ABCMdb

PMID: 25877294

Mokuno J, Hishida A, Morita E, Sasakabe T, Hattori Y, Suma S, Okada R, Kawai S, Naito M, Wakai K
ATP-binding cassette transporter A1 (ABCA1) R219K (G1051A, rs2230806) polymorphism and serum high-density lipoprotein cholesterol levels in a large Japanese population: cross-sectional data from the Daiko Study.
Endocr J. 2015;62(6):543-9. doi: 10.1507/endocrj.EJ14-0577. Epub 2015 Apr 15., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCA1 p.Arg219Lys The rate is lower in East Asian countries compared with Western countries. For example, the age-adjusted mortality rate (per 100,000 in 2004) was 32.1 in Japan, 40.3 in Korea, and 62.8 in China whereas it was ATP-binding cassette transporter A1 (ABCA1) R219K (G1051A, rs2230806) polymorphism and serum high-density lipoprotein cholesterol levels in a large Japanese population: cross-sectional data from the Daiko Study Junichiro Mokuno, Asahi Hishida, Emi Morita, Tae Sasakabe, Yuta Hattori, Shino Suma, Rieko Okada, Sayo Kawai, Mariko Naito and Kenji Wakai Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan Abstract. Login to comment 3 ABCA1 p.Arg219Lys Among polymorphisms in ATP-binding cassette transporter A1 (ABCA1) gene, the available evidence demonstrates that the ABCA1 R219K polymorphism (G1051A, rs2230806) K allele is associated with a higher high-density lipoprotein cholesterol (HDL-C) level and may play a protective role against coronary artery disease (CAD) risk in Asians and Caucasians. Login to comment 13 ABCA1 p.Arg219Lys In the multiple linear regression analysis to estimate the independent effects of the R219K polymorphism on HDL-C level, however, the number of K allele was significantly correlated with an increased level of HDL-C (trend P=0.033). Login to comment 15 ABCA1 p.Arg219Lys The R219K polymorphism of ABCA1 independently associated with serum level of HDL-C in a large Japanese population. Login to comment 53 ABCA1 p.Arg219Lys Therefore, to clarify the association of ABCA1 R219K polymorphism with serum HDL-C levels in a large Japanese population, we examined this associa- tive combined; to explain in detail, we first defined the 5 categories of drinking status as follows: nonhabitual drinker, former habitual drinker, or habitual drinker of ethanol at < 23, 23 - < 46, and > 46 g per day (equivalent to < 1 gou, 1-2 gou and > 2 gou of Japanese sake, respectively; where 1 gou [a unit for Japanese sake] = 180mL) per day, and then converted each category into indicator variables. Login to comment 56 ABCA1 p.Arg219Lys Genotyping of ABCA1 R219K polymorphism DNA was extracted from buffy coat kept at -80&#b0;C using a Biorobot M48 (QIAGEN Group, Tokyo). Login to comment 65 ABCA1 p.Arg219Lys The difference in the serum HDL-C level between the ABCA1 R219K genotypes by sex was tested by the analysis of variance (ANOVA). Login to comment 71 ABCA1 p.Arg219Lys The logic of PCR-CTPP for R219K polymorphism (corresponding base change from A to G) can be explained as follows: as described in elsewhere [14], confronting pairs of primers are used; one pair is for the K allele and the other is for the R allele. Login to comment 77 ABCA1 p.Arg219Lys In the multiple linear regression analysis to estimate the independent effects of the R219K polymorphism on HDL-C level (Table 3), the number of K allele was significantly associated with an increased level of HDL-C (trend P=0.033). Login to comment 80 ABCA1 p.Arg219Lys Results Clinical profiles of subjects by ABCA1 R219K genotype were shown in Table 1. Login to comment 83 ABCA1 p.Arg219Lys The mean HDL-C concentration was higher in men and women with RK or KK genotype than those with RR, although the difference between Table 1 Clinical Profiles of subjects by ABCA1 R219K (rs2230806) genotype (n =5,133) KK RK RR P (26.8%, n = 1,376) (49.3%, n = 2,532) (23.9%, n = 1,225) Female 988 (71.8%) 1,818 (71.8%) 869 (70.9%) 0.84 Age (years) 52.6 &#b1; 10.4 52.5 &#b1; 10.3 52.5 &#b1; 10.3 0.98 Body mass index (kg/m2 ) 21.8 &#b1; 3.3 21.7 &#b1; 3.1 21.7 &#b1; 3.1 0.65 Current smokers 163 (11.8%) 298 (11.8%) 146 (11.9%) 0.99 Current drinkers 757 (55.0%) 1,357 (53.6%) 663 (54.1%) 0.70 Hypertension 226 (16.4%) 363 (14.3%) 192 (15.7%) 0.19 Diabetes mellitus 54 (3.9%) 89 (3.5%) 42 (3.4%) 0.75 Values are expressed as means &#b1; standard deviation, or n (%). Login to comment 84 ABCA1 p.Arg219Lys Table 2 Mean &#b1; standard deviation of HDL-C level (mg/dL) by sex and ABCA1 R219K (rs2230806) genotype and sex KK RK RR P* (n = 1,376) (n = 2,532) (n = 1,225) Male (n =1,458) 57.3 &#b1;15.0 56.4 &#b1; 13.7 55.7 &#b1; 14.0 0.31 Female (n =3,675) 68.7&#b1; 14.5 68.7 &#b1; 14.9 67.7 &#b1; 14.9 0.26 * By analysis of variance (ANOVA). Login to comment 88 ABCA1 p.Arg219Lys Concerning ABCA1 R219K polymorphism, the frequency of K allele was reported to be 0.488 in Japanese [22] while that in the Caucasian population ranged between 0.25 and 0.46 [21]. Login to comment 90 ABCA1 p.Arg219Lys Moreover, there is a great variation and diversity in the effects of dietary and other lifestyle factors on lipid levels between ethnicities or study populations, which may also lead to the different interaction with the effect of this ABCA1 R219K polymorphism. Login to comment 97 ABCA1 p.Arg219Lys R219K polymorphism is located in the two major extracellular loops of ABCA1 protein, which is important for the interaction with apoA-I and for cholesterol efflux. Login to comment 98 ABCA1 p.Arg219Lys Therefore, it is likely that the R219K variant is a functional mutation to modulate HDL-C level. Login to comment 101 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Either way, given that based on the functional analysis using SIFT and PolyPhen, this R219K variation of ABCA1 is suggested not to be functional in itself, it could rather be causal The analysis results of the association between ABCA1 R219K polymorphism and HDL-C level adjusted by drinking status and in males were substantially in the same direction compared to that of overall, with the b2;-coefficient of 0.840 for RK genotype, 1.818 for KK genotype, 0.911 with the number of K allele, with the P-values of 0.321, 0.058 and 0.057, respectively. Login to comment 102 ABCA1 p.Arg219Lys The association between R219K of ABCA1 and triglyceride (TG) levels was neither statistically significant (data not shown). Login to comment 103 ABCA1 p.Arg219Lys Discussion We found a significant association between the R219K polymorphism K allele of ABCA1 and a higher serum HDL-C level in a large Japanese population. Login to comment 104 ABCA1 p.Arg219Lys Previous studies have reported that the R219K polymorphism was associated with increased circulating HDL-C. Login to comment 106 ABCA1 p.Arg219Lys It was reported by Clee et al. that the R219K K allelle was associated with a higher level of HDL-C and a lower level of TG [15]. Login to comment 107 ABCA1 p.Arg219Lys Additional studies in Caucasian, Asian and multi-ethnic populations have also shown the association between the ABCA1 R219K polymorphism and the HDL-C level [6]. Login to comment 108 ABCA1 p.Arg219Lys Our data based on a Japanese population revealed consistent elevations in blood HDL-C levels associated with the K allele of ABCA1 R219K polymorphism. Login to comment 116 ABCA1 p.Arg219Lys Given the considerably large sample size, the present study may have a significant impact by providing the first robust evidence for the protective effect of the K variant in the ABCA1 R219K polymorphism in Japanese. Login to comment 117 ABCA1 p.Arg219Lys However, because we focused on ABCA1 R219K polymorphism, we could not evaluate the influence of other polymorphisms of ABCA1 gene. Login to comment 119 ABCA1 p.Arg219Lys In summary, the R219K polymorphism of ABCA1 was independently associated with serum level of HDL-C in a large Japanese population. Login to comment 128 ABCA1 p.Arg219Lys The effect of the K variant in the ABCA1 R219K polymorphism examined was in the same direction compared to that in the recent meta-analysis in the Asian populations [29], and in the opposite direction to that in the Japanese subjects [22]. Login to comment 129 ABCA1 p.Arg219Lys The forementioned recent meta-analysis of HDL-C and ABCA1 R219K consisted of mixture of cohort studies and hospital-based case-control studies; the population of which consisted of Caucasians, Chinese, Japanese and Iraqis, most of the Asian populations of which were Chinese. Login to comment 143 ABCA1 p.Arg219Lys Ma XY, Liu JP, Song ZY (2011) Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: a meta-analysis. Login to comment 176 ABCA1 p.Arg219Lys Liu N, Hou M, Ren W, Cao J, Wu H, Zhou W (2015) The R219K polymorphism on ATP-binding cassette transporter A1 gene is associated with coronary heart disease risk in Asia population: evidence from a meta-analysis. Login to comment 185 ABCA1 p.Arg219Lys Yin YW, Li JC, Gao D, Chen YX, Li BH et al. (2014) Influence of ATP-binding cassette transporter 1 R219K and M883I polymorphisms on development of atherosclerosis: a meta-analysis of 58 studies. Login to comment 211 ABCA1 p.Arg219Lys Li J, Wang LF, Li ZQ, Pan W (2009) Effect of R219K polymorphism of the ABCA1 gene on the lipid-lowering effect of pravastatin in Chinese patients with coronary heart disease. Login to comment 214 ABCA1 p.Arg219Lys Li Y, Zhang SZ, Ma YX, He Y, Dong JT, et al. (2005) Relationship between the R219K polymorphism of ATP-binding cassette transporter 1 gene and coronary heart disease. Login to comment 217 ABCA1 p.Arg219Lys Zhao S, Xiao Z (2004) The study on ABCA1 R219K Login to comment