Follow-up association study of linkage regions reveals multiple candidate genes for carotid plaque in Dominicans

ObjectiveCarotid plaque is a marker of subclinical atherosclerosis with a genetic component. The aim of this follow-up fine mapping study was to identify candidate genes for carotid plaque within four linkage regions.MethodsWe successfully genotyped 3712 single nucleotide polymorphisms (SNPs) under the four linkage regions that were previously identified in 100 extended Dominican families. Family-based association tests were performed to investigate their associations with carotid plaque. Promising SNPs were evaluated in an independent population-based subcohort (N = 941, 384 Dominicans) from the Northern Manhattan Study (NOMAS).ResultsIn the family study, evidence for association (p < 0.0005) was found regarding several genes (NAV2, EFCAB11/TDP1, AGBL1, PTPN9, LINGO1 and LOC730118), with the strongest association at rs4143999 near EFCAB11/TDP1 (p = 0.00001 for carotid presence and 0.00003 for plaque area, multiple testing corrected p ≤ 0.02). The association in AGBL1 and PTPN9 was mainly driven by the families with linkage evidence (p = 0.00008-0.00001 and 0.76-0.32, respectively, in the families with and without linkage evidence). However, these associations explained only a small portion of the observed linkage. In NOMAS, replication (p < 0.05 in the whole NOMAS subcohort and p < 0.10 in the smaller Dominican subcohort) was found for SNPs within/near EFCAB11, NAV2, AGBL1 and other genes.ConclusionThis follow-up study has identified multiple candidate genes for carotid plaque in the Dominican population. Many of these genes have been implicated in neurodegenerative and cardiovascular diseases. Further studies with in-depth re-sequencing are needed to uncover both rare and common functional variants that contribute to the susceptibility to atherosclerosis.

► We investigate genetic associations in four linkage regions for carotid plaque among Dominican families. ► Associations with carotid plaque are marked for NAV2, EFCAB11, AGBL1, PTPN9, LINGO1 genes. ► Replications are found for EFCAB11, NAV2, AGBL1 and other several genes.