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BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.METHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.RESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10−9 and 2.97 × 10−8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10−6 ≤ p ≤ 3.06 ×10−6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.CONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

Introduction: Studies in non-Hispanic whites suggest that early adaptive changes in cardiac structure due to hypertension may influence the development of heart failure (HF). The predictive value of left ventricular (LV) structure to incident acute decompensated HF (ADHF) has not been well-studied in African Americans (AA) despite the higher incidence of HF in this group. Hypothesis: We hypothesized that incidence of ADHF in AA varies according to cardiac structures and LV geometry type. Methods: The study sample included 1,737 participants who attended the third examination cycle of the Jackson cohort of ARIC between 1993 and1995 and underwent echocardiography, anthropometry and phlebotomy for glucose and lipids. Left atrial size, aortic root diameter (AOD), LV wall thicknesses and chamber dimensions, LV mass, LV mass index, LV hypertrophy (LVH) and LV geometric patterns [normal geometry, concentric hypertrophy, eccentric hypertrophy (EH), concentric remodeling] were determined by echocardiography. Cutoff for LVH was defined as above the 80th percentile of LV mass index. HF data was available up to December 31, 2011. In the primary analyses we adjusted for age, sex, smoking, diabetes, body mass index, systolic blood pressure, and use of hypertension medications in the multivariable model. Results: Over a follow-up period of approximately 18 years, 188 participants developed ADHF. Incident ADHF was significantly related to AOD [HR 1.42 (1.03, 1.97)], LV internal diameter in diastole (cm) [HR 1.60 (1.24, 2.05)], LV mass [HR 1.003 (1.002, 1.005)], LVM index [HR 1.01 (1.004, 1.02) and LVH [HR 1.62 (1.16, 2.27)]. In terms of LV geometry, EH was significantly related to incident ADHF in the multivariable model [HR 2.94 (1.70-5.10)]. Conclusion: In our large community-based sample of AAs, we observed that AOD, LV internal diameter in diastole, LV mass, LV mass index, LVH and EH geometry were significantly related to long-term incidence of ADHF independent of standard risk factors. These findings suggest echocardiography may be helpful in risk stratifying members of this high risk population for ADHF.

Background: The presence of chronic kidney disease is greater in African Americans than in non-Hispanic whites. Though there is data to show a relation between endothelial dysfunction and end-stage kidney disease, the relation to mild and moderate chronic kidney disease (particularly in African Americans) is unclear. Methods and Results: Digital arterial tonometry was performed during Exam 2 and 3 of the Jackson Heart Study using the endoPAT2000. Data from digital arterial tonometry included baseline pulse wave amplitude (BPA) as a measure of endothelial tone and reactive hyperemic index (F-RHI) as a measure of endothelial function. For this study, the estimated glomerular filtration rate (eGFR) was calculated using the MDRD equation. Those participants with eGFR < 60 ml/min/1.73m2 were defined as having CKD. Participants with eGFR < 15 ml/min/1.73m2 were excluded from the analysis. Microalbuminuria in this study was defined as a urinary albumin:creatinine ratio ≥ 17mg/g in men and ≥ 25 mg/g in women. We compared the differences in least square means adjusted for age and sex, and adjusted for multiple traditional clinical covariates using a generalized linear model. Results: There were 834 participants in the study population (mean age 58.5 years, 61% women); 87 (10.4%) participants with CKD and 108 (13.0%) with microalbuminuria. In age and sex adjusted samples, we found that both BPA and F-RHI were significantly associated with CKD in the pooled samples. However in multivariable adjusted analysis the relation was no longer significant in either the pooled or sex-specific samples. In the multivariable adusted analysis,BPA was significantly (P=0.036) associated with microalbuminuria in men and F-RHI was weakly significantly (P=0.08) associated with microalbuminuria in women. Conclusion: We found that endothelial dysfunction as measured by digital arterial tonometry is not significantly associated with chronic kidney disease. There is an association of endothelial tone in men and endothelial dysfunction in women with microalbuminuria.

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived “null” variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P, Author Summary Although recent genome-wide association studies have identified common genetic variants associated with total white blood cell (WBC) and WBC sub-type counts in European and Japanese ancestry populations, whether these or other loci account for differences in WBC count among African Americans is unknown. By examining >16,000 African Americans, we show that, in addition to the previously identified Duffy Antigen Receptor for Chemokines (DARC) locus on chromosome 1, another variant, rs9131, and other nearby variants on human chromosome 4 are associated with total WBC count in African Americans. The variants span the CXCL2 gene, which encodes an inflammatory mediator involved in WBC production and migration. We show that the association is not restricted to African Americans but is also present in independent samples of European Americans, Hispanic Americans, and Japanese. This finding is potentially important because WBC mediate or have altered counts in a variety of acute and chronic disorders.

Studies were conducted to examine the population genetic structure of Anopheles arabiensis (Patton) in Mwea Rice Irrigation Scheme and surrounding areas in Central Kenya, under different agricultural systems. This study was motivated by observed differences in malaria transmission indices of An. arabiensis within the scheme compared with adjacent nonirrigated areas. Agricultural practices can modify local microclimate and influence the number and diversity of larval habitats and in so doing may occasion subpopulation differentiation. Thirty samples from each of the three study sites were genotyped at eight microsatellite loci. Seven microsatellite loci showed high polymorphism but revealed no genetic differentiation (FST = 0.006, P = 0.312) and high gene flow (Nm = 29–101) among the three populations. Genetic bottleneck analysis showed no indication of excess heterozygosity in any of the populations. There was high frequency of rare alleles, suggesting that An. arabiensis in the study area has a high potential of responding to selective pressures from environmental changes and vector control efforts. These findings imply that An. arabiensis in the study area occurs as a single, continuous panmictic population with great ability to adapt to human-imposed selective pressures.