Xiping Xu

An association between air pollution and mortality in six U.S. cities

BACKGROUND Recent studies have reported associations between particulate air pollution and daily mortality rates. Population-based, cross-sectional studies of metropolitan areas in the United States have also found associations between particulate air pollution and annual mortality rates, but these studies have been criticized, in part because they did not directly control for cigarette smoking and other health risks. METHODS In this prospective cohort study, we estimated the effects of air pollution on mortality, while controlling for individual risk factors. Survival analysis, including Cox proportional-hazards regression modeling, was conducted with data from a 14-to-16-year mortality follow-up of 8111 adults in six U.S. cities. RESULTS Mortality rates were most strongly associated with cigarette smoking. After adjusting for smoking and other risk factors, we observed statistically significant and robust associations between air pollution and mortality. The adjusted mortality-rate ratio for the most polluted of the cities as compared with the least polluted was 1.26 (95 percent confidence interval, 1.08 to 1.47). Air pollution was positively associated with death from lung cancer and cardiopulmonary disease but not with death from other causes considered together. Mortality was most strongly associated with air pollution with fine particulates, including sulfates. CONCLUSIONS Although the effects of other, unmeasured risk factors cannot be excluded with certainty, these results suggest that fine-particulate air pollution, or a more complex pollution mixture associated with fine particulate matter, contributes to excess mortality in certain U.S. cities.

Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms.

Haplotypes have gained increasing attention in the mapping of complex-disease genes, because of the abundance of single-nucleotide polymorphisms (SNPs) and the limited power of conventional single-locus analyses. It has been shown that haplotype-inference methods such as Clarks algorithm, the expectation-maximization algorithm, and a coalescence-based iterative-sampling algorithm are fairly effective and economical alternatives to molecular-haplotyping methods. To contend with some weaknesses of the existing algorithms, we propose a new Monte Carlo approach. In particular, we first partition the whole haplotype into smaller segments. Then, we use the Gibbs sampler both to construct the partial haplotypes of each segment and to assemble all the segments together. Our algorithm can accurately and rapidly infer haplotypes for a large number of linked SNPs. By using a wide variety of real and simulated data sets, we demonstrate the advantages of our Bayesian algorithm, and we show that it is robust to the violation of Hardy-Weinberg equilibrium, to the presence of missing data, and to occurrences of recombination hotspots.

Efficacy of folic acid supplementation in stroke prevention: a meta-analysis

BACKGROUND The efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease remains controversial. Our aim was to do a meta-analysis of relevant randomised trials to assess the efficacy of folic acid supplementation in the prevention of stroke. METHODS We collected data from eight randomised trials of folic acid that had stroke reported as one of the endpoints. Relative risk (RR) was used as a measure of the effect of folic acid supplementation on the risk of stroke with a random effect model. The analysis was further stratified by factors that could affect the treatment effects. FINDINGS Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0.82, 95% CI 0.68-1.00; p=0.045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0.71, 0.57-0.87; p=0.001), a decrease in the concentration of homocysteine of more than 20% (0.77, 0.63-0.94; p=0.012), no fortification or partly fortified grain (0.75, 0.62-0.91; p=0.003), and no history of stroke (0.75, 0.62-0.90; p=0.002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. INTERPRETATION Our findings indicate that folic acid supplementation can effectively reduce the risk of stroke in primary prevention.

The direction of microsatellite mutations is dependent upon allele length.

Microsatellites, comprising tandemly repeated short nucleotide sequences, are ubiquitous in eukaryotic genomes. Mutations within microsatellites are frequent, altering their overall length by insertion or deletion of a small number of repeat units, with a rate as high as 10−3 in humans. Despite their high mutability, stable allele frequency distributions are typically observed for microsatellites in humans as well as other primates, although the mechanism maintaining these stable distributions remains unclear. Previous studies have suggested that microsatellite mutations occur more frequently in longer alleles and favour expansion. Generalizing these results has been hindered because the sample sizes were small, only a small subset of alleles for any marker was studied and the direction of mutation (expansion or contraction) was not rigorously determined. Here we examine 236 mutations at 122 tetranucleotide repeat markers and find that the rate of contraction mutations increases exponentially with allele size, whereas the rate of expansion mutations is constant across the entire allele distribution. The overall rate of expansion mutations does not differ from that of contractions. Our findings offer an explanation for the stationary allele distribution of microsatellites.

An extreme-sib-pair genome scan for genes regulating blood pressure.

Hypertension, a risk factor for many cardiovascular, cerebrovascular, and renal diseases, affects one in four Americans, at an annual cost of>

Airways responsiveness and development and remission of chronic respiratory symptoms in adults

30 billion. Although genetic mutations have been identified in rare forms of hypertension, including Liddle syndrome and glucocorticoid-remediable aldosteronism, the abundance of plausible candidate genes and potential environmental risk factors has complicated the genetic dissection of more prevalent essential hypertension. To search systematically for chromosomal regions containing genes that regulate blood pressure, we scanned the entire autosomal genome by using 367 polymorphic markers. Our study population, selected from a blood-pressure screen of >200,000 Chinese adults, comprises rare but highly efficient extreme sib pairs (207 discordant, 258 high concordant, and 99 low concordant) and all but a single parent of these sibs. By virtue of the sampling design, the number of sib pairs, and the availability of genotyped parents, this study represents one of the most powerful of its kind. Although no regions achieved a 5% genomewide significance level, maximum LOD-score values were >2.0 (unadjusted P<.001) for regions containing five markers (D3S2387, D11S2019, D15S657, D16S3396, and D17S1303), in our primary analysis. Other promising regions identified through secondary analyses include loci near D4S3248, D7S2195, D10S1423, D20S470, D20S482, D21S2052, PAH, and AGT.

Air Pollution and Daily Mortality in Shenyang, China

BACKGROUND Many patients with chronic obstructive lung disease show increased airways responsiveness to histamine. We investigated the hypothesis that increased airways responsiveness predicts the development and remission of chronic respiratory symptoms. METHODS We used data from 24-year follow-up (1965-90) of 2684 participants in a cohort study in Vlagtwedde and Vlaardingen, Netherlands. Increased airways responsiveness was defined as a PC10 value (concentration of histamine for which challenge led to a 10% fall in forced expiratory volume in 1 s) of less than 8 mg/mL. Information on respiratory symptoms was collected by means of a standard questionnaire every 3 years. Logistic regression was used to control for age, area of residence, cigarette smoking status, and sex. FINDINGS Participants with increased airways responsiveness (1281 observations) were more likely than those without increased airways responsiveness (5801 observations) to develop the following symptoms during any 3-year follow-up interval: chronic cough (odds ratio 1.9 [95% CI 1.2-2.9]), chronic phlegm (2.0 [1.3-3.0]), dyspnoea (2.3 [1.5-3.5]), asthmatic attacks (3.7 [2.2-6.1]), and persistent wheeze (2.7 [1.7-4.4]). The estimate of the odds ratio for the development of any of the six symptoms was 1.7 (1.2-2.3). Participants with increased airways responsiveness were less likely than those without this characteristic to show remission of these respiratory symptoms. The estimate of the odds ratio for the remission of any of the six symptoms was 0.42 (0.28-0.61). INTERPRETATION These prospective analyses show that increased airways responsiveness is positively associated with the development of chronic respiratory symptoms and negatively associated with the remission of these symptoms in adults.

14 The future of genetic case-control studies

Abstract The authors analyzed daily mortality data in Shenyang, China, for calendar year 1992 to identify possible associations with ambient sulfur dioxide and total suspended particulates. Both total suspended particulate concentrations (mean = 430 μmlg/m3, maximum = 1,141 μmlg/m3) and sulfur dioxide concentrations (mean 197 = μmlg/m3, maximum = 659 μmlg/m3) far exceeded the World Health Organizations recommended criteria. An average of 45.5 persons died each day. The lagged moving averages of air-pollution levels, calculated as the mean of the nonmissing air-pollution levels of the concurrent and 3 preceding days, were used for all analyses. Locally weighted regression analysis, including temperature, humidity, day of week, and a time variable, showed a positive association between daily mortality and both total suspended particulates and sulfur dioxide. When the authors included total suspended particulates and sulfur dioxide separately in the model, both were highly significant predictors of daily mortality. The risk of all-cause mortality increased by an estimated 1.7% and 2.4% with a 100-μmlg/m3 concomitant increase in total suspended particulate and sulfur dioxide, respectively. When the authors analyzed mortality separately by cause of death, the association with total suspended particulates was significant for cardiovascular disease (2.1%), but not statistically significant for chronic obstructive pulmonary diseases (2.6%). In contrast, the association with sulfur dioxide was significant for chronic obstructive pulmonary diseases (7.4%), but not for cardiovascular disease (1.8%). The mortality from cancer was not associated significantly with total suspended particles or with sulfur dioxide. The correlation between sulfur dioxide and total suspended particulates was high (correlation coefficient = .66). When the authors included sulfur dioxide and total suspended particulates simultaneously in the model, the association between total suspended particulates and mortality from all causes and cardiovascular diseases remained significant. Sulfur dioxide was associated significantly with increased mortality from chronic obstructive pulmonary diseases and other causes. The results of the current study reveal increased mortality associated with both total suspended particulates and sulfur dioxide.

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men

The case-control study design has been a veritable workhorse in epidemiological research since its inception and acceptance as a valid and valued field of inquiry. The reasons for this owe to the simplicity of the required sampling and the (potential) ease of analysis and interpretation of results. Unfortunately, there are a number of problems that plague the use of the case-control design in assessing relationships between genetic variation and disease susceptibility in the population at large. Many of these problems are entirely analogous to problems that inhere in applications of the case-control design in nongenetic settings. These problems include stratification, the assessment of statistical significance, heterogeneity, and the interpretation of multiple outcomes or phenotypic information. In this chapter we describe 10 problems thought to plague genetic case-control studies and offer potential solutions to each. Many of our proposed solutions require the use of multiple DNA markers to accommodate the genetic background of the individuals sampled as cases and controls. It is hoped that our discussions and proposals will spark further debate about the analysis and ultimate utility of the case-control study in genetic epidemiology research.

A Common Mutation in the Defensin DEFB126 Causes Impaired Sperm Function and Subfertility

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5′ UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P=0.004), and lower whole body BMD (P<0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P<0.01), and higher whole body BMD (P<0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P<0.05), and higher whole body BMD (P<0.01). Significant gene–gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.