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991.
Lynch AI Boerwinkle E Davis BR Ford CE Eckfeldt JH Leiendecker-Foster C Arnett DK 《JAMA》2008,299(3):296-307
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 -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. 相似文献
992.
The genetics of systemic sclerosis 总被引:3,自引:0,他引:3
The etiopathogenesis of systemic sclerosis (SSc) is unclear. With no definitive evidence supporting an environmental cause,
recent attention has focused on genetic factors. Familial clustering and ethnic influences have been demonstrated. Human leukocyte
antigen (HLA) associations exist but are more related to the presence of particular autoantibodies rather than to the disease.
In addition, no single major histocompatibility complex (MHC) allele predisposes to SSc in all ethnic groups. The role of
microchimerism in SSc is a novel yet unproven hypothesis that may be related to intergenerational HLA compatibility. Recent
studies investigating polymorphisms in genes coding for extracellular matrix proteins and cell-signaling molecules implicate
non-MHC areas in SSc pathogenesis. The data reviewed suggest that SSc is a multigenic complex disorder. 相似文献
993.
Tsao BP Grossman JM Riemekasten G Strong N Kalsi J Wallace DJ Chen CJ Lau CS Ginzler EM Goldstein R Kalunian KC Harley JB Arnett FC Hahn BH Cantor RM 《Arthritis and rheumatism》2002,46(10):2678-2685
OBJECTIVE: To evaluate familiality of 15 clinical and laboratory features in systemic lupus erythematosus (SLE)-affected sibpairs, and to estimate correlations with the age at SLE diagnosis in affected sibpairs and parent-offspring pairs. METHODS: Concordance rates and sibling risk ratios were used as indicators of familiality for 15 manifestations of SLE. Pearson's correlations and paired t-tests were used to compare the age at SLE diagnosis in affected sibpairs and in parent-offspring pairs. RESULTS: Increased sibling risk ratios (1.9-3.9) for thrombocytopenia, discoid rash, neurologic disorder (defined as seizure or psychosis), and hemolytic anemia were observed in 159 SLE-affected sibpairs. Among these clinical features, paired expression of hemolytic anemia plus thrombocytopenia and hemolytic anemia plus neurologic disorder appeared to be more frequent in 709 SLE patients than would be expected by chance (P < 0.00001 and P < 0.007, respectively). The ratio of the presence of both hemolytic anemia and neurologic disorder was approximately 13 times higher in the younger affected sib than in the older affected sib (P < 0.02). Familiality of patient age at SLE diagnosis, as observed by relative correlations, was greater in 125 affected sibpairs (r = 0.67, P < 0.0001) than in 37 affected parent-offspring pairs (r = 0.47, P = 0.003). The median +/- SD age at SLE diagnosis was significantly lower in offspring (21.5 +/- 10.1 years) than in their parents (41.6 +/- 15.8 years) (P < 0.0001) but was not different in sibpairs. The combined non-Caucasian sibpairs had a younger mean age at SLE diagnosis compared with Caucasian sibpairs (P = 0.014). CONCLUSION: Evidence for familiality of thrombocytopenia, discoid rash, neurologic disorder, hemolytic anemia, and co-occurring neurologic disorder plus hemolytic anemia in SLE was observed in 159 affected sibpairs. Familiality of the age at SLE diagnosis in relative pairs suggests that shared genes and/or shared environmental exposures impact disease susceptibility. Shared immediate environmental triggers appear less compelling, because the average time between dates of diagnosis was 11 years in parent-offspring pairs and 7.5 years in affected sibpairs. The significantly earlier age at disease diagnosis in offspring compared with their parents suggests that some forms of anticipation might play a role in susceptibility to SLE. Stratifying families by subphenotypes that are familial may reduce heterogeneity and facilitate identification of genetic risk factors for SLE. 相似文献
994.
Mildly elevated plasma total homocysteine (tHcy) levels have been associated with increased risk of coronary heart disease (CHD). Carotid artery intimal-medial wall thickening is a predictor of cardiovascular disease and has been previously shown to be positively associated with plasma tHcy in studies of asymptomatic subjects. In the current study we examined 1467 subjects with regard to their fasting plasma tHcy levels and intimal-medial wall thickness as measured by B-mode ultrasound and early onset CHD. The results showed that there is a significant positive association between plasma tHcy levels and carotid-artery wall thickness in participants 55 years or older even after the tHcy levels are adjusted for age, smoking and anti-hypertensive medication. The direction and magnitude of the relationship is similar although the result was not statistically significant in younger participants ( < 55 years). Early onset CHD at any age was not significantly different across the tHcy quintiles. The lack of an association of tHcy and CHD in the presence of a positive association with intimal-medial wall thickening may be a reflection of increased statistical power of quantitative versus qualitative traits. We conclude that the present finding of a positive association between tHcy and intimal-medial wall thickness strengthens the in vitro finding of the stimulating effect of homocysteine on vascular smooth muscle cell growth. Vascular smooth muscle cell proliferation may be an important mechanism through which mildly elevated plasma tHcy promotes atherosclerosis. 相似文献
995.
Nunez E Arnett DK Benjamin EJ Liebson PR Skelton TN Taylor H Andrew M 《Hypertension》2005,45(1):58-63
The distribution of echocardiographic left ventricular (LV) mass differs among ethnicities. Because ethnic-specific echocardiographic criteria for LV hypertrophy (LVH) are not established, we determined whether threshold values derived from overwhelmingly white populations are appropriate for blacks, a subgroup having more LVH. Between 1992 and 1994, LV mass was measured echocardiographically in the Jackson, Mississippi, black cohort of the Atherosclerosis Risk in Communities study. Participants free of prevalent cardiovascular disease (CVD) (n=1616; mean+/-SD, age 59+/-5.7; 65% women and 57% with hypertension) were included. The optimal LVH threshold value was selected from the continuum of LV mass index (LVMI=LV mass/height(2.7)) using 3 methods: (1) the best operating point from the area under the resulting receiver-operating characteristic (ROC) curve predicting incident CVD; (2) the value with the smallest probability value associated with incident CVD; and (3) visual inspection of functions of LVMI and CVD in the general additive model (GAM) plot. At a median follow-up of 6.8 years, there were 192 events (coronary heart disease=87, stroke=62, and congestive heart failure=43; incidence=17.6/1000 person-years). The best operating point from the resulting ROC analysis was 51.2 g/m(2.7) for sensitivity (53.4%) and specificity (61.5%). The Cox and GAM models adjusted for age, gender, systolic blood pressure, hypertension, diabetes, smoking, total cholesterol-to-high-density lipoprotein ratio, LVH by ECG criterion, and socioeconomic status found 50 to 51 g/m(2.7) as the optimal threshold for LVH in middle-aged blacks, corresponding to a minimum probability value and to a log-hazard ratio of zero, respectively. Because these values are close to the 51 g/m(2.7) established from predominantly white populations, this cutpoint is appropriate for both groups. 相似文献
996.
IgA and IgG autoantibodies against alpha-fodrin as markers for Sjögren's syndrome. Systemic lupus erythematosus 总被引:1,自引:0,他引:1
Witte T Matthias T Arnett FC Peter HH Hartung K Sachse C Wigand R Braner A Kalden JR Lakomek HJ Schmidt RE 《The Journal of rheumatology》2000,27(11):2617-2620
OBJECTIVE: To determine the prevalence of IgA and IgG autoantibodies against alpha-fodrin in patients with primary and secondary Sj?gren's syndrome (SS) and controls. METHODS: An ELISA detecting IgA and IgG antibodies against alpha-fodrin was developed. We examined the prevalence of IgA and IgG antibodies against alpha-fodrin in patients with primary and secondary SS, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) and blood donors. RESULTS: IgA antibodies against alpha-fodrin were detected in 64% of patients with primary SS (n = 85), 47% of patients with secondary SS and SLE (n = 15), and 86% of patients with secondary SS and RA (n = 7). IgA autoantibodies against alpha-fodrin were detected in only one of 160 sera obtained from blood donors and in one of 50 and 2 of 12 sera obtained from SLE and RA patients without sicca syndrome, respectively. The prevalence of IgG antibodies against alpha-fodrin in SS was lower: they were detected in 55% of sera obtained from patients with primary SS, 40% of patients with secondary SS and SLE, and in 43% of patients with secondary SS and RA. Three of 160 sera from blood donors and one of 50 and 5 of 12 sera from SLE and RA patients without sicca syndrome, respectively, contained IgG antibodies against alpha-fodrin. CONCLUSION: IgA rather than IgG antibodies against alpha-fodrin are specific for and frequently observed in primary and secondary SS and are useful markers for this autoimmune disorder. 相似文献
997.
Systemic lupus erythematosus: a review of clinico-laboratory features and immunogenetic markers in 150 patients with emphasis on demographic subsets 总被引:23,自引:0,他引:23
M C Hochberg R E Boyd J M Ahearn F C Arnett W B Bias T T Provost M B Stevens 《Medicine》1985,64(5):285-295
Clinical and laboratory features as well as immunogenetic markers were analyzed in 150 patients with SLE to determine if demographic factors--age at diagnosis, sex and race--influenced the expression of disease. The overall series included 103 white females, 35 black females, 10 white males and 2 black males; the mean age at diagnosis was 32.5 years. Males had a significantly older mean age at diagnosis than females (40.4 versus 31.8 years) and a significantly higher frequency of peripheral neuropathy (50% versus 18.8%). No other differences in clinical or laboratory features or HLA-DR or DQ phenotype frequencies were noted. Blacks had a significant younger mean age at diagnosis than whites (26.9 versus 33.4 years) as well as significantly higher frequencies of nephritis, hypertension, acute lupus pneumonitis, discoid rash, hyperglobulinemia and hypocomplementemia. There were no differences in autoantibody frequencies between race-specific subgroups. HLA-DR2, DRw52 and DQ1 were significantly associated with SLE in whites compared to controls; no HLA-DR or DQ associations were found with SLE in blacks. In whites, HLA-DR2 was associated with the presence of anti-Ro(SS-A) antibody while HLA-DR3 was associated with the presence of both anti-Ro(SS-A) and anti-La(SS-B) antibody. In blacks, HLA-DR2 was associated with the presence of anti-nDNA antibody. In whites, patients with late-onset SLE (age at diagnosis greater than or equal to 50 years) had significantly lower frequencies of nephritis and mesenteric vasculitis but, on the other hand, a higher frequency of secondary Sj?gren syndrome than patients with age at diagnosis less than or equal to 22 years. Similar findings were noted when blacks aged 35 and above were compared to those aged 17 and below at diagnosis. In whites, the frequency of both anti-Ro(SS-A) and La(SS-B) antibodies increased with increasing age as did that of HLA-DR3; HLA-DR2, however, was more frequent in those with younger age at diagnosis. These data suggest the existence of two serologic-genetic subsets of SLE with different age at diagnosis. 相似文献
998.
The effects of acute thrombocytopenia on megakaryocyte-CFC and granulocyte-macrophage-CFC in mice: studies of bone marrow and spleen 总被引:3,自引:1,他引:3
The effects of acute thrombocytopenia, produced by platelet antiserum (PAS), on both megakaryocyte colony-forming cells (Meg-CFC) and granulocyte-macrophage colony-forming cells (GM-CFC) were studied. During the 1-hr to 14-day period following acute thrombocytopenia (platelet counts < 5% of normal), bone marrow and splenic cells of C57BL/6J mice were obtained and cultured for 7 days in 0.3% agar. Numbers of GM and Meg colonies were determined. At no times were alterations in frequency of GM-CFC and Meg-CFC detected in femoral bone marrow. In contrast, GM-CFC in spleen were increased from 3 to 7 days after PAS and from 4 to 7 days after normal serum (NS). Increase in Meg- CFC in the spleen occurred from 3 to 5 days after PAS with a lesser, not significant increase after NS. Alterations in white blood cells and hematocrit values were not detected. Similar responses were observed in germ-free mice and after rechallenge of animals that had received PAS or NS 14 days previously. The delayed increase in Meg-CFC indicates that they are unlikely to be responsible for the altered megakaryopoiesis previously reported in bone marrow after acute thrombocytopenia and was not due to inhibition by PAS. The increase in GM-CFC may reflect stimulation of the reticuloendothelial system by heterologous proteins. 相似文献
999.
Bielinski SJ Pankow JS Li N Hsu FC Adar SD Jenny NS Bowden DW Wasserman BA Arnett D 《Atherosclerosis》2008,201(2):339-344
Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may be important contributors to the development and progression of atherosclerosis. Using a stratified random sample of 2880 participants of the Multi-Ethnic Study of Atherosclerosis we investigated the relationship of 12 ICAM1 and 17 VCAM1 SNPs and coronary artery calcium (CAC) and ICAM1 SNPs and circulating levels of soluble ICAM-1 (sICAM-1). There were no ICAM1 or VCAM1 SNPs significantly associated with CAC in any of the four race/ethnic groups. In a subset of 1451 subjects with sICAM-1 measurements, we observed a significant association with rs5491 in all four race/ethnic groups corroborating previous research that has shown that the T-allele of rs5491 interferes with the monoclonal antibody used to measure sICAM-1 in this study. After excluding all rs5491 T-allele carriers, several ICAM1 SNPs were significantly associated with sICAM-1 levels; rs5496 in African Americans, rs5498 and rs3093030 in European Americans, and rs1799969 in Hispanics. Our results identified ICAM1 polymorphisms that were significantly associated with sICAM-1 level but not CAC, a subclinical marker of atherosclerosis. 相似文献
1000.