Multi-ethnic Study Population Research Articles

Extending the allelic spectrum at noncoding risk loci of orofacial clefting.

Genome-wide association studies (GWAS) have generated unprecedented insights into the genetic etiology of orofacial clefting (OFC). The moderate effect sizes of associated noncoding risk variants and limited access to disease-relevant tissue represent considerable challenges for biological interpretation of genetic findings. As rare variants with stronger effect sizes are likely to also contribute to OFC, an alternative approach to delineate pathogenic mechanisms is to identify private mutations and/or an increased burden of rare variants in associated regions. This report describes a framework for targeted resequencing at selected noncoding risk loci contributing to nonsyndromic cleft lip with/without cleft palate (nsCL/P), the most frequent OFC subtype. Based on GWAS data, we selected three risk loci and identified candidate regulatory regions (CRRs) through the integration of credible SNP information, epigenetic data from relevant cells/tissues, and conservation scores. The CRRs (total 57 kb) were resequenced in a multiethnic study population (1061 patients; 1591 controls), using single-molecule molecular inversion probe technology. Combining evidence from in silico variant annotation, pedigree- and burden analyses, we identified 16 likely deleterious rare variants that represent new candidates for functional studies in nsCL/P. Our framework is scalable and represents a promising approach to the investigation of additional congenital malformations with multifactorial etiology.

4325Change in left atrial function predicts incident atrial fibrillation: the multi-ethnic study of atherosclerosis

Abstract Background Longitudinal change in left atrial (LA) structure and function could be helpful in predicting risk for incident AF. We used cardiac magnetic resonance (CMR) imaging to explore the relationship between change in LA structure and function and incident AF in a multi-ethnic population free of clinical cardiovascular disease at baseline. Methods and results In the Multi-Ethnic Study of Atherosclerosis (MESA), 2338 participants, free at baseline of clinically recognized AF and cardiovascular disease, had LA volume and function assessed with CMR imaging, at baseline (2000–02), and at Exam 4 (2005–07) or 5 (2010–12). Free of AF, 124 participants developed AF over 3.8±0.9 years (to 2015) following the second imaging. In adjusted Cox regression models, an average annualized change in all LA parameters were significantly associated with an increased risk of AF. An annual decrease of 1–SD unit in total LA emptying fractions (LAEF) was most strongly associated with risk of AF after adjusting for AF clinical risk factors, baseline LA parameters and left ventricular mass-to-volume ratio (hazard ratio per SD=1.91,95% confidence interval=1.53–2.38, P<0.001). The addition of change in total LAEF to an AF risk score improved model discrimination and reclassification (net reclassification improvement=0.107, P=0.017; integrative discrimination index=0.049, P<0.001). Model discrimination, NRI and IDI Model: CHARGE-AF risk factors# + Baseline LA variable + ΔLA variable CHARGE-AF ΔLAVImin (mL/m2/y) ΔTotal LAEF (%/y) ΔPeak LA Strain (%/y) C-statistic (95% CI) 0.757 (0.721–0.794) 0.787 (0.749–0.824) 0.779 (0.737–0.820) 0.770 (0.732–0.808) NRI† (p-value) – 0.000 (0.991) 0.107 (0.017) 0.017 (0.634) IDI (p-value) – 0.049 (<0.001) 0.049 (<0.001) 0.018 (<0.001) Calibration chi2* (p-value) 19.3 (0.02) 11.68 (0.232) 5.751 (0.765) 3.673 (0.932) AF: atrial fibrillation; LA: left atrium; EF: emptying fractions; Δ: annual change; VImin: minimum indexed volume; CI: confidence interval; NRI: net reclassification improvement; IDI: integrative discrimination index #CHARGE-AF risk factors: age, race, height, weight, systolic and diastolic blood pressure, use of antihypertensive medication, smoking status, diabetes, MI and CHF by the second imaging. † Categories for NRI: <2.5%, 2.5%-5% and >5%. *Model calibration: Grønnesby and Borgan's modified Hosmer-Lemeshow chi-square statistic for survival analysis. Kaplan-Meier curves of ΔTotal LAEF Conclusion In this multi-ethnic study population free of clinical cardiovascular disease at baseline, a greater increase in LA volumes and decrease in LA function were associated with incident AF. The addition of change in total LAEF to risk prediction models for AF improved model discrimination and reclassification of AF risk. Acknowledgement/Funding This research was supported by contracts HHSN2682015ehz745.01623I,N01-HC-95159-69 from the NHLBI and UL1-TR-ehz745.016240,UL1-TR-001079,R01-HL-127659 from NIH

Change in left atrial function predicts incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis.

AimsLongitudinal change in left atrial (LA) structure and function could be helpful in predicting risk for incident atrial fibrillation (AF). We used cardiac magnetic resonance (CMR) imaging to explore the relationship between change in LA structure and function and incident AF in a multi-ethnic population free of clinical cardiovascular disease at baseline.Methods and resultsIn the Multi-Ethnic Study of Atherosclerosis (MESA), 2338 participants, free at baseline of clinically recognized AF and cardiovascular disease, had LA volume and function assessed with CMR imaging, at baseline (2000–02), and at Exam 4 (2005–07) or 5 (2010–12). Free of AF, 124 participants developed AF over 3.8 ± 0.9 years (2015) following the second imaging. In adjusted Cox regression models, an average annualized change in all LA parameters were significantly associated with an increased risk of AF. An annual decrease of 1-SD unit in total LA emptying fractions (LAEF) was most strongly associated with risk of AF after adjusting for clinical risk factors for AF, baseline LA parameters, and left ventricular mass-to-volume ratio (hazard ratio per SD = 1.91, 95% confidence interval = 1.53–2.38, P < 0.001). The addition of change in total LAEF to an AF risk score improved model discrimination and reclassification (net reclassification improvement = 0.107, P = 0.017; integrative discrimination index = 0.049, P < 0.001).ConclusionIn this multi-ethnic study population free of clinical cardiovascular disease at baseline, a greater increase in LA volumes and decrease in LA function were associated with incident AF. The addition of change in total LAEF to risk prediction models for AF improved model discrimination and reclassification of AF risk.

Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

HYPERPHOSPHATEMIA IN END STAGE RENAL DISEASE: PREVALENCE AND PATIENTS CHARACTERISTICS OF MULTIETHNIC POPULATION OF UNITED ARAB EMIRATES

Objective: Hyperphosphatemia is significantly associated with increased mortality among end stage renal disease (ESRD) patients on hemodialysis. There is paucity of data on hyperphosphatemia in ESRD patients of the multiethnic population of United Arab Emirates (UAE). The study aimed to investigate the prevalence and characteristics of hyperphosphatemia in ESRD patients of the multiethnic population of UAE undergoing maintenance hemodialysis.Methods: Adults ESRD patients undergoing maintenance hemodialysis for more than six months at the study site were included. Demographic, clinical and biological data of the patients were collected. Patient characteristics were compared as per the serum phosphate level, between patients with or without hyperphosphatemia. Univariate and multivariate logistic regression analyses were carried out to identify the predictors of hyperphosphatemia.Results: Hyperphosphatemia was present in 73.8% of the study population, while 31.3% presented with high calcium-phosphate product. Univariate logistic analysis revealed that hyperphosphatemia was inversely correlated with age, hemoglobin, serum calcium, and hypertensive nephropathy as cause of renal disease, and positively correlated with female gender, expatriate status, body mass index (BMI), higher number of comorbidities, calcium-phosphate product and parathyroid hormone (PTH). Multivariate logistic regression model revealed that only age, BMI, hemoglobin and PTH independently correlated with hyperphosphatemia.Conclusion: We report a high prevalence of hyperphosphatemia in multiethnic study population undergoing maintenance hemodialysis at a secondary care hospital in UAE. In this study population, only age, BMI, hemoglobin and PTH were identified as independent predictors of hyperphosphatemia.

This Month in Pediatric Urology

No AccessJournal of UrologyThis Month in Pediatric Urology1 May 2015This Month in Pediatric Urology Laurence S. Baskin Laurence S. BaskinLaurence S. Baskin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.008AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "This Month in Pediatric Urology." The Journal of Urology, 193(5), pp. 1457–1458 References 1 : Phenotype specific association of the TGFBR3 locus with nonsyndromic cryptorchidism. J Urol2015; 193. 1637. Google Scholar 2 : Congenital penile pathology is associated with abnormal development of the dartos muscle: a prospective study of primary penile surgery at a tertiary referral center. J Urol2015; 193. 1620. Google Scholar 3 : Genetic polymorphisms in ESR1 and ESR2 genes, and risk of hypospadias in a multiethnic study population. J Urol2015; 193. 1625. Google Scholar 4 : Serum inhibin B values in boys with unilateral vanished testis or unilateral cryptorchidism. J Urol2015; 193. 1632. Google Scholar © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 5May 2015Page: 1457-1458 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Laurence S. Baskin More articles by this author Expand All Advertisement PDF downloadLoading ...

Genetic Polymorphisms in ESR1 and ESR2 Genes, and Risk of Hypospadias in a Multiethnic Study Population

Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births. We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe). Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2. The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.

019 Ethnic differences in type 2 diabetes risk markers in children in the UK are not explained by socio-economic status: Child Heart and Health Study in England

ObjectivesTo examine the influence of socio-economic position on type 2 diabetes risk markers in different ethnic groups and determine whether differences in socio-economic position can explain ethnic differences in type...

Socioeconomic and race/ethnic differences in daily salivary cortisol profiles: The Multi-Ethnic Study of Atherosclerosis

It has often been hypothesized that stress and its biological consequences mediate the relationship between low socioeconomic status (SES) or minority status and poor cardiovascular disease outcomes. The objective of this study was to determine if daily cortisol patterns, a biomarker of the stress response, differ by race/ethnicity and socioeconomic status. Data were collected from 935 Black, White and Hispanic adults age 48-90 years old. Salivary cortisol samples were collected six times per day over 3 days: at awakening, 30min later, at 1000h, noon, 1800h and at bedtime. Blacks and Hispanics had lower levels of wake-up cortisol and less steep early declines, while Blacks had flatter and Hispanics steeper late day declines relative to Whites. Similarly the low socioeconomic status group also had lower levels of wake-up cortisol and less steep decline during the early part of the day. These patterns remained after adjustment for health behaviors and psychosocial factors. This study finds an association between salivary cortisol and race/ethnicity and SES in a multi-ethnic study population. Further work is needed to determine the health consequences of these differences.

External apical root resorption and the interleukin-1B gene polymorphism in the Japanese population

External apical root resorption (EARR) is a common consequence of orthodontic treatment. Recently, several studies have reported an association between EARR and an underlying genetic cause. This study investigated whether a single interleukin (IL)-1B gene polymorphism (rs1143634) was associated with EARR in the Japanese population. Genomic DNA, lateral cephalograms, and panoramic radiographs were obtained from 54 Japanese. We measured the EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar, and analyzed statistically the association between IL-1B polymorphism and EARR. We also examined differences in allelic frequency of this IL-1B polymorphism in a multi-ethnic study population consisting of Japanese, Han Chinese, African American, European Caucasian, and Hispanic individuals. We found no significant difference in the frequency of the IL-1B polymorphism between EARR cases and controls in the Japanese population. We also report marked diversities in the allelic frequencies of the IL-1B polymorphism within the multi-ethnic study population. The European Caucasian population carried the T allele at a frequency of 29.2%, whereas the Japanese population carried the T allele at a frequency of 5.6%. The low frequency of the T allele in Japanese population made it difficult to compare population allelic frequencies among different populations. Further studies are required to confirm our findings and to investigate the effect of other single nucleotide polymorphisms in IL-1B or other genetic risk factors underlying susceptibility to EARR.

Predictors of Postmenopausal Body Mass Index and Waist Hip Ratio in the Oklahoma Postmenopausal Health Disparities Study

Objective: The goal of the current study has been to examine systematically the respective roles of nutrition, exercise, menopausal weight gain, moderate drinking and smoking as determinants of body mass index (BMI) and waist hip ratio (WHR) in a setting in which the role of race or ethnic group could be simultaneously or individually evaluated as predictors of BMI and WHR. Because the use of estrogen replacement has been reported to affect estimates of body fat mass in postmenopausal women, endocrine factors have also been evaluated.Methods: The design is cross-sectional with historical prospective elements. The study has a biomedical focus and is not an epidemiologic study. Data are from 649 women recruited into The Postmenopausal Health Disparities Study in Oklahoma. The study population was composed of 649 postmenopausal women: American Indian: 226 (34.9%), Asian: 21 (3.2%), Black: 78 (12.0%), Hispanics: 54 (8.3%) and Whites: 270 (41.6%). Recruitment occurred between 1994 and late 1999 in Oklahoma.Results: In this multi-racial, multi-ethnic study population, there was statistical heterogeneity in all nutrition/dietary and exercise variables as well as in other potential determinants of BMI and WHR. In contrast to the literature available for postmenopausal women in which postmenopausal status, estrogen replacement and race have rarely been taken into account, the results of multi-linear regression revealed the following: Significant predictors for BMI, with or without WHR specified, included the neuroendocrine factors, menopausal weight gain, smoking, mean fitness (i.e., difficulty performing physical activities), fat as percent of total calories, moderate drinking and being Asian or Black. When WHR was not included, total calories and socioeconomic status also entered the model. The statistical predictors of WHR in the total study population with BMI in the equation included BMI and the neuroendocrine variables of FSH, E2, but not ERT, as well as the interaction of higher intensity exercise fitness with frequency, socioeconomic status and being American Indian or Asian. When BMI was not included in the model, in addition to the neuroendocrine factors, the interaction of lower intensity exercise fitness with frequency, fat as percent of total calories, age living alone and being American Indian or and Black were significant predictors of WHR. The predictors of both BMI and WHR were found to differ among individual racial and ethnic groups.Conclusions: Given the role of increased body fat and obesity in disease risk and the substantial differences in life expectancy among the racial and ethnic groups, the findings of this study, particularly in contrast to literature reports, strongly suggest that a whole variety of factors including hormonal status and race need to be considered when examining the role of dietary factors and physical activity in relation to estimates of body fat mass and disease risk.

Social Readjustment and Ischemic Stroke: Lack of an Association in a Multiethnic Population

Clinical experience has suggested that stressful life events and ongoing stressful illness, collectively termed ‘social readjustment’, may precipitate stroke. We investigated the association between a simple in-office evaluation of such stressors and stroke in an urban, multiethnic study population. Cases were patients from the Northern Manhattan Stroke Study with first ischemic stroke; controls were derived through random digit dialing with n:m matching for age, gender, and race-ethnicity. Social readjustment was measured through in-person interview using Amster and Krauss’ Geriatric Social Readjustment Rating Scale (GSRRS), a one-time, 35-item, checklist type weighted questionnaire of stressful life events occurring in the previous 6 months. Conditional logistic regression was used to analyze the GSRRS and its quartiles as well as stressful events subgroups, adjusting for education, hypertension, cardiac disease, diabetes, and number of weekly visits as a measure of socialization. Six hundred and fifty-five cases of ischemic stroke and 1,087 controls were utilized. The mean age of the cases was 69.8 years, with 55.4% women, 51.0% Hispanics, 28.4% blacks, and 19.1% whites. GSRRS scores ranged from 0 to 812; the mean score was 205.5 for the cases and 206.2 for the controls. The analysis showed no association between stroke and a 20-point increase on the GSRRS (OR = 1.01, 95% CI = 0.99–1.01). There was also no effect for the second, third or highest versus lowest quartile. No association was found in age, gender or race-ethnic subgroups, or when analyzing negative events, severely threatening events, or ongoing stressful illnesses separately. While this study does not preclude social readjustment as a stroke risk factor, it suggests that the one-time assessment often done in the medical office setting has little relevance for stroke prevention planning.