Biology subjects

Meade, K.

Publications and source records attributed to Meade, K..

4 recordsLinked to original sources

bioRxiv2024

The role of β-defensin 103 (DEFB103) copy number variation in bull fertility

Pregnancy rates for elite bulls used in artificial insemination (AI) can vary significantly and therefore the identification of molecular markers for fertility and targets to improve bull selection is important. {beta}-defensins are peptides which have diverse regulatory roles in sperm function across multiple species. In this study, Holstein-Friesian bulls were screened based on field fertility data to identify two groups (High and Low fertility (HF and LF, respectively)) of n=10 bulls per group which were genotyped for copy number variation (CNV) in the DEFB103 gene. Overall, low DEFB103 copy number (CN) was associated with increased sperm motility across all bulls (n=20, p<0.05). As genetic diversity of DEFB103 CN was only apparent in the LF group, three bulls per CNV class (low, intermediate and high CN) were chosen for functional analysis. Sperm from LF bulls with low CN exhibited higher binding to the oviduct epithelium in vitro, while high CN affected sperm membrane fluidity in non-capacitating conditions in vitro (p<0.05). To investigate the functional effect of DEFB103 CNV on the uterine response in vivo, 18 heifers were inseminated with sperm from bulls with low, intermediate and high CN. Transcriptomic analysis on uterine tissue harvested 12 h post-insemination showed significant differential expression of 58 genes (FDR<0.1) involved in sperm migration, immune signalling and chemotaxis. These novel results confirm an important role for DEFB103 CN in both sperm function and the uterine response to bull sperm, thereby potentially influencing pregnancy outcomes in cattle. Summary SentenceDEFB103 copy number (CN) is associated with sperm motility and binding to the oviduct epithelium and uterine gene expression, thereby potentially influencing fertility outcomes.

genomics↗

bioRxiv2018

Genetic Determinants of Telomere Length in African American Youth

Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

genetics↗

bioRxiv2017

A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

BackgroundShort-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S 1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3\n\nObjectiveTo identify genetic variants that may contribute to differences in BDR in African Americans with asthma.\n\nMethodsWe performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.\n\nResultsWe identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69 x 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p[≤]5 x 10-8).\n\nConclusionsOur findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.\n\nKey messagesO_LIA GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).\nC_LIO_LIA meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron of PRKG1 to be associated with differences in BDR.\nC_LIO_LIFurther genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.\nC_LI

genomics↗

bioRxiv2017

Whole Genome Sequencing of Pharmacogenetic Drug Response in Racially and Ethnically Diverse Children with Asthma

Asthma is the most common chronic disease of children, with significant racial/ethnic differences in prevalence, morbidity, mortality and therapeutic response. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. We performed the largest whole genome sequencing (WGS) pharmacogenetics study to date using data from 1,441 minority children with asthma who had extremely high or low bronchodilator drug response (BDR). We identified population-specific and shared pharmacogenetic variants associated with BDR, including genome-wide significant (p < 3.53 x 10-7) and suggestive (p < 7.06 x 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and {beta}-adrenergic signaling pathways (ADAMTS3 and COX18). Functional analyses centered on NFKB1 revealed potential regulatory function of our BDR-associated SNPs in bronchial smooth muscle cells. Specifically, these variants are in linkage disequilibrium with SNPs in a functionally active enhancer, and are also expression quantitative trait loci (eQTL) for a neighboring gene, SLC39A8. Given the lack of other asthma study populations with WGS data on minority children, replication of our rare variant associations is infeasible. We attempted to replicate our common variant findings in five independent studies with GWAS data. The age-specific associations previously found in asthma and asthma-related traits suggest that the over-representation of adults in our replication populations may have contributed to our lack of statistical replication, despite the functional relevance of the NFKB1 variants demonstrated by our functional assays. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.\n\nAUTHOR SUMMARYAsthma is the most common chronic disease among children. Albuterol, a bronchodilator medication, is the first-line therapy for asthma treatment worldwide. In the U.S., asthma prevalence is the highest among Puerto Ricans, intermediate among African Americans and lowest in Whites and Mexicans. Asthma disparities extend to mortality, which is four- to five-fold higher in Puerto Ricans and African Americans compared to Mexicans [1]. Puerto Ricans and African Americans, the populations with the highest asthma prevalence and death rate, also have the lowest albuterol bronchodilator drug response (BDR). We conducted the largest pharmacogenetic study using whole genome sequencing data from 1,441 minority children with asthma who had extremely high or low albuterol bronchodilator drug response. We identified population-specific and shared pharmacogenetic variants associated with BDR. Our findings help inform the direction of future development of asthma medications and our study advances the foundation of precision medicine for at-risk, yet understudied, racially/ethnically diverse populations.

genetics↗