To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with ...hepatitis C and B viruses.
A case-control study nested in the Swiss HIV Cohort Study.
Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression.
All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68 and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91).
Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.
Background: It has been known for more than 20 years that estrogen replacement therapy substantially increases a woman's risk of developing endometrial cancer. To reduce this increased risk, ...progestins have been added to estrogen replacement therapy for between 5 and 15 days (usually 7 or 10 days) per “month” in a sequential fashion (sequential estrogen-progestin replacement therapy) or with each dose of estrogen replacement therapy (continuous combined replacement therapy). At the present time, however, little is known about the effects of varying the number of days that progestin is used in sequential estrogen-progestin replacement therapy. Purpose: We sought to determine the effects of sequential estrogen-progestin replacement therapy and continuous combined replacement therapy on a woman's risk of developing endometrial cancer. Methods: A populationbased, case-control study of 833 case subjects and 791 control subjects was conducted. Women were postmenopausal, white, and aged 50–74 years when first diagnosed with invasive endometrial cancer or were aged 50–74 years at the matching date for control subjects. All subjects were interviewed in person with the aid of a month-by-month calendar. Relative risks were estimated by odds ratios (ORs); ORs were adjusted simultaneously for the different forms of hormone replacement therapy and for the known endometrial cancer risk factors. Results: The adjusted OR was 2.17 (95% confidence interval CI = 1.91–2.47) per 5 years of estrogen replacement therapy use (based on 422 users among the case subjects and 262 users among the control subjects). For women who received sequential estrogen-progestin replacement therapy with the progestin given for less than 10 days (effectively 7 days) per month, the adjusted OR was only slightly reduced to 1.87 (95% CI = 1.32–2.65) per 5 years of use (74 case subjects and 47 control subjects). However, when progestin was given for 10 or more days (effectively 10 days), there was essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.82–1.41) (79 case subjects and 88 control subjects). Continuous combined replacement therapy was also associated with essentially no increased risk (adjusted OR = 1.07 per 5 years of use; 95% CI = 0.80–1.43) (94 case subjects and 81 control subjects). Conclusions: The progestin in sequential estrogen-progestin replacement therapy needs to be given for at least 10 days to block effectively any increased risk of endometrial cancer. Continuous combined estrogen-progestin therapy is similarly effective. Neither regimen reduces a woman's underlying risk of endometrial cancer. The sharp distinction between the effects of less than 10 days (effectively 7 days) and 10 or more days (effectively 10 days) of progestin use in sequential estrogen-progestin replacement therapy suggests that the extent of endometrial sloughing may play a critical role in determining endometrial cancer risk.
Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed ...to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the SCN5A gene. The lead variant, rs7373862, located in an intron of SCN5A, was associated with an increase of 0.12 95% CI 0.08–0.16 standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10−5). However, several AF risk loci, including PITX2, were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF.
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•Variants in SCN5A are associated with premature atrial contractions (PAC) frequency•Other atrial fibrillation (AF) risk variants are also associated with PAC frequency•Both shared and distinct genetic mechanisms exist for PAC frequency and AF
Clinical genetics; Cardiovascular medicine; Human genetics; Genomics
Improved air quality has been found associated with attenuated age-related decline in lung function. But whether genetic polymorphisms strongly associated with lung function play a modifying role in ...this attenuation process has so far not been investigated.
We selected ten single nucleotide polymorphisms derived from the largest genome-wide association studies on lung function and examined whether they modified the association between the change in exposure to particulate matter ≤10μm (ΔPM10) and lung function decline. 4310 participants from the SAPALDIA cohort provided valid spirometry measurements, a detailed pulmonary health questionnaire both at baseline and 11years later as well as blood samples for genetic testing. Spatially and temporally resolved air pollution exposures were assigned on an individual level based on participants' residences.
Statistically significant interactions of moderate strength with ΔPM10 were detected for rs2284746. Individuals with the CC genotype had a 21ml slower annual decline of the mid expiratory flow per 10μg/m3 PM10 reduction over an 10-year period, while the benefits of CG and GG carriers were smaller (14 and 7ml per year, respectively; Pinteraction=0.04). The attenuated annual decline in the percentage of the forced expiratory volume in one second relative to the forced vital capacity (FEV1/FVC) was also increased with the presence of each C-allele (Pinteraction=0.009). We observed further suggestive interactions of similar magnitude in never-smokers, but none of the results would remain statistically significant after correction for multiple testing.
We could not find strong evidence that lung function benefits from improved air quality are modified by polymorphisms associated with lung function level in large meta-analyzed genome-wide association studies.
•We study gene-air pollution interaction on age-related lung function decline•We focus on gene variants associated with lung function level in GWAS metaanalysis•We find no strong evidence that the variants modify effect of improved air quality
Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respiratory disease and mortality risk. We studied the association of bilirubin with lung function in the ...Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. Associations between natural logarithmised bilirubin and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and mean forced expiratory flow between 25%-75% of FVC (FEF25-75%) were tested using multiple linear regression in the whole study population (n=4195) and strata of ever-smoking and high body mass index (BMI, defined by the highest distribution quartile). Associations were retested with single nucleotide polymorphism rs6742078, a genetic determinant of bilirubin. High bilirubin levels were significantly associated with higher FEV1/FVC and FEF25-75% overall. Upon stratification, significant associations persisted in ever-smokers, amounting to 1.1% (95% CI 0.1-2.2%) increase in FEV1/FVC, and 116.2 mL·s(-1) (95% CI -15.9-248.4 mL·s(-1)) in FEF25-75% per interquartile range of bilirubin exposure in smokers with high BMI. Associations were positive but nonsignificant in never-smokers with high BMI. Similarly, rs6742078 genotype TT was associated with increased FEV1/FVC and FEF25-75%. Our results suggest a possible protective role of bilirubin on lung tissue, which could be important for prevention and therapy.
Variation in the circulating concentrations of the insulin-like growth factor (IGF) system has been implicated in the etiology
of chronic diseases including cancer (prostate, breast, colon, and ...lung), heart disease, type 2 diabetes, and osteoporosis.
We searched for sociodemographic, anthropometric, reproductive, lifestyle, and dietary determinants of IGF-I and insulin-like
growth factor binding protein (IGFBP) -3 serum concentrations. Serum samples were collected in a Singapore Chinese cohort
with a mean age of 61 years. Subject information was assessed during an in-person interview. Radioimmunometrically measured
IGF-I and IGFBP-3 concentrations were available for 312 men and 326 postmenopausal women ages 50 years or older. Mean IGF-I
concentrations were 144 ng/ml and 121 ng/ml for men and women, respectively (gender difference, P < 0.0001), and mean IGFBP-3 concentrations were 3710 ng/ml and 4147 ng/ml for men and women, respectively (gender difference,
P < 0.0001). IGF-I and IGFBP-3 decreased with age ( P for trend <0.0001); the age-related decrease in the IGF-I:IGFBP-3 molar ratio was stronger in women than men. IGF-I concentrations
were higher among physically inactive subjects and among women with an early age at menarche. Consumption of saturated fat
was found to decrease, and intake of ω-3 polyunsaturated fatty acids and of dietary fiber was found to increase circulating
IGFBP-3 concentrations. Intake of calcium from food and supplement was associated positively with circulating IGF-I, IGFBP-3,
and molar ratio. Intake of soy was associated positively with IGF-I and molar ratio concentrations, but only in men. The results
of this study lend additional support to the hypothesis that circulating IGF-I concentrations increase the risk of prostate,
bladder, colorectal, and breast cancer.
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Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for ...longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life.
This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children.
This study used data from 3 adult cohorts (TESAOD Tucson Epidemiological Study of Airway Obstructive Disease, SAPALDIA Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, LSC Lovelace Smoker Cohort) and 1 birth cohort (TCRS Tucson Children’s Respiratory Study) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life.
After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: −2.9%; 95% CI: −3.9%, −1.9%; P = 2.4 × 10−16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001).
A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory ...volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We assessed associations between physical activity and lung function, and its decline, in the prospective population-based European Community Respiratory Health Survey cohort.
FEV
and FVC were ...measured in 3912 participants at 27-57 years and 39-67 years (mean time between examinations=11.1 years). Physical activity frequency and duration were assessed using questionnaires and used to identify active individuals (physical activity ≥2 times and ≥1 hour per week) at each examination. Adjusted mixed linear regression models assessed associations of regular physical activity with FEV
and FVC.
Physical activity frequency and duration increased over the study period. In adjusted models, active individuals at the first examination had higher FEV
(43.6 mL (95% CI 12.0 to 75.1)) and FVC (53.9 mL (95% CI 17.8 to 89.9)) at both examinations than their non-active counterparts. These associations appeared restricted to current smokers. In the whole population, FEV
and FVC were higher among those who changed from inactive to active during the follow-up (38.0 mL (95% CI 15.8 to 60.3) and 54.2 mL (95% CI 25.1 to 83.3), respectively) and who were consistently active, compared with those consistently non-active. No associations were found for lung function decline.
Leisure-time vigorous physical activity was associated with higher FEV
and FVC over a 10-year period among current smokers, but not with FEV
and FVC decline.
α1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management ...of replacement therapy require the availability of precise and updated ranges for protein serum levels.
This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population.
The authors correlated mean AAT serum levels with the main SERPINA1 variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort.
The following ranges (5th-95th percentile) of AAT were found in the serum (g/litre): 1.050-1.640 for PI*MM, 0.880-1.369 for PI*MS, 0.730-1.060 for PI*SS, 0.660-0.997 for PI*MZ and 0.490-0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ).
This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based 'protective threshold' of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention.
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