ABCMdb

PMID: 23241408

Horenstein RB, Mitchell BD, Post WS, Lutjohann D, von Bergmann K, Ryan KA, Terrin M, Shuldiner AR, Steinle NI
The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish.
Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):413-9. doi: 10.1161/ATVBAHA.112.245480. Epub 2012 Dec 13., [PubMed]

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13 ABCG8 p.Gly574Arg Methods and Results-In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Login to comment 16 ABCG8 p.Gly574Arg The G574R variant was not associated with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels. Login to comment 19 ABCG8 p.Gly574Arg Conclusion-Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.ߒ Èa;Èa;(Arterioscler Thromb Vasc Biol. Login to comment 21 ABCG8 p.Gly574Arg Key Words: ABC transporter fc; atherosclerosis fc; lipids fc; plant sterols fc; sitosterol The ABCG8 G574R Variant, Serum Plant Sterol Levels, and Cardiovascular Disease Risk in the Old Order Amish Richard B. Horenstein, Braxton D. Mitchell, Wendy S. Post, Dieter L&#fc;tjohann, Klaus von Bergmann, Kathleen A. Ryan, Michael Terrin, Alan R. Shuldiner, Nanette I. Steinle Simvastatin Survival Study, individuals within the upper quartile of campesterol:cholesterol ratios were more likely to require statin titration and less likely to receive risk reduction from simvastatin.8,9 It has also been reported that postmenopausal women with heart disease had higher phytosterol concentrations than their respective controls.10 In the Prospective Cardiovascular M&#fc;nster Study, sitosterol concentrations were associated with increased risk of major coronary events in men at high risk of coronary heart disease.11 By contrast, Silbernagel found no association between increased absorption of plant sterol levels and coronary disease,12 nor were elevated levels of plant sterol associated with atherosclerosis in middle-aged men and women in the Dallas Heart Study.13 The potential role of plant sterols in CVD pathogenesis has become a topic of clinical interest with the finding that long-term high dose HMG-CoA reductase inhibitor (statin) use increases plasma plant sterol levels,9 and that ezetimibe, a drug used to block intestinal absorption of sterols, lowers plasma plant sterol levels.14 The prevalent use of plant sterol-enriched foods (eg, stanol margarines) to lower low-density lipoprotein cholesterol (LDL-C) levels adds to the interest in the relation of phytosterols and CVD risk. Login to comment 22 ABCG8 p.Gly574Arg ABCG8 p.Gly574Arg Sitosterolemia was initially identified in 2 sisters of Amish-Mennonite background,15 and the disease was further characterized in additional members of the Amish, including in a 13-year-old boy from the Old Order Amish community in Lancaster County, Pennsylvania who died from coronary artery disease.16 The disease in the boy resulted from a single-nucleotide change, at position 574 in ABCG8, leading to an amino acid substitution from glycine to arginine (Gly574Arg, or G574R; rs137852988). Login to comment 23 ABCG8 p.Gly574Arg Because of the unique ancestral background of the Lancaster County Amish, we hypothesized that this community would have multiple members who are heterozygous for 1 copy of the ABCG8 mutation, and that these individuals would demonstrate moderate elevations in plasma plant sterols and mildly accelerated atherosclerosis. We sought to identify individuals heterozygous for the ABCG8 G574R mutation to further study the role of plant sterols in CVD and to evaluate the association of the carrier or heterozygous status, with subclinical atherosclerosis as assessed by ultrasound measurement of carotid artery intima-media wall thickness (IMT). Login to comment 24 ABCG8 p.Gly574Arg Methods Subjects and Study Design We screened banked DNA samples from 984 participants from our ongoing studies of complex genetic diseases and traits in the Lancaster County Amish17-19 to identify carriers for the ABCG8 G574R mutation and then recruited family members of these individuals to increase the yield of carriers. Login to comment 57 ABCG8 p.Gly574Arg We then recruited 290 family members of these carriers of whom 99 were carriers, thereby increasing our yield to 114 G574R heterozygote carriers, 190 noncarriers, and 1 574R homozygote. Login to comment 62 ABCG8 p.Gly574Arg Thus the final sample included 110 G574R heterozygote carriers and 181 noncarriers. Login to comment 81 ABCG8 p.Gly574Arg ABCG8 p.Gly574Arg Table 1.ߓ Mean Lipid Levels (&#b1;SE) and Baseline Characteristics of Old Order Amish ABCG8 G574R Variant Heterozygotes and Noncarriers (G574G) G574R Heterozygotes (n=110) G574G (n=181) Age, Sex, and BMI-Adjusted Pߙߙ* Age, y 42.2&#b1;2.0 47.2&#b1;1.7 0.01 Sex, % male 45.5 51.9 0.14 BMI, kg/m2 25.8&#b1;0.6 26.5&#b1;0.5 0.22 Total cholesterol, mg/dL 212&#b1;5.8 217&#b1;5.7 0.40 HDL-cholesterol, mg/dL 49.7&#b1;1.7 51.2&#b1;1.5 0.39 LDL-cholesterol, mg/dL 148&#b1;5.4 149&#b1;5.2 0.89 Glucose, mg/dL 87.6&#b1;2.5 90.2&#b1;2.1 0.30 Systolic blood pressure, mmߕHg 123&#b1;1.9 124&#b1;1.5 0.54 Diastolic blood pressure, mmߕHg 75&#b1;1.1 76&#b1;0.9 0.18 Type 2 diabetes mellitus, % 1.8 3.3 >0.95 History of hypertension, % 5.7 14.4 0.17 History of heart surgery, % 0.0 2.3 0.19 History of MI, % 0.0 1.7 0.17 BMI indicates body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; and MI, myocardial infarction. Login to comment 83 ABCG8 p.Gly574Arg Because cIMT is strongly associated with aging, we assessed whether the association of the G574R variant with IMT was modified by age by including a single-nucleotide polymorphism &#d7; age interaction term in the model. Login to comment 85 ABCG8 p.Gly574Arg Discussion The Old Order Amish provide a unique opportunity to test the hypothesis that modestly elevated plant sterol levels are associated with increased subclinical atherosclerosis as the ABCG8 G574R mutation is enriched in this population and we were able to identify additional carriers through targeted recruitment of families. Login to comment 88 ABCG8 p.Gly574Arg The ABCG8 G574R variant present in the Lancaster Amish has been found in contemporary Switzerland.23 Haplotype analyses have revealed that the initial Amish index cases and the contemporary case identified in Switzerland share a common haplotype, consistent with a common ancestral source for this variant that originated in Switzerland (or before) and was carried to Pennsylvania by ࣙ1 emigrants in the early 1700s. Login to comment 93 ABCG8 p.Gly574Arg ABCG8 p.Gly574Arg ABCG8 p.Gly574Arg As our major conclusion from this study, we find no evidence to Table 2.ߓ Mean Levels (&#b1;SE) of Plant Sterols, Cholesterol Precursors, Sterol/Total Cholesterol Ratios in Old Order Amish ABCG8 G574R Variant Heterozygotes (G574R) and Noncarriers (G574G) G574R Heterozygotes (n=110) G574G (n=181) Age-and Sex-Adjusted P Plant sterols ߓ Sitosterol, mg/dL 0.47&#b1;0.02 0.34&#b1;0.02 <0.0001 ߓ Sitosterol/chol ratio* 2.13&#b1;0.07 1.52&#b1;0.06 <0.0001 ߓ Campesterol, mg/dL 0.60&#b1;0.03 0.44&#b1;0.03 <0.0001 ߓ Campesterol/chol ratio 2.72&#b1;0.10 1.97&#b1;0.08 <0.0001 ߓStigmasterol, bc;g/dL 16.29&#b1;0.84 12.06&#b1;0.79 <0.0001 ߓ Stigmasterol/chol ratio 0.07&#b1;0.003 0.05&#b1;0.003 <0.0001 ߓAvenasterol 1.65&#b1;0.09 1.20&#b1;0.08 <0.0001 ߓ Avena/chol ratio 7.47&#b1;0.40 5.43&#b1;0.35 <0.0001 ߓBrassicasterol, bc;g/dL 26.27&#b1;1.89 22.08&#b1;1.71 0.03 ߓ Brassicasterol/chol ratio 0.12&#b1;0.008 0.010&#b1;0.006 0.008 Proxy for cholesterol absorption ߓ Cholestanol, mg/dL 0.38&#b1;0.01 0.32&#b1;0.01 <0.0001 ߓ Cholestanol/chol ratio 1.75&#b1;0.04 1.45&#b1;0.03 <0.0001 Plant stanols ߓCampestanol, bc;g/dL 5.86&#b1;0.20 4.74&#b1;0.18 <0.0001 ߓ Campestanol/chol ratio 0.03&#b1;0.001 0.02&#b1;0.001 <0.0001 ߓSitostanol, bc;g/dL 7.80&#b1;0.28 6.39&#b1;0.25 <0.0001 ߓ Sitostanol/chol ratio, bc;g/mg 0.04&#b1;0.001 0.03&#b1;0.001 <0.0001 Markers of cholesterol synthesis ߓLanosterol, bc;g/dL 15.68&#b1;0.74 18.15&#b1;0.69 0.0009 ߓ Lanosterol/chol ratio 0.08&#b1;0.003 0.08&#b1;0.003 0.007 ߓ Lathosterol, mg/dL 0.20&#b1;0.01 0.24&#b1;0.01 <0.0001 ߓ Lathosterol/chol ratio 0.95&#b1;0.05 1.12&#b1;0.04 0.0006 ߓ Desmosterol, mg/dL 0.17&#b1;0.007 0.18&#b1;0.006 0.09 ߓ Desmosterol/chol ratio 0.78&#b1;0.03 0.82&#b1;0.03 0.15 Markers of bile acid synthesis ߓ7 b1; cholesterol 71.3&#b1;4.5 83.9&#b1;4.3 0.005 ߓ7 b1; cholesterol/chol ratio 0.33&#b1;0.02 0.38&#b1;0.02 0.02 *Chol indicates total cholesterol; and sitosterol/chol ratio, ratio of sitosterol to total cholesterol levels. Login to comment 96 ABCG8 p.Gly574Arg suggest that G574R carriers are at higher risk for subclinical atheroscelerosis in light of their moderately higher plant sterol levels. Login to comment 97 ABCG8 p.Gly574Arg Yet, our results offer an intriguing suggestion that G574R carriers may actually experience lower risk. Login to comment 110 ABCG8 p.Gly574Arg Mean (and SD) values of intima-media wall thickness (IMT, in mm) between ABCG8 G574R heterozygotes and G574G (noncarriers) (A) and carotid IMT values in heterozygotes and noncarriers by age (B). Login to comment 119 ABCG8 p.Gly574Arg In conclusion, our study presents the first data on a large cohort of carriers of the ABCG8 G574R variant. Login to comment