RESUMO
C5L2, a G protein-coupled receptor, is known to be a functional receptor of acylation-stimulating protein, which is a stimulator of triglyceride synthesis and glucose transport. A novel C5L2 variant (S323I) was identified and its association with familial combined hyperlipidemia (FCH) was recently reported. We looked for this SNP in three Chinese ethnic groups, including Han, Uygur, and Kazakh controls and patients with FCH and type 2 diabetes. One hundred and eighty-two unrelated subjects (77 of Han, 57 of Uygur, and 48 of Kazakh) with FCH were genotyped by direct sequencing, and 852 subjects (342 of Han, 338 of Uygur, 172 of Kazakh) with type 2 diabetes and 200 healthy controls (67 of Han, 72 of Uygur, and 61 of Kazakh) chosen from a cardiovascular risk survey study were genotyped with PCR-RFLP analysis. All 182 subjects with FCH, 99.5% of the type 2 diabetes patients and 100% of the healthy controls were successfully genotyped. Neither the FCH subjects nor the type 2 diabetes patients were found to have the S323I variant. This variant was also not identified in the healthy controls. We found no evidence to demonstrate that the S323I polymorphism contributes to familial combined hyperlipidemia or type 2 diabetes in the Chinese population.
Assuntos
Povo Asiático , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Hiperlipidemia Familiar Combinada/genética , Polimorfismo de Nucleotídeo Único , Receptores de Quimiocinas/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , China/epidemiologia , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Feminino , Frequência do Gene , Genótipo , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/etnologia , Isoleucina/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Receptor da Anafilatoxina C5a , Fatores de Risco , Serina/genéticaRESUMO
BACKGROUND AND PURPOSE: Although the Mexican population has a high predisposition to dyslipidemias and premature coronary artery disease, this population is underinvestigated for the genetic factors conferring the high susceptibility. This study attempted to determine these genetic factors. METHODS AND RESULTS: First, we investigated apolipoprotein B (apoB) levels in Mexican extended families with familial combined hyperlipidemia using a two-step testing strategy. In the screening step, we screened 5721 single-nucleotide polymorphisms (SNPs) for linkage signals with apoB. In the test step, we analyzed the 130 SNPs residing in regions of suggestive linkage signals for association with apoB. We identified significant associations with two SNPs (ie, rs1424032 [P=6.07x10(-6)] and rs1349411 [P=2.72x10(-4)]) that surpassed the significance level for the number of tests performed in the test step (P<3.84x10(-4)). Second, these SNPs were tested for replication in Mexican hyperlipidemic case-control samples. The same risk alleles as in the families with familial combined hyperlipidemia were significantly associated (P<0.05) with apoB in the case-control samples. The rs1349411 resides near the apoB messenger RNA editing enzyme (APOBEC1) involved in the processing of APOB messenger RNA in the small intestine. The rs1424032 resides in a highly conserved noncoding region predicted to function as a regulatory element. CONCLUSIONS: We identified two novel variants, rs1349411 and rs1424032, for serum apoB levels in Mexicans.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Apolipoproteínas B/genética , Citidina Desaminase/genética , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemias/genética , Polimorfismo de Nucleotídeo Único , Desaminase APOBEC-1 , Adulto , Apolipoproteínas B/metabolismo , Estudos de Casos e Controles , Citidina Desaminase/metabolismo , Feminino , Frequência do Gene , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/etnologia , Hiperlipidemias/sangue , Hiperlipidemias/etnologia , Masculino , México/epidemiologia , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , RNA Mensageiro/metabolismo , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the largely unknown genetic component of the common lipid disorder, familial combined hyperlipidemia (FCHL) in Mexicans, we analyzed the upstream transcription factor 1 (USF1) gene that was recently associated with FCHL and high triglycerides (TG) in Finns. We also analyzed the Mexican FCHL families for 26 microsatellite markers residing in the seven chromosomal regions on 2p25.1, 9p23, 10q11.23, 11q13, 16q24.1, 19q13, and 21q21, previously linked to FCHL in whites. METHODS AND RESULTS: We genotyped 314 individuals in 24 Mexican families for 13 SNPs spanning an 88-kb region, including USF1. The FCHL and TG traits showed significant evidence for association with 3 SNPs, hCV1459766, rs3737787, and rs2073658, and haplotype analyses further supported these findings (probability values of 0.05 to 0.0009 for SNPs and their haplotypes). Of these SNPs, hCV1459766 is located in the F11 receptor (F11R) gene, located next to USF1, making it difficult to exclude. Importantly, the association was restricted to a considerably smaller region than in the Finns (14 kb versus 46 kb), possibly because of a different underlying linkage disequilibrium structure. In addition, 1 of the 7 regions, 16q24.1, showed suggestive evidence for linkage (a lod score of 2.6) for total cholesterol in Mexicans. CONCLUSIONS: This study, the first to extensively investigate the genetic component of the common FCHL disorder in Mexicans, provides independent evidence for the role of USF1 in FCHL in an outbred population and links the 16q24.1 region to an FCHL-component trait in Mexicans.