Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos

Abstract

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10^-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10^-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10^-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.

Figure 1

LocusZoom plot (top) and forest plot (bottom) of the SYBU locus, detected as associated with the ankle brachial index (ABI) in the Caribbean group. In the locusZoom plots, each point represents a variant, with location marked on the x-axis, and p-values marked as the location on the y-axis. The lead SNP is represented by the triangle, indicating that it is imputed. The colors of the variants correspond to the strength of their LD (r²) with the lead SNP, with LD estimated using the combined population of the HCHS/SOL Caribbean group. Circles correspond to genotyped variants, x symbols to imputed variants. The p-value of heterogeneity (across all HCHS/SOL genetic analysis groups) was 9.3 × 10⁻⁴. The bottom of the forest plot provides results from MESA replication groups.

Figure 2

LocusZoom plot (top) and forest plot (bottom) of the COMMD10 locus, detected as associated with ankle brachial index (ABI) in the Puerto Rican subgroup. In the locusZoom plot, each point represents a variant, with location marked on the x-axis, and p-values marked as the location on the y-axis. The lead SNP is represented by the diamond, indicating that it is genotyped. The colors of the variants correspond to the strength of their LD (r²) with the lead SNP, with LD estimated using the Puerto Rican population of the HCHS/SOL. Circles correspond to genotyped variants, x symbols to imputed variants. The p-value of heterogeneity (across all HCHS/SOL genetic analysis groups was 1 × 10⁻¹⁰. The bottom of the forest plot provides results from MESA replication groups.

Figure 3

LocusZoom plot (top) and forest plot (bottom) of the DMD locus, detected as suggestively associated with ABI in the Central American genetic analysis group. In the locusZoom plots, each point represents a variant, with location marked on the x-axis, and p-values marked as the location on the y-axis. The lead SNP is represented by the diamond, indicating that it is genotyped. The colors of the variants correspond to the strength of their LD (r²) with the lead SNP, with LD estimated using the Central American population of the HCHS/SOL. Circles correspond to genotyped variants, x symbols to imputed variants. The p-value of heterogeneity (across all HCHS/SOL genetic analysis groups) was 2.41 × 10⁻⁵. The bottom of the forest plot provides results from MESA replication groups.