Transferability of genome-wide associated loci for asthma in African Americans

<p><i>Objective:</i> Transferability of significantly associated loci or GWAS “hits” adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. <i>Methods:</i> Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an “exact” approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a “local” approach that examined all the regional SNPs in LD with the index SNP. <i>Results:</i> Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], <i>P</i> = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149–4.013], <i>P</i> = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected <i>P</i> values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of <i>IL33</i> were significantly associated with asthma. <i>Conclusions:</i> This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the <i>IL33</i>, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding.</p

Multiple Loci Associated with Renal Function in African Americans

<div><p>The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR). We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in <em>APOL1</em> associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry <em>vs</em>. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.</p> </div

Association with eGFR stratified by ancestry.

a<p>Positions are based on NCBI build 36.</p>b<p>Shown are the nominal numbers of SNPs in the set for each locus.</p>c<p>“DoF” indicates the effective degrees of freedom for each locus, which is the correction factor used to adjust <i>p</i>-values.</p>d<p>β_meta and SE_meta refer to the estimates from the meta-analysis combined across the three strata of local ancestry.</p

Characteristics of the study sample.

a<p>Ranges are presented as median (first quartile, third quartile).</p

Gene-Based Sequencing Identifies Lipid-Influencing Variants with Ethnicity-Specific Effects in African Americans

<div><p>Although a considerable proportion of serum lipids loci identified in European ancestry individuals (EA) replicate in African Americans (AA), interethnic differences in the distribution of serum lipids suggest that some genetic determinants differ by ethnicity. We conducted a comprehensive evaluation of five lipid candidate genes to identify variants with ethnicity-specific effects. We sequenced <i>ABCA1</i>, <i>LCAT</i>, <i>LPL</i>, <i>PON1</i>, and <i>SERPINE1</i> in 48 AA individuals with extreme serum lipid concentrations (high HDLC/low TG or low HDLC/high TG). Identified variants were genotyped in the full population-based sample of AA (n = 1694) and tested for an association with serum lipids. rs328 (<i>LPL</i>) and correlated variants were associated with higher HDLC and lower TG. Interestingly, a stronger effect was observed on a “European” vs. “African” genetic background at this locus. To investigate this effect, we evaluated the region among West Africans (WA). For TG, the effect size among WA was the same in AA with only African local ancestry (2–3% lower TG), while the larger association among AA with local European ancestry matched previous reports in EA (10%). For HDLC, there was no association with rs328 in AA with only African local ancestry or in WA, while the association among AA with European local ancestry was much greater than what has been observed for EA (15 vs. ∼5 mg/dl), suggesting an interaction with an environmental or genetic factor that differs by ethnicity. Beyond this ancestry effect, the importance of African ancestry-focused, sequence-based work was also highlighted by serum lipid associations of variants that were in higher frequency (or present only) among those of African ancestry. By beginning our study with the sequence variation present in AA individuals, investigating local ancestry effects, and seeking replication in WA, we were able to comprehensively evaluate the role of a set of candidate genes in serum lipids in AA.</p></div

Participant characteristics¹.

<p><i>Abbreviations: Body Mass Index (BMI); ¹Mean (± standard deviation) given except where indicated; ²median and interquartile range given due to non-normality.</i></p

Serum lipids by rs328 genotype and local ancestry in African Americans and West Africans.

<p>Difference in serum HDLC and logTG with the variant genotype for African Americans with 0, 1, or 2 African ancestry alleles at this locus, and West African individuals. Results for other <i>LPL</i> variants in LD with rs328 were similar.</p

Common variants in candidate genes associated with serum lipids in African Americans (n = 1694).

<p>Abbreviations: Additive (Add), Chromosome (Chr), Dominant (Dom), Minor Allele Frequency (MAF), High-density Lipoprotein Cholesterol (HDLC), Recessive (Rec), Log-transformed Triglycerides (logTG); ¹Build 37 position; ² βs are given for the minor (“Alt”) allele. TG values were log-transformed: β values represent the percent change in TG. ³Correction for multiple hypotheses conducted by calculating the effective degrees of freedom using the covariance matrix for variants in each gene. All P-values have been multiplied by the effective degrees of freedom for that gene (see methods and reference<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004190#pgen.1004190-Ramos1" target="_blank">[54]</a>); ⁴Similar results observed for the following CVs in high LD (R²>0.8) with listed SNP: rs114851717 (rs138618449, rs148714575, rs115761095, rs76729624), rs256 (rs271), rs328 (rs325, rs117199990, rs145391587, rs75278536, rs77069344, rs11570891, rs1803924, rs3735964), rs1059611 (rs149865365), rs2515602 (rs2472386), rs1800977 (rs2437817, rs2243312).CVs in LD (R²>0.6); ⁵These associations would no longer be statistically significant if adjusted for model selection (4 genetic models compared).</p