Analyses of genetic polymorphism data have the potential to be highly informative about the demographic history of Native American populations, but due to a combination of historical and political factors, there are essentially no autosomal sequence polymorphism data from any Native American group. However, there are many resequencing studies involving Latinos, whose genomes contain segments inherited from their Native American ancestors. In this study, we introduce a new method for estimating local ancestry across the genomes of admixed individuals and show how this method, along with dense genotyping and targeted resequencing, can be used to assay genetic variation in ancestral Native American groups. We analyze roughly 6 Mb of resequencing data from 22 Mexican Americans to provide the first large-scale view of sequence level variation in Native Americans. We observe low levels of diversity and high levels of linkage disequilibrium in the Native American-derived sequences, consistent with a recent severe population bottleneck associated with the initial peopling of the Americas. Using two different computational approaches, one novel, we estimate that this bottleneck occurred roughly 12.5 Kya; when uncertainty in the estimation process is taken into account, our results are consistent with archeological estimates for the colonization of the Americas.

Background

Alcohol, insulin resistance (IR), and hepatitis C (HCV) are all significant contributors to adverse outcomes of chronic liver disease. Latinos are disproportionately affected by these risk factors. We investigated the relationship between alcohol use and insulin action in a prospective cohort of Latino individuals with and without HCV.

Methods

One hundred fifty-three nondiabetic Latino individuals (60 HCV+, 93 HCV-) underwent clinical evaluation and metabolic testing; 56 had repeat testing over a median follow-up of 1.5 years. Peripheral IR and hepatic IR were measured via steady-state plasma glucose (SSPG) and endogenous glucose production during a two-step, 240-min insulin suppression test. Insulin secretion (IS) was measured using the graded glucose infusion test. Alcohol use was categorized as none, moderate (≤1 drink/day for women and ≤2 drinks/day for men), and heavy (>moderate). Multivariable models including HCV status assessed associations of alcohol use with baseline SSPG, hepatic IR and IS, and changes in these parameters over time.

Results

Overall, the median age was 44 years, 63.4% were male, 66.7% overweight/ obese, and 31.9% had heavy lifetime alcohol use while 60.4% had moderate lifetime alcohol use. SSPG and IS were similar by levels of alcohol use at baseline and alcohol use was not statistically significantly associated with change in these measures over time. However, lifetime daily heavy alcohol use (vs. not heavy, coef 2.4 μU-mg/kg-min-ml, p = 0.04) and HCV status (coef 4.4 μU-mg/kg-min-ml, p = 0.0003) were independently associated with higher baseline hepatic IR, and current heavy alcohol use was associated with greater change in hepatic IR in follow-up (coef 5.8 μU-mg/kg-min-ml, p = 0.03).

Conclusions

In this cohort of Latino individuals, lifetime and current heavy alcohol use influenced hepatic IR and its change over time. Strategies to decrease rates of heavy alcohol use or increase abstinence along with lifestyle modification and anti-HCV therapy to reduce metabolic risk are critical to prevent adverse liver and metabolic outcomes in Latino individuals.

Background

Variation in genetic ancestry among genetically admixed racial and ethnic groups may influence the fit of guideline-recommended spirometry reference equations, which rely on self-identified race and ethnicity.

Research question

What is the influence of genetic ancestry on the fit of race- and ethnicity-based spirometry reference equations in populations of genetically admixed children?

Study design and methods

Cross-sectional fit of guideline-recommended race- and ethnicity-based spirometry reference equations was evaluated in healthy control participants from case-control studies of asthma. Anthropometry, blood samples, and spirometric measurements were obtained for 599 genetically admixed children 8 to 21 years of age. Genetic ancestry was estimated using genome-wide genotype data. Equation fit, measured as a mean z score, was assessed in self-identified African American (n = 275) and Puerto Rican (n = 324) children as well as genetic ancestry-defined strata of each population.

Results

For African American children, African American-derived equations fit for predicting FEV₁ and FVC in those with an African ancestry more than the median (81.4%-100.0%), whereas composite equations for "other/mixed" populations fit for predicting FEV₁ and FVC in those with African ancestry at or less than the median (30.7%-81.3%). For Puerto Rican children with African ancestry at or less than the median (6.4%-21.3%), White-derived equations fit both FEV₁ and FVC, whereas for those with African ancestry more than the median (21.4%-87.5%), White-derived equations fit the FEV₁ and the composite equations fit the FVC.

Interpretation

Guideline-recommended spirometry reference equations yielded biased estimates of lung function in genetically admixed children with high variation of African ancestry. Spirometry could benefit from reference equations that incorporate genetic ancestry, either for more precise application of the current equations or the derivation and use of new equations.

Identifying segments in the genome of different individuals that are identical-by-descent (IBD) is a fundamental element of genetics. IBD data is used for numerous applications including demographic inference, heritability estimation, and mapping disease loci. Simultaneous detection of IBD over multiple haplotypes has proven to be computationally difficult. To overcome this, many state of the art methods estimate the probability of IBD between each pair of haplotypes separately. While computationally efficient, these methods fail to leverage the clique structure of IBD resulting in less powerful IBD identification, especially for small IBD segments.

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.

In epigenome-wide association studies (EWAS), different methylation profiles of distinct cell types may lead to false discoveries. We introduce ReFACTor, a method based on principal component analysis (PCA) and designed for the correction of cell type heterogeneity in EWAS. ReFACTor does not require knowledge of cell counts, and it provides improved estimates of cell type composition, resulting in improved power and control for false positives in EWAS. Corresponding software is available at http://www.cs.tau.ac.il/~heran/cozygene/software/refactor.html.

Background

Maternal smoking during pregnancy is a risk factor for chronic disease later in life and has been associated with variability of DNA methylation at specific cytosine-phosphate-guanine (CpG) loci. We assessed the role of DNA methylation as a potential mediator of adverse effects of in utero tobacco smoke exposures on asthma outcomes in Latino children from the US mainland and Puerto Rico.

Methods

Relationships between self-reported exposure and DNA methylation at CpG loci previously reported to be associated with maternal smoking were assessed in a subsample consisting of 572 children aged 8-21 years (310 cases with asthma, 262 healthy controls), sampled from a larger asthma case-control study. Subsequently, we assessed associations between top loci and asthma-related outcomes, followed by mediation analysis for loci for which associations with outcomes were observed.

Results

Self-reported maternal smoking was associated with a -1.5% (95% confidence interval (CI) = -2.4%, -0.6%) lower methylation at CpG locus cg05575921 on the AHRR gene; a 1% increase in DNA methylation at the same locus resulted in an odds ratio (OR) of 0.90 (95% CI = 0.83, 0.96) for the odds of asthma. The OR for the indirect effect of maternal smoking on asthma mediated through methylation at the cg05575921 locus was 1.18 (95% CI = 1.07, 1.68), compared to the OR for the total effect of exposure in the parent study of 1.48 (95% CI = 1.03, 2.11).

Conclusions

Our findings suggest potential mediation by DNA methylation in the association between maternal smoking during pregnancy and asthma status.

Importance

Asthma is a multifactorial disease composed of endotypes with varying risk profiles and outcomes. African Americans experience a high burden of asthma and of psychosocial stress, including racial discrimination. It is unknown which endotypes of asthma are vulnerable to racial/ethnic discrimination.

Objective

We examined the association between self-reported racial/ethnic discrimination and bronchodilator response (BDR) among African American youth with asthma ages 8 to 21 years (n = 576) and whether this association varies with tumor necrosis factor alpha (TNF-α) level.

Materials and methods

Self-reported racial/ethnic discrimination was assessed by a modified Experiences of Discrimination questionnaire as none or any. Using spirometry, BDR was specified as the mean percentage change in forced expiratory volume in one second before and after albuterol administration. TNF-α was specified as high/low levels based on our study population mean. Linear regression was used to examine the association between self-reported racial/ethnic discrimination and BDR adjusted for selected characteristics. An interaction term between TNF-α levels and self-reported racial/ethnic discrimination was tested in the final model.

Results

Almost half of participants (48.8%) reported racial/ethnic discrimination. The mean percent BDR was higher among participants reporting racial/ethnic discrimination than among those who did not (10.8 versus 8.9, p = 0.006). After adjustment, participants reporting racial/ethnic discrimination had a 1.7 (95% CI: 0.36-3.03) higher BDR mean than those not reporting racial/ethnic discrimination. However, we found heterogeneity of this association according to TNF-α levels (p-interaction = 0.040): Among individuals with TNF-α high level only, we observed a 2.78 higher BDR mean among those reporting racial/ethnic discrimination compared with those not reporting racial/ethnic discrimination (95%CI: 0.79-4.77).

Conclusions

We found BDR to be increased in participants reporting racial/ethnic discrimination and this association was limited to African American youth with TNF-α high asthma, an endotype thought to be resistant to traditional asthma medications. These results support screening for racial/ethnic discrimination in those with asthma as it may reclassify disease pathogenesis.

Several studies have shown that the airways of asthma patients contain higher diversity of bacteria and are enriched in pathogenic species. However, sampling the airways in children is challenging. Here we aimed to identify differences in the salivary bacterial composition between African Americans children with and without asthma. Saliva samples from 57 asthma cases and 57 healthy controls were analyzed by means of 16S ribosomal RNA amplicon profiling. Measurements of bacterial diversity and genus relative abundance were compared between cases and controls using the nonparametric Wilcoxon test and multivariate regression models. A total of five phyla and a mean of 56 genera were identified. Among them, 15 genera had a relative abundance greater than 1%, being Prevotella, Haemophilus, Streptococcus, and Veillonella the most abundant genera. Differences between cases and controls were found in terms of diversity, as well as in relative abundance for Streptococcus genus (13.0% in cases vs 18.3% in controls; P = .003) and Veillonella genus (11.1% in cases vs 8.0% in controls; P = .002). These differences remained significant after correction for multiple comparisons and when potential confounders were taken into account in logistic regression models. In conclusion, we identified changes in the salivary microbiota associated with asthma among African Americans.

Importance

Asthma is a multifactorial disease composed of endotypes with varying risk profiles and outcomes. African Americans experience a high burden of asthma and of psychosocial stress, including racial discrimination. It is unknown which endotypes of asthma are vulnerable to racial/ethnic discrimination.

Objective

We examined the association between self-reported racial/ethnic discrimination and bronchodilator response (BDR) among African American youth with asthma ages 8 to 21 years (n = 576) and whether this association varies with tumor necrosis factor alpha (TNF-α) level.

Materials and methods

Self-reported racial/ethnic discrimination was assessed by a modified Experiences of Discrimination questionnaire as none or any. Using spirometry, BDR was specified as the mean percentage change in forced expiratory volume in one second before and after albuterol administration. TNF-α was specified as high/low levels based on our study population mean. Linear regression was used to examine the association between self-reported racial/ethnic discrimination and BDR adjusted for selected characteristics. An interaction term between TNF-α levels and self-reported racial/ethnic discrimination was tested in the final model.

Results

Almost half of participants (48.8%) reported racial/ethnic discrimination. The mean percent BDR was higher among participants reporting racial/ethnic discrimination than among those who did not (10.8 versus 8.9, p = 0.006). After adjustment, participants reporting racial/ethnic discrimination had a 1.7 (95% CI: 0.36-3.03) higher BDR mean than those not reporting racial/ethnic discrimination. However, we found heterogeneity of this association according to TNF-α levels (p-interaction = 0.040): Among individuals with TNF-α high level only, we observed a 2.78 higher BDR mean among those reporting racial/ethnic discrimination compared with those not reporting racial/ethnic discrimination (95%CI: 0.79-4.77).

Conclusions

We found BDR to be increased in participants reporting racial/ethnic discrimination and this association was limited to African American youth with TNF-α high asthma, an endotype thought to be resistant to traditional asthma medications. These results support screening for racial/ethnic discrimination in those with asthma as it may reclassify disease pathogenesis.