Changzhong Chen

Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study

OBJECTIVE To examine rates of conception and pregnancy loss and their relations with time to clinical pregnancy and reproductive outcomes. DESIGN A prospective observational study. SETTING Population-based cohort in China. PATIENT(S) Five hundred eighteen healthy newly married women who intended to conceive. Upon stopping contraception, daily records of vaginal bleeding and daily first-morning urine specimens were obtained for < or =1 year or until a clinical pregnancy was achieved. Daily urinary hCG was assayed to detect early pregnancy loss (EPL). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Conception, pregnancy loss, and time to clinical pregnancy. RESULT(S) The conception rate per cycle was 40% over the first 12 months. Of the 618 detectable conceptions, 49 (7.9%) ended in clinical spontaneous abortion, and 152 (24.6%) in EPL. Early pregnancy loss was detected in 14% of all the cycles without clinically recognized pregnancy, but the frequencies were lower among women with delayed time to clinical pregnancy. Early pregnancy loss in the preceding cycle was associated with increased odds of conception (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.8-3.9), clinical pregnancy (OR, 2.0; 95% CI, 1.3-3.0), and EPL (OR, 2.4; 95% CI, 1.4-4.2) but was not associated with spontaneous abortion, low birth weight, or preterm birth in the subsequent cycle. CONCLUSION(S) We demonstrated substantial EPL in the non-clinically pregnant cycles and a positive relation between EPL and subsequent fertility.

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>

A Common Haplotype of the Nicotine Acetylcholine Receptor α4 Subunit Gene Is Associated with Vulnerability to Nicotine Addiction in Men

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.

A genome-wide scan for loci linked to forearm bone mineral density

Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction. We studied six single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and four SNPs in the CHRNB2 gene with respect to nicotine dependence in a collection of 901 subjects (815 siblings and 86 parents) from 222 nuclear families with multiple nicotine-addicted siblings. The subjects were assessed for addiction by both the Fagerstrom Test for Nicotine Dependence (FTND) and the Revised Tolerance Questionnaire (RTQ). Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses (621 men from 206 families). Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles at two SNPs, rs1044396 and rs1044397, in exon 5 of the CHRNA4 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype (i.e., age-adjusted FTND and RTQ scores), which was consistent with the results of the global haplotype FBAT. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype, GCTATA, which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait (Z=-3.04, P<.005) and significant decreases of age-adjusted FTND (Z=-3.31, P<.005) or RTQ scores (Z=-2.73, P=.006). Our findings provide strong evidence suggesting a common CHRNA4 haplotype might be protective against vulnerability to nicotine addiction in men.

A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

Abstract Osteoporosis is a chronic disorder characterized by low bone mass and fragility fractures. It affects more than 25 million men and women in the United States alone. Although several candidate genes, such as the vitamin-D-receptor gene or the estrogen-receptor gene, have been suggested in the pathogenesis of osteoporosis, the genetic dissection of this disorder remains a daunting task. To search systematically for chromosomal regions containing genes that regulate bone mineral density (BMD), we scanned the entire autosomal genome by using 367 polymorphic markers among 218 individuals (153 sibpairs) from 96 nuclear families collected from three townships of Anqing, China. In these 96 families, DNA samples from both parents were available for 82 (85.4%) families. By using age- and gender-adjusted forearm BMD measurements, a peak on chromosome 2 near D2S2141, D2S1400, and D2S405, a region previously linked to spinal BMD, showed evidence of linkage to both proximal and distal forearm BMD (multipoint LOD=2.15 and 2.14 for proximal and distal forearm BMD, respectively). One region on chromosome 13 (multipoint LOD=1.67) in the proximity of D13S788 and D13S800 showed evidence of linkage to distal forearm BMD only. Possible candidate genes included CALM2 (calmodulin 2) at 2p21.3-p21.1, a putative STK (serine/threonine kinase) at 2p23–24, POMC (pro-opiomelanocortin) at 2p23.3, and COL4A1 and COL4A2 (collagen IV alpha-1 and alpha-2 subunits) at 13q34. Because of the limited sample size, the suggestive evidence of linkage of this study should be considered as tentative and needs to be replicated in other larger populations.

Exposure to benzene, occupational stress, and reduced birth weight

A genomewide screen for quantitative-trait loci (QTLs) that underlie asthma was performed on 533 Chinese families with asthma, by the unified Haseman-Elston method. Nine asthma-related phenotypes were studied, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), airway responsiveness as indicated by methacholine (MTCH)-challenge test, serum total immunoglobulin E (TIgE), serum-specific immunoglobulin E, eosinophil count in peripheral blood, and skin-prick tests with three different allergens (cockroach, Dermatophagoides pteronyssinus, and D. farinae). Our study showed significant linkage between airway responsiveness to MTCH and D2S1780 on chromosome 2 (P<.00002) and provided suggestive evidence (P<.002) for six additional possible QTLs: D10S1435 and D22S685, for FEV1; D16S412, for FVC; D19S433, for airway responsiveness to MTCH; D1S518, for TIgE; and D4S1647, for skin reactivity to cockroach. No significant or suggestive evidence of linkage for the other four traits was found.

Polymorphisms of the paraoxonase gene and risk of preterm delivery.

OBJECTIVES The association between birth weight and exposure to benzene, work stress, and other occupational and environmental hazards was investigated. METHODS In a large petrochemical industry, 792 pregnant workers were enrolled and followed up through delivery between May 1996 and December 1998. Exposure to benzene and other solvents was assessed by an industrial hygienist based on each womans job title and workplace information. Other occupational and environmental exposures and personal information, including perceived work stress, exposure to noise, physical exertion at work, and passive smoking, were obtained by an interview questionnaire. Univariate and multivariate regression models were used to examine the individual and combined associations of occupational and environmental exposures with birth weight, with adjustment for major confounders including gestational age. RESULTS In the univariate model, birth weight was negatively associated with exposure to benzene (−58 g (95% confidence interval (95% CI), −115 to −2)) and with work stress (−84 g (95% CI, −158 to −10)). In the multivariate model, there was a significant interaction between exposure to benzene and work stress relative to reduced birth weight, after adjustment for other environmental and occupational exposures and personal variables. Adjusted mean birth weight was 3445 g (95% CI 3401 to 3489) among those with neither exposure, 3430 g for those with exposure to benzene only, 3426 g for those with work stress only, and 3262 g (95% CI 3156 to 3369) for those with both exposures. In other words, there was 183 g (95% CI 65 to 301) reduction in birth weight among those with both exposure to benzene and work stress compared with those with neither exposure. Other work or environmental factors could not explain these findings. CONCLUSIONS Low level exposure to benzene and work stress interact to reduce birth weight in this population.

Microsomal epoxide hydrolase polymorphism and risk of spontaneous abortion.

Background: Human paraoxonase (PON) is an enzyme involved in vasodilation and thrombosis. Disruption of blood blow through the placenta could be part of the pathophysiological mechanism leading to preterm delivery. The purpose of this study was to examine the association between polymorphisms in 2 paraoxonase genes (PON1 and PON2) and preterm delivery. Methods: We conducted a case-control study using infant-parents triads in Anqing, China. Between July 1999 and June 2001, we enrolled the families of 105 infants born at term and 80 infants born preterm. Genotyping was performed for the polymorphisms of PON1 Q192R, PON2 A148G, and PON2 S311C using standard techniques. We used log-linear modeling to analyze the association of PON1 and PON2 gene polymorphisms with the risk of preterm delivery. Results: In the analysis of children’s genotypes, the relative risk was 3.6 (95% confidence interval [CI] = 1.3–11) for PON1 RR compared with PON1 QQ. An association was also seen for PON2 CC compared with PON2 SS (relative risk = 4.6; CI = 1.5–14). There was no association between the mother’s PON1 and PON2 genotypes and preterm delivery, and we did not observe an interaction between mothers’ and children’s genotypes. Analysis of control triads suggests Mendelian transmissions of the variant alleles of PON1 192R, PON2 148G, and PON2 311C. Conclusion: Infant PON1 RR and PON2 CC genotypes were associated with preterm delivery in our study population, which suggests a possible role for human paraoxonase variability in the etiology of preterm delivery.

Environmental and occupational determinants of blood pressure in rural communities in China

We conducted a nested case-control study to examine the association of microsomal epoxide hydrolase polymorphism with spontaneous abortion. The analysis included 127 cases and 107 controls from a rural community in China. The prevalence of the homozygous wild-type (AA), the heterozygous variant (Aa), and the homozygous variant (aa) in exon 3 of epoxide hydrolase was 13.4%, 34.6%, and 52.0% in cases and 27.1%, 30.8%, and 42.1% in controls, respectively. In contrast, the variant genotypes in exon 4 of epoxide hydrolase were less frequent in cases than controls. Using women with genotype AA as the referent, the adjusted odds ratio of spontaneous abortion was 2.69 [95% confidence interval (CI) = 1.33–5.42] for those with genotype Aa or aa in exon 3; but it was 0.45 (95% CI = 0.22–0.94) for those with genotype Aa or aa in exon 4, indicating that the two variants have opposite associations with spontaneous abortion. The findings persisted after adjustment for age, education, parity, smoking, alcohol use, occupation, and pesticide exposure, as well as in subgroup analysis. Moreover, for the variant genotypes Aa or aa in exon 3, the odds ratio was twice as great in those cases with three or more spontaneous abortions than in those with fewer spontaneous abortions. (Epidemiology 1998;9:540–544)

Effect of environmental tobacco smoke on levels of urinary hormone markers

PURPOSE To identify and characterize major environmental and occupational determinants of blood pressure in rural communities in China. METHODS In 1993 we conducted a large cross-sectional, community-based study of 20,216 residents aged 15 years or older, from the Yijing area of Anhui Province (8022 men, 12,194 women), one of whom were receiving treatment for hypertension. The mean systolic blood pressure was 116.7 +/- 19.5 mmHg for men and 113.2 +/- 19.4 mmHg for women. RESULTS The mean diastolic blood pressure was 72.4 +/- 12.1 mmHg for men and 70.4 +/- 11.6 mmHg for women. Age and body mass index were the two most important determinants of blood pressure in this population. With controls for age and body mass index, height and weight remained significant predictors of blood pressure. Multiple linear regression analysis indicated that alcohol consumption, self-reported exposure to noise, drinking of tap water and pond water, occupational exposure to dust/fumes/gases, rice consumption, inferior housing, household crowdedness, and being unmarried were related to increased blood pressure levels. Vegetable intake, frequent consumption of meat at meals, high level of physical activity, exposure to straw-combustion smoke, and pesticide use were negatively associated with blood pressure. CONCLUSIONS Our study demonstrated that a broad array of demographic, ergonomic, nutritional, and environmental factors are critical determinants of blood pressure in this rural Chinese population.