Assessing the Attitudes and Perceptions of the Old Order Amish toward Genetic Testing for Familial Defective Apolipoprotein B-100

Through a founder effect, one in eight Lancaster County, PA, Amish harbors the pathogenic APOB variant R3527Q, causing Familial Defective Apolipoprotein B-100 (FDB) that is rare in the general population. Affected individuals are at increased risk for high low density lipoprotein (LDL) cholesterol levels and cardiovascular disease and may benefit from early screening and treatment. A qualitative interview approach was used to investigate the genetic risk perceptions of the Amish and their attitudes towards genetic testing for FDB. The goal was to identify elements necessary for a successful program that would identify high risk individuals in the Lancaster County Amish community and provide them with potentially lifesaving education and interventions. Thirty interviews were conducted. Collected data were analyzed and coded for common themes. Participants perceived a great deal of importance in genetic risk and were aware of the significant impact genetics have on health. Most individuals perceived genetic risk as more significant than family history. Twenty-four of 30 individuals would consider testing; of these, all 24 reported they would take proactive measures to reduce risks if given a positive result. Most would prefer diet modification and natural health remedies, with prescription medication only as a last resort. Several participants stated that most Amish people would be unlikely to test if they were feeling healthy. Cost was the most significant barrier to pursuing testing. Implementing a successful screening program would require community outreach and awareness, risk reduction education and support, and minimal out-of-pocket expenses. The program’s success provides insights into the efficacy of predictive genetic screening for the general population. [Abstract by authors.

Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference

Background: Elevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure. Methods: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels. Results: Serum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01). Conclusions: Our findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity

Body Image and Life Satisfaction in Amish, Catholic, and Non-Religious Women

Dissatisfaction with one's appearance is commonplace in Western women. Body image dissatisfaction is believed to be a consequence of societal emphases on appearance reinforced through norms and media. However, some Amish cultural values and norms differ from prevailing Western influences, which may result in a rate of body image dissatisfaction at variance within women. The following pilot study explores how religious affiliation and religiosity may relate to body image factors (body dissatisfaction, appearance investment, and body image coping strategies) and life satisfaction in Amish (n = 32), Catholic (n = 40), and non-religious (n = 40) women. Results show that the Amish women reported having more positive body image on several factors than Catholic women, but the same results were not always replicated in non-religious women. Specifically, non-religious women showed similar levels of body satisfaction in comparison to Amish women, although they demonstrated use of different body image coping strategies. Additionally, when comparing women's reported current versus ideal figure, all women showed a preference for a thinner ideal. As this pilot study's methodology is preliminary, our ability to draw definitive conclusions is limited: future research should address these methodological limitations. If results from this study are confirmed, research is needed that examines the specific aspects of the Amish culture that may be associated with higher rates of body image satisfaction

Extent and distribution of linkage disequilibrium in the Old Order Amish

Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02–0.09, and for autosomal SNPs 10–20 kb apart with common alleles (minor allele frequency≥0.05), the LD measure r 2 was at least 0.8 for 15 and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA (∼88%) at r 2 ≥0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations. Genet. Epidemiol . 34: 146–150, 2010. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64895/1/20444_ftp.pd

Genetic variation of Glucose Transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) Study

<p>Abstract</p> <p>Background</p> <p>Evidence suggests glucose transporter-1(<it>GLUT1</it>) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six <it>GLUT1 </it>single nucleotide polymorphisms(SNPs), particularly <it>XbaI </it>and the previously associated <it>Enhancer-2(Enh2</it>) SNP.</p> <p>Methods</p> <p>A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio(ACR). Cases comprised albuminuria(N = 825; ≥ 30 μg/mg) and macroalbuminuria(N = 173; ≥ 300 μg/mg). ACR < 30 μg/mg classified controls(n = 9453). Logistic regression and odds ratios(OR) assessed associations. The evaluation phase(stage 1, n = 2938) tested associations of albuminuria(n = 305) with six <it>GLUT1 </it>SNPs: rs841839, rs3768043, rs2297977, <it>Enh2</it>(rs841847) <it>Xba</it>I(rs841853), and rs841858. <it>Enh2 </it>was examined separately in the replication phase(stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes.</p> <p>Results</p> <p>In European Americans, after adjusting for diabetes and other <it>GLUT1 </it>SNPs in stage 1, <it>Enh2 </it>risk genotype(TT) was more common in albuminuric cases(OR = 3.37, P = 0.090) whereas <it>XbaI </it>(OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the <it>Enh2 </it>association with albuminuria was significant among diabetic European Americans(OR = 2.36, P = 0.025). In African Americans, <it>Enh2 </it>homozygosity was rare(0.3%); <it>XbaI </it>was common(18.0% AA) and not associated with albuminuria. In stage 2(n = 7,340), <it>Enh2 </it>risk genotype had increased but non-significant OR among diabetic European Americans(OR = 1.66, P = 0.192) and not non-diabetics(OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, <it>Enh2 </it>was associated with albuminuria(OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria(OR 2.69, [1.02-7.09], P = 0.045) in diabetic European Americans. The <it>Enh2 </it>association with macroalbuminuria among non-diabetic European Americans with fasting insulin(OR = 1.84, P = 0.210) was stronger at the highest insulin quartile(OR = 4.08, P = 0.040).</p> <p>Conclusions</p> <p>As demonstrated with type 1 diabetic nephropathy, the <it>GLUT1 Enh2 </it>risk genotype, instead of <it>Xba</it>I, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the <it>Enh2 </it>risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role.</p

Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program

OBJECTIVE: We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo. RESEARCH DESIGN AND METHODS: Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end). RESULTS: Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, P$_{lifestyle*SNP}$ = 0.032; GNPDA2 rs10938397, P$_{lifestyle*SNP}$ = 0.016; MTCH2 rs10838738, P$_{lifestyle*SNP}$ = 0.022) and long-term (NEGR1 rs2815752, P$_{metformin*SNP}$ = 0.028; FTO rs9939609, P$_{lifestyle*SNP}$ = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (P$_{lifestyle*SNP}$ < 0.05). CONCLUSIONS: Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention

Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk

Background Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis. Methods and Results CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity ( p =0.03) and CIMT ( p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT. Conclusions Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences