Genome-wide association study of asthma, total IgE, and lung function in a cohort of Peruvian children.

BACKGROUND: Genetic ancestry plays a role in asthma health disparities. OBJECTIVE: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. METHODS: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. RESULTS: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV1 percent predicted values (P < .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10-10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P = 1.55 × 10-05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005). CONCLUSION: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.

Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population.

AIMS: In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. METHODS: Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. RESULTS: We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p=0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. CONCLUSIONS: Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes.

Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.

BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial. METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10-4>P>1.1×10-16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (ß=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10-3; Pinteraction=1×10-3 for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits. CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.

Single nucleotide polymorphism in toll-like receptor 6 is associated with a decreased risk for ureaplasma respiratory tract colonization and bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Ureaplasma spp. respiratory tract colonization is a risk factor for bronchopulmonary dysplasia (BPD) in preterm infants, but differences in host susceptibility have not been elucidated. We hypothesized that variants in genes regulating the innate immune response are associated with altered risk for Ureaplasma spp. respiratory colonization and BPD in preterm infants. METHODS: Twenty-four tag single nucleotide polymorphisms (SNPs) from Toll-like receptor (TLR)1, TLR2, TLR4 and TLR6 were assayed in 298 infants <33 weeks gestation who had serial respiratory cultures for Ureaplasma spp. and were evaluated for BPD. RESULTS: The majority of subjects (N = 205 [70%]) were African-American. One hundred ten (37%) were Ureaplasma positive. Four SNPs in TLR2 and TLR6 were significantly associated with Ureaplasma respiratory tract colonization. Single SNPs in TLR2, TLR4 and TLR6 were associated with BPD. TLR6 SNP rs5743827 was associated with both a decreased risk for Ureaplasma respiratory tract colonization and decreased risk for BPD (odds ratio: 0.54 [0.34-0.86] and odds ratio: 0.54 [0.31-0.95], respectively). There was a significant additive interaction between Ureaplasma colonization and genotype at TLR6 SNP rs5743827 (Padditive = 0.023), with an attributable proportion due to interaction of 0.542. CONCLUSIONS: Polymorphisms in host defense genes may alter susceptibility to Ureaplasma infection and severity of the inflammatory response contributing to BPD. These observations implicate host genetic susceptibility as a major factor in BPD pathogenesis in Ureaplasma-infected preterms.