Zhian Fang

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

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.

Serum DDT, age at menarche, and abnormal menstrual cycle length

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.

A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

Background: Although dichlorodiphenyl trichloroethane (DDT) exposure is known to affect human endocrine function, few previous studies have investigated the effects of DDT exposure on age at menarche or menstrual cycle length. Methods: A cross sectional study was conducted to study the effects of DDT exposure on age at menarche and menstrual cycle length among 466 newly married, nulliparous female Chinese textile workers aged 20–34 years enrolled between 1996 and 1998. Serum was analysed for DDT and its major metabolites. Multivariate linear regression was used to estimate DDT exposure effects on age at menarche and multivariate logistic regression was used to estimate DDT exposure effects on odds of experiencing short or long cycles. Results: Relative to those in the lowest DDT quartile, the adjusted mean age at menarche was younger in those in the fourth quartile (−1.11 years). Modeled as a continuous variable, a 10 ng/g increase in serum DDT concentration was associated with an adjusted reduction in age at menarche of 0.20 years. Relative to those in the lowest DDT quartile, odds of any short cycle (<21 days) in the previous year were higher for those in the fourth quartile (odds ratio = 2.78; 95% CI 1.07 to 7.14). There were no associations between serum DDT concentrations and odds of experiencing a long cycle (>40 days). Conclusion: Results suggest that DDT exposure was associated with earlier age at menarche and increased risk of experiencing a shortened menstrual cycle.

Stress and dysmenorrhoea: a population based prospective study.

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.

Linkage analysis of candidate genes and gene-gene interactions in chinese hypertensive sib pairs.

Background: Dysmenorrhoea is the most common gynaecological disorder in women of reproductive age. Despite the association between stress and pregnancy outcomes, few studies have examined the possible link between stress and dysmenorrhoea. Aims and Methods: Using a population based cohort of Chinese women, the independent effect of women’s perceived stress in the preceding menstrual cycle on the incidence of dysmenorrhoea in the subsequent cycle was investigated prospectively. The analysis included 1160 prospectively observed menstrual cycles from 388 healthy, nulliparous, newly married women who intended to conceive. The perception of stress and the occurrence of dysmenorrhoea in each menstrual cycle were determined from daily diaries recorded by the women. Results: After adjustment for important covariates, the risk of dysmenorrhoea was more than twice as great among women with high stress compared to those with low stress in the preceding cycle (OR = 2.4; 95% CI 1.4 to 4.3). The risk of dysmenorrhoea was greatest among women with both high stress and a history of dysmenorrhoea compared to women with low stress and no history of dysmenorrhoea (OR = 10.4, 95% CI 4.9 to 22.3). Stress in the follicular phase of the preceding cycles had a stronger association with dysmenorrhoea than stress in the luteal phase of the preceding cycles. Conclusion: This study shows a significant association between stress and the incidence of dysmenorrhoea, which is even stronger among women with a history of dysmenorrhoea.

Angiotensinogen Gene Polymorphisms M235T/T174M: No Excess Transmission to Hypertensive Chinese

Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the beta- and gamma-subunits of the epithelial sodium channel (beta/gamma-ENaC), alpha-adducin, and kallikrein (KLK). To examine the role of possible contribution of these genes in ethnic Chinese, as well as the epistatic interaction among them, we studied a large cohort of hypertensive sib pairs from China. DNA samples from 310 concordant affected sibling pairs with hypertension were tested for linkage with the use of excess allele-sharing algorithms based on genotyping with highly informative GT-repeat microsatellite markers localized in the immediate vicinity of the genes encoding angiotensinogen, renin, beta- and gamma-ENaC, alpha-adducin, and KLK. Affected sib pair analysis conducted according to 3 different methods (Statistical Analysis for Genetic Epidemiology [S.A.G.E. ]/SIBPAL, MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed no evidence for linkage of any of these genes to primary hypertension in the population studied. Moreover, 2-locus sib pair linkage analyses to test for gene-gene interactions among each possible pair of candidate genes failed to yield any statistically significant results. Our findings provide no support for a significant contribution of the angiotensinogen, renin, beta/gamma-ENaC, alpha-adducin, or KLK genes, alone or in concert, to the pathogenesis of essential hypertension among Chinese. Our results emphasize the possible role of ethnic differences for complex disease genetics, as well as the need for large, well-characterized investigations.

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

The gene encoding angiotensinogen (AGT) has been widely studied as a candidate gene for hypertension. Most studies to date have relied on case-control analysis to test for an excess of AGT variants among hypertensive cases compared with normotensive controls. However, with this design, nothing guarantees that a positive finding is due to actual allelic association as opposed to an inappropriate control population. To avoid this difficulty in our study of essential hypertension in Anqing, China, we tested AGT variants using the transmission/disequilibrium test, a procedure that bypasses the need for a control sample by testing for excessive transmission of a genetic variant from parents heterozygous for that variant. We analyzed two AGT polymorphisms, M235T and T174M, which have been associated with essential hypertension in whites and Japanese, using data on 335 hypertensive subjects from 315 nuclear families and their parents. Except in the group of subjects younger than 25 years, M235 and T174 were the more frequently transmitted alleles. We found that 194 parents heterozygous for M235T transmitted M235 106 times (P=0.22) and that 102 parents heterozygous for T174M transmitted T174 60 times (P=0.09). Stratifying offspring by gender, M235 and T174 were transmitted 60 of 106 times (P=0.21) and 44 of 75 times (P=0.17), respectively, in men, and 46 of 88 times (P=0.75) and 16 of 27 times (P=0.44), respectively, in women. Our results were also negative in all age groups and for the affected offspring with blood pressure values >/=160/95 mm Hg. Thus, this study provides no evidence that either allele of M235T or T174M contributes to hypertension in this Chinese population.

Blood Pressure and the T174M and M235T Polymorphisms of the Angiotensinogen Gene

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.

Indoor air pollution and respiratory health in urban and rural China.

PURPOSE The angiotensinogen gene (AGT), which encodes the precursor of the vasoactive hormone angiotensin II, has been reported to be associated with hypertension in Caucasian and Japanese populations. We examined the relationship between two common molecular variants of AGT, T174M and M235T and blood pressure in two cohorts from the Anqing region of China. Cohort I (N = 794) consisted of families ascertained by either hypertensive or hypotensive siblings; and Cohort II (N = 761) represented a collection of randomly selected families. METHODS Blood pressure was measured according to standard protocols, and information on age, sex, body mass index, alcohol consumption, and cigarette smoking was collected by trained interviewers using standardized questionnaires. The association of AGT genotypes and blood pressure was examined in multivariate linear regression models, with adjustment for potential intrafamilial correlations. The respective T and M allele frequencies for T174M were 0.93 and 0.07, and 0.80 and 0.20 for M235T among the parents for randomly selected families. All the analyses were conducted after exclusion of individuals currently under antihypertensive medication. RESULTS In the pooled analysis of the two cohorts, neither the T174M nor the M235T polymorphism was significantly associated with variations of blood pressure assuming a recessive (T174M: p = 0.73 and 0.61; M235T: p = 0.99 and 0.24; for SBP and DBP), dominant (T174M: p = 0.54 and 0.72; M235T: p = 0.79 and 0.12; for SBP and DBP), or additive (T174M: p = 0.52 and 0.67, M235T: p = 0.91 and 0.11; for SBP and DBP) model. Likewise, no statistically significant association was detected when the two cohorts were analyzed separately. The logistic regression analysis of hypertension also failed to reveal any association with these markers. CONCLUSIONS In summary, our analyses suggest that the molecular variants of AGT may not be associated with variations of blood pressure in this rural Chinese population.