RESUMEN
CONTEXT: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. OBJECTIVE: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. DESIGN AND PARTICIPANTS: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, Nâ =â 1721 on GWAS array) and the Living Biobank study (Nâ =â 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. RESULTS: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (Pâ <â 5â ×â 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38â ±â 0.06% (Pâ =â 3.5â ×â 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. CONCLUSION: We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.
Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito/genética , Glucemia/metabolismo , Eliminación de Gen , Hemoglobina Glucada/genética , Adolescente , Adulto , Anciano , Pueblo Asiatico/genética , Glucemia/genética , Estudios de Casos y Controles , Estudios de Cohortes , Estudios Transversales , Eliptocitosis Hereditaria/etnología , Eliptocitosis Hereditaria/genética , Etnicidad/genética , Etnicidad/estadística & datos numéricos , Femenino , Estudio de Asociación del Genoma Completo , Hemoglobina Glucada/metabolismo , Humanos , Malasia/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Singapur/epidemiología , Adulto JovenAsunto(s)
Ancirinas/metabolismo , Eliptocitosis Hereditaria/sangre , Espectrina/genética , Espectrina/metabolismo , Eliptocitosis Hereditaria/etnología , Eliptocitosis Hereditaria/genética , Membrana Eritrocítica/química , Humanos , Países Bajos/etnología , Unión Proteica , Sudáfrica , Espectrina/deficienciaRESUMEN
We studied an African population in Benin and discovered an unexpectedly high frequency (1.6%) of hereditary elliptocytosis (HE) among the 1447 subjects studied. In approximately two-thirds of HE individuals we identified molecular defects, primarily those in erythrocyte alpha-spectrin (dupL154, L260P and L207P mutations), as well as a novel mutation of erythrocyte beta-spectrin (beta-W2061R mutation). We also identified the genetic basis of a previously identified protein polymorphism of the alpha III domain of spectrin (R1331I mutation). The genetic background of HE in the African population was studied using a number of polymorphisms of the alpha-spectrin gene, including the alpha III domain polymorphism. These studies suggest that the HE mutations appear to have originated from separate genetic backgrounds in this population.
Asunto(s)
Eliptocitosis Hereditaria/genética , Mutación , Polimorfismo Genético , Espectrina/genética , Benin/epidemiología , Eliptocitosis Hereditaria/etnología , Pruebas Genéticas , Humanos , Mutación Puntual , Reacción en Cadena de la PolimerasaRESUMEN
The alpha I/65 variant of spectrin has been described in black people, in North Africans and recently in two southern Italian families. This variant is associated in the heterozygous state with mild Hereditary Elliptocytosis (HE) and the molecular basis of the defect is invariably the duplication of TTG at codon 154 of the alpha spectrin gene. The present study reports the identification of five Calabrian families with SP alpha I/65 HE and their distribution in the population.
