ABCMdb

PMID: 23273975

Aguilar-Salinas CA, Munoz-Hernandez LL, Cobos-Bonilla M, Ramirez-Marquez MR, Ordonez-Sanchez ML, Mehta R, Medina-Santillan R, Tusie-Luna MT
The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus.
Metabolism. 2013 May;62(5):638-41. doi: 10.1016/j.metabol.2012.11.006. Epub 2012 Dec 27., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg230Cys The R230C variant of the ATP binding cassette protein A1 (ABCA1) gene is associated with a decreased response to glyburide therapy in patients with type 2 diabetes mellitus Carlos A. Aguilar-Salinasa, b,Ìe;, Linda Liliana Mu&#f1;oz-Hernandeza , Monica Cobos-Bonillaa , Marcos Rafael Ram&#ed;rez-M&#e1;rqueza , Maria Luisa Ordo&#f1;ez-Sanchezc , Roopa Mehtaa , Roberto Medina-Santillanb , Maria Teresa Tusie-Lunac a Department of Endocrinology and Metabolism. Login to comment 4 ABCA1 p.Arg230Cys To test the hypothesis that persons with the R230C allele of ABCA1 show a decreased glycemic response to glyburide. Login to comment 8 ABCA1 p.Arg230Cys Each person with the risk allele (R230C) was matched by age, gender and BMI to three others with the wild type variant (R230R). Login to comment 12 ABCA1 p.Arg230Cys No significant difference was observed in the glucose lowering effect of glyburide between subjects with the R230C and R230R alleles. Login to comment 13 ABCA1 p.Arg230Cys However, the dose of sulfonylurea was significantly higher in the R230C participants compared with the R230R subjects (3.3&#b1;2.1 vs 6.3&#b1;5 mg/day, p<0.001). Login to comment 14 ABCA1 p.Arg230Cys A higher percentage of R230C participants required at least 5 mg of glyburide per day to achieve treatment goals. Login to comment 17 ABCA1 p.Arg230Cys Patients with type 2 diabetes who have the R230C allele of ABCA1 needed a higher dose of glyburide in order to achieve the same glucose lowering effect as that in persons with the wild type variant. Login to comment 27 ABCA1 p.Arg230Cys One such variant, the R230C allele (rs9282541) is common in the Mexican population; a population-based survey, reported a prevalence of 18.7% among participants [3,4]. Login to comment 29 ABCA1 p.Arg230Cys In addition, two cross-sectional studies have shown that the R230C variant of ABC-A1 is associated with type 2 diabetes. Login to comment 36 ABCA1 p.Arg230Cys In this report, our hypothesis is that persons with type 2 diabetes who have the R230C variant of ABCA1 may have a decreased hypoglycemic response to a sulfonylurea, compared to participants with the wild type variant (R230R). Login to comment 39 ABCA1 p.Arg230Cys One group had the R230C variant of ABC-A1 and the other had the R230R variant. Both groups were matched for gender, age (&#b1;5 years) and BMI (&#b1;2 kg/m2 ). Login to comment 62 ABCA1 p.Arg230Cys The R230C variant was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Login to comment 69 ABCA1 p.Arg230Cys Results Our study sample included 17 individuals with the R230C variant and 68 subjects with the R230R variant. Both groups were successfully matched by age, gender and body mass index (Table 1). Login to comment 77 ABCA1 p.Arg230Cys However, individuals with the R230C variant required a significantly higher glyburide dose (3.3&#b1;2.1 vs 6.3&#b1;5 mg/day, p<0.001) to achieve the same glucose lowering effect as persons with the wild type variant. Login to comment 78 ABCA1 p.Arg230Cys A glyburide doseࣙ5 mg/ day was more common in the R230C group. Login to comment 83 ABCA1 p.Arg230Cys Discussion Our data show that persons with type 2 diabetes who have the ABCA1 R230C polymorphism require a higher glyburide dose to achieve similar glucose lowering as matched subjects with the wild type variant. Login to comment 85 ABCA1 p.Arg230Cys The R230C allele was independently associated with the glyburide dosage, even after adjusting for FPG, BMI and adherence to therapy. Login to comment 90 ABCA1 p.Arg230Cys This abnormality would occur in the R230C variant individuals as a result of a decrease in ABC-A1 activity [13,14]. Login to comment 93 ABCA1 p.Arg230Cys In addition, the R230C variant is independently associated with lower HDL-C concentrations [4]. Login to comment 94 ABCA1 p.Arg230Cys Since HDL particles may have beneficial effects on beta cell function and survival [15,16], the coexistence of lower HDL-C concentrations may be another mechanism by which the R230C variant is associated with a decreased response to glyburide. Login to comment 99 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Additional studies are needed to measure insulin secretory capacity in patients with or without the R230C polymorphism and to elucidate the Table 1 - Clinical and biochemical parameters in R230C carriers of ATP-binding cassette transporter A1 gene and their controls (R230R) at baseline. Login to comment 100 ABCA1 p.Arg230Cys Total (n=85) R230R (n=70) R230C (n=17) P value Age (years) 53.6&#b1;11 54.4&#b1;10 50.2&#b1;12 0.166 Females (n (%)) 55 (64.7) 44 (64.7) 11 (64.7) 1.0 Waist circumference (cm) 99&#b1;10 99&#b1;10 96&#b1;7 0.211 Time since diagnosis (years) 6.1&#b1;5.4 6.0&#b1;5.4 6.4&#b1;5.7 0.760 Body mass index (kg/m2 ) 30.3&#b1;6 30.4&#b1;6 30.1&#b1;4 0.827 Systolic blood pressure 120&#b1;13 121&#b1;14 118&#b1;10 0.375 Diastolic blood pressure 75&#b1;8 76&#b1;8 74&#b1;9 0.284 Fasting glycemia a (mg/dl) 150&#b1;54 146&#b1;52 163&#b1;62 0.266 Fasting insulin (mU/ml)a 12&#b1;7 12&#b1;7 11&#b1;7 0.616 HbA1c (%)a 8.9&#b1;1.5 8.7&#b1;1.5 9.4&#b1;1.7 0.086 Triglycerides (mg/dl)a 195&#b1;135 189&#b1;129 220&#b1;160 0.399 Cholesterol (mg/dl)a 182&#b1;51 188&#b1;53 171&#b1;40 0.209 HDL-cholesterol (mg/dl)a 43.6&#b1;12 44.7&#b1;13 38.9&#b1;7.9 0.093 Apolipoprotein B (mg/dl) a 106&#b1;31 107&#b1;30 102&#b1;36 0.494 a After the run-in period. Login to comment 101 ABCA1 p.Arg230Cys Table 2 - Glycemic response to glyburide therapy of R230C carriers of the ATP-binding cassette transporter A1 gene and their controls (R230R). Login to comment 102 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Total (n=85) R230R (n=68) R230C (n=17) P value Percent change in fasting plasma glucose (%) -10.9&#b1;22 -11.8&#b1;23 -7.7&#b1;18 0.502 Absolute change in HbA1c (% units) -2.2&#b1;1.4 -2.2&#b1;1.5 -2.0&#b1;1.3 0.725 Mean glyburide dosage (mg/day) 3.9&#b1;3.1 3.3&#b1;2.1 6.3&#b1;5.0 0.001 Percentage of cases with glyburideࣙ5 mg/day (% (n)) 34.1 (29) 30.8 (21) 47 (8) 0.020 Percentage of cases with HbA1c <7% (%(n)) 60 (51) 63.2 (43) 47 (8) 0.411 Percentage of cases with fasting plasma glucose <110 mg/dl (%(n)) 43.5 (37) 42.6 (29) 47.9 (8) 0.438 640 M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 2 ( 2 0 1 ) 6 3 8 - 6 4 1 mechanisms which explain the higher sulfonylurea requirement in the R230C group. Login to comment 122 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys [4] Aguilar-Salinas CA, Canizales-Quinteros S, Rojas-Mart&#ed;nez R, et al. The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study. Login to comment 124 ABCA1 p.Arg230Cys [5] Villarreal-Molina MT, Aguilar-Salinas CA, Rodr&#ed;guez-Cruz M, et al. The ABCA1 R230C variant affects HDL cholesterol levels and body mass index in the Mexican population: association with obesity and obesity-related comorbidities. Login to comment 126 ABCA1 p.Arg230Cys [6] Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, et al. Association of the ABCA1 R230C variant with early-onset type 2 diabetes in the Mexican population. Login to comment