTL L55L frequencies were greater in whites with high TS/SF than controls (0.0811 vs. 0.0200, P = 0.0144; 0.5743 vs. 0.4400, P = 0.0204, respectively). One Hispanic with high TS/SF (1.3%) had HAMP G71D heterozygosity. In blacks, SLC40A1 Q248H frequencies did not differ significantly between high TS/SF and control participants. Among Asians, 2.8% with high TS/SF were HFE V295A heterozygotes. Mutations other than HFE C282Y and H63D reported to be pathogenic were infrequently detected in high TS/SF participants. Genetic regions in linkage disequilibrium with HJV c.-6C>G and FTL L55L could partly explain high TS/SF phenotypes in whites. Am. J. Hematol., 2009. Published 2009 Wiley-Liss, Inc.
Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Apoferritinas/genética , Proteínas de Transporte de Cátions/genética , Antígenos de Histocompatibilidade Classe I/genética , Ferro/análise , Proteínas de Membrana/genética , Mutação , Receptores da Transferrina/genética , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA/métodos , Etnicidade , Ferritinas/sangue , Genótipo , Proteína da Hemocromatose , Hepcidinas , Humanos , Desequilíbrio de Ligação , Mutação de Sentido Incorreto , Transferrina/análiseRESUMO
BACKGROUND: The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations. METHODS: A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization. RESULTS: Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects. CONCLUSIONS: Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.
Assuntos
Testes Genéticos , Hemocromatose/diagnóstico , Hemocromatose/etnologia , Hemocromatose/genética , Programas de Rastreamento , Etnicidade , Feminino , Predisposição Genética para Doença/etnologia , Testes Genéticos/ética , Genótipo , Hemocromatose/metabolismo , Humanos , Ferro/metabolismo , Masculino , Programas de Rastreamento/ética , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Mutação , América do NorteRESUMO
BACKGROUND: Iron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population. METHODS: Participants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload. RESULTS: Of the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 mug per liter in 78 of 89 men (88 percent) and greater than 200 microg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 microg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations. CONCLUSIONS: The C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites.
Assuntos
Ferritinas/sangue , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Mutação , Transferrina/análise , Artrite/etiologia , Complicações do Diabetes , Feminino , Frequência do Gene , Genótipo , Cardiopatias/etiologia , Hemocromatose/complicações , Hemocromatose/etnologia , Proteína da Hemocromatose , Homozigoto , Humanos , Ferro , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/etnologia , Sobrecarga de Ferro/genética , Hepatopatias/etiologia , Modelos Logísticos , Masculino , Fenótipo , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND & AIMS: The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload. METHODS: A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload. RESULTS: The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41-28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53-38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload. CONCLUSIONS: Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
Assuntos
Hemocromatose/diagnóstico , Sobrecarga de Ferro/diagnóstico , Anamnese/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite/diagnóstico , Estudos de Casos e Controles , Diabetes Mellitus/diagnóstico , Feminino , Genótipo , Cardiopatias/diagnóstico , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Hepatopatias/diagnóstico , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care-based Hemochromatosis and Iron Overload Screening (HEIRS) Study. METHODS: We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log(10) serum ferritin (SF), HFE genotype, log(10) TSH, and log(10) free T4. RESULTS: Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log(10) SF with log(10) free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log(10) free T4 were log(10) TSH (negative association) and age (positive association); positive predictors of log(10) SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly. CONCLUSIONS: Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.
Assuntos
Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Tireotropina/sangue , Tiroxina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Ferritinas/sangue , Genótipo , Hemocromatose/sangue , Proteína da Hemocromatose , Homozigoto , Humanos , Hipertireoidismo/epidemiologia , Hipotireoidismo/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , População Branca/genéticaRESUMO
BACKGROUND: Asians and Pacific Islanders in the Hemochromatosis and Iron Overload Screening (HEIRS) Study had the highest prevalence of elevated serum ferritin (SF) and transferrin saturation (TS) levels, but to our knowledge, the reasons for this have not been investigated. METHODS: Using multiple linear regression, we compared TS and SF distributions for 42 720 Asian, Pacific Islander, and white HEIRS Study participants recruited through 5 field centers in North America who did not have HFE C282Y or H63D alleles. RESULTS: Compared with their white counterparts, Asian men had a 69-ng/mL (155-pmol/L) higher adjusted mean SF level and a 3% higher TS level (P<.001); Asian women had 23-ng/mL (52-pmol/L) higher adjusted mean SF level and a 3% higher TS level (P<.001). The mean TS level of Asian women was higher than that of Pacific Islander women, and the mean SF level of Pacific Islander men was significantly higher than that of white men. These differences remained significant after adjusting for self-reported history of diabetes or liver disease. Additional information for selected participants suggested that these differences are largely unrelated to mean corpuscular volume less than 80 fL, body mass index, or self-reported alcohol intake. Available liver biopsy and phlebotomy data indicated that iron overload is probably uncommon in Asian participants. CONCLUSION: Higher TS and SF levels in persons of Asian or Pacific Island heritage may need to be interpreted differently than for whites, although the biological basis and clinical significance of higher levels among Asians and Pacific Islanders are unclear.
Assuntos
Asiático , Ferritinas/sangue , Havaiano Nativo ou Outro Ilhéu do Pacífico , Transferrina/metabolismo , População Branca , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: The NPPA gene codes for the precursor of atrial natriuretic polypeptide, suggesting that NPPA may modulate the efficacy of some antihypertensive drugs. OBJECTIVE: To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (BP) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications. DESIGN, SETTING, AND PATIENTS: Post hoc analysis of 38,462 participants with hypertension from ALLHAT, a multicenter randomized clinical trial conducted in the United States and Canada. Genotyping was performed from February 2004 to January 2005. INTERVENTION: Participants were randomly assigned to receive a diuretic (chlorthalidone; n = 13,860), a calcium antagonist (amlodipine; n = 8174), an angiotensin-converting enzyme inhibitor (lisinopril; n = 8233), or an alpha-blocker (doxazosin; n = 8195). MAIN OUTCOME MEASURE: The primary outcome measure was coronary heart disease (CHD), defined as fatal CHD or nonfatal myocardial infarction (mean follow-up, 4.9 years). Secondary outcomes were stroke, all-cause mortality, combined cardiovascular disease outcomes, and 6-month systolic and diastolic BP changes. Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly. RESULTS: Depending on genotype, the event rates per 1000 person-years were 15.3 to 19.7 for CHO, 9.6 to 15.4 for stroke, and 27.4 to 30.7 for all-cause mortality. For the NPPA T2238C variant, lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine (CHD: CC = 0.86; TC = 0.90; TT = 1.09; P = .03 [dominant model]; stroke: CC = 1.18; TC = 0.82; TT = 1.26; P = .01 [additive and dominant models]; all-cause mortality: CC = 0.87; TC = 0.98; TT = 1.12; P = .05 [dominant model]). Combined end points yielded similar results. Consistent with these clinical findings, 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone (-6.5 mm Hg) than with amlodipine (-3.8 mm Hg), lisinopril (-2.4 mm Hg), or doxazosin (-3.8 mm Hg). Among those with the TT genotype, systolic BP differences between drugs were less (range, -5.4 to -7.5 mm Hg; P value, <.001 to .003 for interaction); diastolic BP showed similar results. We found no pharmacogenetic associations with the NPPA G664A variant. CONCLUSIONS: The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP. Minor C allele carriers experienced more favorable cardiovascular disease outcomes when randomized to receive a diuretic, whereas TT allele carriers had more favorable outcomes when randomized to receive a calcium channel blocker.
Assuntos
Anti-Hipertensivos/uso terapêutico , Fator Natriurético Atrial/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Diuréticos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/genética , Idoso , Anlodipino/uso terapêutico , Pressão Sanguínea , Clortalidona/uso terapêutico , Doxazossina/uso terapêutico , Feminino , Genótipo , Humanos , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion-deletion (ID) polymorphism interacts with pravastatin to modify the risk of coronary heart disease (CHD) and other cardiovascular end points in a large clinical trial. METHODS: GenHAT is an ancillary study of the ALLHAT. The ACE ID genotyped population in the lipid-lowering arm of ALLHAT included 9467 participants randomly assigned to pravastatin (n = 4741) or to usual care (n = 4726). The efficacy of pravastatin in reducing the risk of primary outcome (all-cause mortality) and secondary outcomes (fatal CHD and nonfatal myocardial infarction, cardiovascular disease [CVD] mortality, CHD, stroke, other CVD, non-CVD mortality, stroke, and heart failure) was compared between the genotype strata (dominant model ID + II vs DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional hazards model. RESULTS: The relative risk of fatal CHD and nonfatal myocardial infarction among subjects randomized to pravastatin compared with subjects randomized to usual care was similar in subjects with the II genotype (hazard ratio [HR] 0.84, 95% CI 0.59-1.18), the ID genotype (HR 0.84, 95% CI 0.68-1.03), and the DD genotype (HR 0.99, 95% CI 0.77-1.27). CONCLUSIONS: We found no evidence that the ACE ID genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events.
Assuntos
Doença das Coronárias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/genética , Peptidil Dipeptidase A/genética , Pravastatina/uso terapêutico , Idoso , Anti-Hipertensivos , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Farmacogenética , Polimorfismo Genético , Pravastatina/farmacologia , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
Adiponectin has demonstrated insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, and may be an important risk factor for coronary heart disease and diabetes. Relatively few previous studies of plasma adiponectin have included sizable numbers of African Americans. The objective of the study was to investigate plasma concentrations of adiponectin and correlates of these concentrations in African Americans. This was a cross-sectional analysis that took place within the Hypertension Genetic Epidemiology Network. This study included 211 normotensive offspring (aged 22-37 years) of hypertensive siblings recruited by the Hypertension Genetic Epidemiology Network Birmingham, AL, field center. In addition to measuring plasma adiponectin, demographic and lifestyle data were collected, and anthropometric, clinical, and laboratory measurements were obtained. Mean plasma adiponectin concentration was 5.5+/-3.8 microg/mL. Adiponectin was 55% higher in women than in men: 6.5+/-4.4 vs 4.2+/-2.5 microg/mL, respectively (P<.0001). In a multivariable analysis, high-density lipoprotein cholesterol concentration was positively associated and male sex and insulin concentration were negatively associated with plasma adiponectin concentration. Plasma adiponectin concentrations in these African Americans were lower than those reported in other racial/ethnic groups, including Japanese, whites, and Pima Indians. The directions of the associations of plasma adiponectin with other factors were in agreement with results in other racial/ethnic groups.
Assuntos
Adiponectina/sangue , Adiponectina/genética , Hipertensão/sangue , Hipertensão/epidemiologia , Adulto , Negro ou Afro-Americano/genética , Análise de Variância , Índice de Massa Corporal , HDL-Colesterol/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Insulina/sangue , Modelos Lineares , Masculino , Fatores Sexuais , Estados Unidos/epidemiologiaRESUMO
We characterized HFE C282Y homozygotes aged 25-29 years in the HEmochromatosis and IRon Overload Screening (HEIRS) Study using health questionnaire responses, transferrin saturation (TfSat), serum ferritin (SF), and HFE genotyping. In eight homozygotes, we used denaturing high-performance liquid chromatography and sequencing to search for HFE2 (= HJV), TFR2, HAMP, SLC40A1 (= FPN1), and FTL mutations. Sixteen of 4,008 White or Hispanic participants aged 25-29 years had C282Y homozygosity (15 White, 1 Hispanic); 15 were previously undiagnosed. Eleven had elevated TfSat; nine had elevated SF. None reported iron overload-associated abnormalities. No deleterious non-HFE mutations were detected. The prevalence of C282Y homozygosity in White or Hispanic HEIRS Study participants aged 25-29 years did not differ significantly from the prevalence of C282Y homozygosity in older White or Hispanic HEIRS Study participants. The prevalences of reports of iron overload-associated abnormalities were not significantly different in these 16 C282Y homozygotes and in HFE wt/wt control participants aged 25-29 years who did not report having hemochromatosis or iron overload. We conclude that C282Y homozygotes aged 25-29 years diagnosed by screening infrequently report having iron overload-associated abnormalities, although some have elevated SF. Screening using an elevated TfSat criterion would fail to detect some C282Y homozygotes aged 25-29 years.
Assuntos
Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Homozigoto , Sobrecarga de Ferro/genética , Proteínas de Membrana/genética , Adulto , Peptídeos Catiônicos Antimicrobianos/genética , Apoferritinas , Proteínas de Transporte de Cátions/genética , Análise Mutacional de DNA , Feminino , Ferritinas/genética , Testes Genéticos , Genótipo , Hemocromatose/sangue , Hemocromatose/diagnóstico , Proteína da Hemocromatose , Hepcidinas , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/diagnóstico , Masculino , Mutação , Receptores da Transferrina/genéticaRESUMO
OBJECTIVE: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. DESIGN: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group. RESULTS: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions. CONCLUSION: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.
Assuntos
Etnicidade/genética , Hemocromatose/epidemiologia , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/genética , Proteínas de Membrana/genética , Mutação , Grupos Raciais/genética , Adulto , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , População Negra/genética , População Negra/estatística & dados numéricos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Hemocromatose/etnologia , Proteína da Hemocromatose , Hispânico ou Latino/genética , Hispânico ou Latino/estatística & dados numéricos , Humanos , Indígenas Norte-Americanos/genética , Indígenas Norte-Americanos/estatística & dados numéricos , Sobrecarga de Ferro/etnologia , Masculino , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , América do Norte/epidemiologia , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h(2) = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process.
Assuntos
DNA/genética , Leucócitos , Longevidade/genética , Homeostase do Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. METHODS: Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. RESULTS: Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. CONCLUSIONS: Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.
Assuntos
Hemocromatose/epidemiologia , Ferro/sangue , Programas de Rastreamento , Projetos de Pesquisa , Adulto , Atitude Frente a Saúde , Etnicidade , Feminino , Aconselhamento Genético , Genótipo , Hemocromatose/genética , Humanos , Masculino , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Atenção Primária à Saúde , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Previous cross-sectional studies have suggested that biomarkers of extracellular matrix remodelling are associated with atrial fibrillation (AF), but no prospective data have yet been published. Hence, we examine whether plasma matrix metalloproteinases (MMP) and their inhibitors are related to increased risk of incident AF. METHODS: We used a case-cohort design in the context of the prospective Atherosclerosis Risk in Communities (ARIC) study. From 13718 eligible men and women free from AF in 1990-92, we selected a stratified random sample of 500 individuals without and 580 with incident AF over a mean follow-up of 11.8 years. Using a weighted proportional hazards regression model, the relationships between MMP-1, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and C-terminal propeptide of collagen type-I with incident AF were examined after adjusting for confounders. RESULTS: In models adjusted for age, sex and race, all biomarkers were associated with AF, but only the relationship between plasma MMP-9 remained significant in the fully-adjusted model: each one standard deviation increase in MMP-9 was associated with 27% (95% Confidence Interval: 7% to 50%) increase in risk of AF with no evidence of an interaction with race or sex. Individuals with above mean levels of MMP-9 were more likely to be male, white and current smokers. CONCLUSIONS: The findings suggest that elevated levels of MMP-9 are independently associated with increased risk of AF. However, given the lack of specificity of MMP-9 to atrial tissue, it remains to be determined whether the observed relationship reflects the impact of atrial fibrosis or more generalized fibrosis on risk of incident AF.