ABCMdb

PMID: 24084154

Coban N, Onat A, Komurcu Bayrak E, Gulec C, Can G, Erginel Unaltuna N
Gender specific association of ABCA1 gene R219K variant in coronary disease risk through interactions with serum triglyceride elevation in Turkish adults.
Anadolu Kardiyol Derg. 2014 Feb;14(1):18-25. doi: 10.5152/akd.2013.234. Epub 2013 Sep 26., [PubMed]

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0 ABCA1 p.Arg219Lys Gender specific association of ABCA1 gene R219K variant in coronary disease risk through interactions with serum triglyceride elevation in Turkish adults AddressforCorrespondence:Dr.NihanErginel-&#dc;naltuna,stanbul&#dc;niversitesiDeneyselTpAraf;trmaEnstit&#fc;s&#fc;,GenetikB&#f6;l&#fc;m&#fc;, VakfGurebaCad.e;ehremini,stanbul-T&#fc;rkiye Phone:+902124142200-33324 Fax:+902125324171 E-mail:nihanerginel@yahoo.com Accepted Date: 16.07.2013 Available Online Date: 26.09.2013 (c)Copyright 2014 by AVES - Available online at www.anakarder.com doi:10.5152/akd.2013.234 Neslihan &#c7;oban, Altan Onat1, Evrim K&#f6;m&#fc;rc&#fc;-Bayrak, &#c7;af;r G&#fc;le&#e7;, G&#fc;nay Can2, Nihan Erginel-&#dc;naltuna Department of Genetics, Institute for Experimental Medical Research, stanbul University; stanbul-Turkey Departments of 1Cardiology and 2Public Health, Cerrahpaf;a Medical Faculty, stanbul University; stanbul-Turkey ABSTRACT Objective: ATP binding cassette transporter A1 (ABCA1) controls the reverse cholesterol transport. Login to comment 3 ABCA1 p.Arg219Lys Methods: Selected 627 individuals of the Turkish Adult Risk Factor Study were genotyped for ABCA1 R219K polymorphism using PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method. Login to comment 5 ABCA1 p.Arg219Lys Results: We demonstrated a gender-specific effect of the R219K polymorphism on plasma lipids and CHD. Login to comment 8 ABCA1 p.Arg219Lys R219K heterozygosity in women independently doubled (95% CI 1.00; 3.80) the odds ratio for CHD risk in regression models, after adjustment for several variables. Login to comment 18 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys The K allele of the R219K polymorphism (Arg219Lys, rs2230806) has been associated with decreased triglyceride (TG) concentrations (11, 13) and increased HDL-C concentrations (9, 11, 12), consistent with a net increase in transporter function; the rare allele of the R219K, on the other hand, was found to be associated with increased risk of CHD (14). Login to comment 19 ABCA1 p.Arg219Lys Because findings on the relationship between ABCA1 R219K polymorphism and CHD have been inconclusive, a meta-analysis was recently conducted comprising over 9400 cases and over 16.000 controls (12, 15). Login to comment 21 ABCA1 p.Arg219Lys Among other ABCA1 polymorphisms, R219K variant`s association with HDL-C was examined by Hodof;lugil et al. (10) on a large sample of Turkish adults, and an association was lacking in men. Login to comment 22 ABCA1 p.Arg219Lys The KK genotype of R219K polymorphism alone showed no association with elevated HDL-C but an association was observed in combination with TT genotype of C-14T polymorphism. Login to comment 26 ABCA1 p.Arg219Lys We, therefore, explored the role of ABCA1 gene in predisposing Turkish adults to CHD in a nested case-control study comprising 627 genotyped individuals for the R219K polymorphism. Login to comment 28 ABCA1 p.Arg219Lys The specific aim of this study was to examine the relation of the R219K polymorphism with both the lipid concentrations and CHD in a randomly selected sample of the Turkish Adult Risk Factor Study (TARF) cohort, representative of Turkish adults (20). Login to comment 54 ABCA1 p.Arg219Lys Genetics analysis The detection of R219K polymorphism using RFLP (restriction fragment length polymorphism) DNA was extracted from peripheral blood leukocytes using a QIAmpR DNA Maxi KIT (Qiagen, Hilden, Germany). Login to comment 55 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys A 243-bp fragment of exon 7 of the ABCA1 gene involving nucleotide 1051 of the DNA sequence was amplified by polymerase chain reac- tion (PCR), using the following primers: R219K Forward: 5`-tca taa tcc tct tct gct ag-3` and R219K Reverse: 5`-cag tta gca agt cta cgc a-3`. Login to comment 81 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Allele and genotype distributions of ABCA1 R219K polymorphism The genotype frequencies of the ABCA1 R219K polymorphism, determined for 627 participants, disclosed the following distribution: 36.4% (n=228), 50.4% (n=316) and 13.2% (n=83) for the RR, RK and KK genotypes, respectively. Login to comment 83 ABCA1 p.Arg219Lys Genotype distribution of the ABCA1 R219K polymorphism was in Hardy-Weinberg equilibrium for our study population. Login to comment 84 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Association of the ABCA1 R219K variant with biochemical variables We examined the relationship between concentrations of biochemical variables and the R219K polymorphism of the ABCA1 gene in a total of 627 individuals (men=282, women=345). Login to comment 87 ABCA1 p.Arg219Lys Determination of the R219K genotype by PCR amplification and restriction analysis. Login to comment 95 ABCA1 p.Arg219Lys In relation to TG concentration, but not to LDL-C and total cholesterol, the ABCA1 R219K polymorphism had significant gender-by-genotype interaction (p=0.049). Login to comment 102 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Associations of ABCA1 R219K polymorphism with CHD risk We investigated the distribution of the clinical and biochemical characteristics of genotypes of R219K polymorphism in the CHD and there were no significant associations (data not shown). Login to comment 103 ABCA1 p.Arg219Lys The allele and genotype frequencies of R219K polymorphism were examined in 220 cases of CHD and 407 without CHD. Login to comment 106 ABCA1 p.Arg219Lys Frequencies of ABCA1 R219K genotypes (RR, RK and KK) were 25.5% (n=27), 64.1% (n=68) and 10.4% (n=11) in women with CHD (p=0.012) and 40.4% (n=46), 44.7% (n=51) and 14.9% (n=17) in men with CHD (p=0.53), respectively. Login to comment 107 ABCA1 p.Arg219Lys In relation to CHD, the ABCA1 R219K polymorphism had significant gender-by-genotype interaction (p=0.009). Login to comment 108 ABCA1 p.Arg219Lys The R219K polymorphism was found to be associated with CHD only in women using the chi-square test. Login to comment 110 ABCA1 p.Arg219Lys Further analyses adjusted by genetic models of R219K polymor- Variables Males (n) Females (n) **P Age, years 58.9&#b1;12.8 (282) 56.7&#b1;12.3 (345) 0.03 Body mass index, kg/m2 27.7&#b1;4.4 (213) 30.6&#b1;5.9 (361) <0.001 Waist circumference, cm 96.3&#b1;11.9 (267) 94&#b1;13.7 (330) 0.037 Total cholesterol, mg/dL 184&#b1;43.8 (272) 194.5&#b1;42.5 (335) 0.003 HDL-C, mg/dL 43.3&#b1;12.7 (272) 49.7&#b1;12 (337) <0.001 LDL-C, mg/dL 107.2&#b1;34.5 (259) 111.6&#b1;34.2 (307) 0.132 Fasting triglycerides, mg/dL* 136.1&#b1;1.75 (270) 135.8&#b1;1.71 (332) 0.966 Fasting glucose, mg/dL 109.6&#b1;44.4 (259) 105.2&#b1;40.8 (330) 0.218 Apolipoprotein A-I, mg/dL 133.8&#b1;24.1 (156) 145.4&#b1;27.4 (200) <0.001 Apolipoprotein B, mg/dL 97.1&#b1;27.5 (157) 101.7&#b1;26 (204) 0.105 Systolic blood pressure, mmHg 121.0&#b1;21.9 (267) 128.2&#b1;23.6 (332) 0.01 Diastolic blood pressure, mmHg 76.6&#b1;11.7 (267) 78.8&#b1;11.9 (332) 0.026 Diabetes mellitus, %(n) 19.9 (56) 17.7 (61) 0.486 Obesity, %(n) 27.2 (58) 52.1 (136) <0.001 Coronary heart disease, %(n) 40.4 (114) 30.7 (106) 0.011 Cigarette smoking, %(n) 28.9 (77) 14.2 (47) <0.001 Alcohol usage, %(n) 10.2 (27) 1.2 (4) <0.001 Lipid-lowering medication, %(n) 9.9 (28) 10.7 (37) 0.745 Antihypertensive medication, %(n) 30.1 (85) 38.3 (132) 0.034 Medication for diabetes, %(n) 13.1 (37) 12.8 (44) 0.892 Continuous variables are presented as mean&#b1;SD and dichotomous variables as percentages. Login to comment 114 ABCA1 p.Arg219Lys In logistic regression analysis, after adjusting for age, current smoking, alcohol usage, waist circumference, TG, systolic blood pressure and diabetes, the overdominant genetic model (RK genotype vs the RR+KK genotypes) of R219K polymorphism showed significantly higher odd ratios for CHD in women [OR 1.95 (95%CI 1.003.80, p=0.059)] (Table 4, model 1). Login to comment 117 ABCA1 p.Arg219Lys The analysis after adjustment for the same covariates by a recessive genetic model for R219K polymorphism showed no association with CHD in women (OR=0.57, 95%CI; 0.21-1.55, p= 0.27). Login to comment 118 ABCA1 p.Arg219Lys Discussion The ABCA1 gene R219K polymorphism, shown to be related to serum lipids, displayed a sex interaction in a nested case-control sample of Turkish adults with respect to both lipid levels and the CHD risk. Login to comment 121 ABCA1 p.Arg219Lys Female R219K heterozygosity constituted a significant independent factor doubling the CHD risk which could be demonstrated to an interaction of the R219 allele with triglyceride elevation induced by the 219K allele. Login to comment 123 ABCA1 p.Arg219Lys Among other ABCA1 polymorphisms, R219K variant`s association with HDL-C was examined by Hodoglugil at el. (10) on a large sample of Turkish adults, and an association was lacking in men (as well as in women in whom this was confirmed herein). Login to comment 126 ABCA1 p.Arg219Lys p values obtained by ANCOVA for comparisons p* among R219K genotypes, p** RR genotype versus K allele carriers (RK+KK genotypes). Login to comment 127 ABCA1 p.Arg219Lys In relation to TG (not to LDL-C and total cholesterol) concentrations; the ABCA1 R219K polymorphism had gender-by-genotype interaction (p=0.049). Login to comment 135 ABCA1 p.Arg219Lys Interaction between ABCA1 R219K, elevated TG and sex The finding of 219K allele carriage being independently associated with higher TG concentration in women can be accounted for by serum TG being strong independent covariate of total phospholipids (30) and the knowledge that dietary long-chain polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid contribute to plasma phospholipids more in women than men, and mainly in populations with low dietary n-3 fatty acid intake (30, 31) to which Turks belong. Login to comment 142 ABCA1 p.Arg219Lys On the other hand, Villard et al. (35) reported that R219K polymorphism significantly modulates the capacity of whole-plasma to mediate cholesterol efflux from human macrophages in a sex-dependent manner. Login to comment 143 ABCA1 p.Arg219Lys Furthermore, Villard et al. (35) demonstrated impact of the R219K on plasma total cholesterol, LDL-C and Apo A-I concentrations but not HDL-C and TG concentrations in men or women subjects. Login to comment 146 ABCA1 p.Arg219Lys A recent meta-analysis demonstrated ethnic differences in the protective and risk conferring alleles of the ABCA1 R219K polymorphism for CHD (12). Login to comment 151 ABCA1 p.Arg219Lys In relation to CHD, the ABCA1 R219K polymorphism had significant gender-by-genotype interaction (p=0.009). Login to comment 155 ABCA1 p.Arg219Lys Multiple logistic regression analysis for the adjusted association of ABCA1 R219K variant with CHD in men and women According to a proposed a novel hypothesis on systemic inflammation, oxidized phospholipids and fatty acids metabolized from arachidonic acid affect endothelial and small intestinal cells to induce cytokines that influence macrophages or hepatocytes (37). Login to comment 158 ABCA1 p.Arg219Lys Thus, inflammation and oxidized phospholipids are closely linked to ABCA1 R219K polymorphism, gender and CHD risk. Login to comment 160 ABCA1 p.Arg219Lys Focusing on the effect of ABCA1 R219K polymorphism, without assessing the combined effect of other interacting genetic factors on analyses might limit the interpretation of our study. Login to comment 167 ABCA1 p.Arg219Lys Genotyping for the ABCA1 R219K polymorphism might yield practical benefit in prevention. Login to comment 168 ABCA1 p.Arg219Lys Conclusion In conclusion, R219K polymorphism as a common ABCA1 variant influences lipid concentrations and the CHD risk gender-specifically among Turkish adults. Login to comment