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

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

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

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