Amish Population Research Articles

Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population.

In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p=0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes.

Umweltmikrobiom

Es gibt immer mehr Hinweise aus epidemiologischen und tierexperimentellen Studien, dass das Mikrobiom ein wichtiger Faktor fur die Entstehung von Asthma bronchiale und Allergien sein konnte. Diese Studien beruhen auf neuen DNA-basierten Sequenzierungstechniken, die einen tiefen Einblick in die mikrobielle Vielfalt in unserer Umwelt und auf bzw. in unseren Korperoberflachen erlauben. Das Umweltmikrobiom in Innenraumen wird zu einem grosen Teil aus der auseren Umwelt definiert, aber zu einem wesentlichen Teil auch durch das Mikrobiom seiner humanen und tierischen Einwohner bestimmt. Dass das Umweltmikrobiom eine wesentliche Rolle bei der Entstehung von Asthma und Allergien spielen kann, geht am deutlichsten aus den Bauernstudien hervor. Diese haben wiederholt einen erheblichen Schutz vor der Entstehung dieser Krankheiten bei den Kindern gezeigt, die eine hohe mikrobielle Exposition aufweisen. Dabei hat es den Anschein, dass es nicht einzelne Keime sind, die dies bewirken, sondern vielmehr ein mikrobieller Cocktail aus Umweltbakterien und -schimmelpilzen. Der starkste Schutz findet sich bei Kindern der Amischen, die eine sehr traditionelle Landwirtschaft betreiben. In dieser Bevolkerungsgruppe ist der Heuschnupfen eine Raritat, die allergische Sensibilisierung etwa 6‑mal seltener als bei Stadtkindern in Deutschland, und virusinduzierte obstruktive Bronchitiden ohne Progression in ein allergisches Asthma herrschen vor.

Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish.

Alleles associated with lower levels of LDL cholesterol (LDL-C) have recently been associated with an increased risk of type 2 diabetes (T2D), highlighting the complex relationship between LDL-C and diabetes. This observation begs the question of whether LDL-C-raising alleles are associated with a decreased risk of T2D. This issue was recently addressed in a large familial hypercholesterolemia (FH) screening study, which reported a lower prevalence of self-reported diabetes in FH subjects than in age-matched relatives without FH. To extend this observation, we tested the association of FH with diabetes status and glycemia in a large Amish population enriched for the FH-associated APOB R3527Q variant that included 640 APOB R3527Q carriers and 4,683 noncarriers. Each copy of the R3527Q T allele was associated with a 74.9 mg/dL increase in LDL-C. There was little difference in T2D prevalence between subjects with (5.2%) and without (4.5%) the R3527Q allele (P = 0.23), and there was no association between R3527Q variant and impaired fasting glucose, fasting glucose or insulin, or oral glucose tolerance test-derived measures. Our data provide no evidence supporting an association between the APOB R3527Q variant and T2D or glycemia and highlight the asymmetry of the LDL-C-T2D relationship and/or the gene/variant-dependent specificity of the LDL-C-T2D association.

Evaluation of low immunization coverage among the Amish population in rural Ohio

The Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Review included childhood immunizations among the 10 great public health achievements in the United States in the 20th century. Despite this acknowledged success, childhood immunization rates continue to be much lower in select populations. Amish communities have persistently lower immunization rates. Recent outbreaks in Amish communities include a 2014 measles outbreak in Ohio, resulting in 368 cases reported. A recent outbreak of pertussis in an Amish community in Ohio resulted in the death of a 6-week-old Amish baby. A study was designed to determine the knowledge, beliefs, attitudes, and opinions of Amish parents relative to the immunization of Amish children. Data were collected through a questionnaire. Each potential participant was mailed a copy of a letter describing the proposed study. The questionnaire, a copy of the current immunization schedule, and a return stamped envelope were also included in the mailed packet. The study sample consisted of 84 Amish individuals who voluntarily filled out and returned questionnaires. The findings from the data analysis demonstrated that fear, especially concern over too many recommended immunizations and immunizations overwhelming the child's system, was the most frequent reported reasons for not having children immunized according to recommendations. Religious factors and access to care were not among reasons most reported. Designing an educational campaign for educating Amish parents on the risks and benefits of immunizations with focus on specific concerns may improve immunization rates.

Symptom profiles and illness course among Anabaptist and Non-Anabaptist adults with major mood disorders.

BackgroundAnabaptists comprise large and growing Amish and Mennonite populations with a unique genetic heritage and cultural background. Little is known about the symptoms and course of major mood disorders in Anabaptists. Even less is known about the impact of potential moderators on symptom severity and course.MethodsA sample of Amish and Mennonite participants with bipolar, recurrent unipolar, or schizoaffective bipolar disorder (n = 155) were systematically evaluated with a well-validated instrument. Cases were compared with non-Anabaptist participants (n = 155) matched for age, sex, and psychiatric diagnosis and evaluated by the same methods.ResultsDespite substantial cultural differences, the profile of manic and depressive symptoms during illness episodes did not significantly differ between the two groups. Alcohol use disorder (AUD) was significantly less frequent among Anabaptists, and was associated with more major depressive episodes and more hospitalizations for major depression in Anabaptist, but not non-Anabaptist participants. Lifetime history of head injury showed a trend toward association with more episodes of major depression in both Anabaptist and non-Anabaptist groups that did not withstand multiple test correction.ConclusionsThe presentation of a highly heritable psychiatric illness such as bipolar disorder does not differ in cases drawn from genetically unique Anabaptist populations. However, alcohol comorbidity, head injury, and their effects on illness course suggest some differences that deserve further investigation.

Injury risks for on-road farm equipment and horse and buggy crashes in Pennsylvania: 2010–2013

ABSTRACTObjective: The purpose of this study was to investigate characteristics associated with farm equipment and horse and buggy roadway crashes in relation to person, incident, and injury characteristics to identify appropriate points for injury incident prevention.Methods: Information on crashes occurring on public roads during the years 2010–2013 was obtained from the Pennsylvania Department of Transportation (PennDOT) and analyzed.Results: There were 344 farm equipment and 246 horse and buggy crashes during the 4-year study period. These crashes involved 666 and 504 vehicles and 780 and 838 people, respectively. In incidents with farm equipment, the non-farm equipment drivers had an almost 2 times greater injury risk than farm equipment operators. Horse and buggy crashes were almost 3 times more injurious to the horse and buggy drivers than the drivers of the other vehicles.Conclusions: The average crash rate for farm equipment was 198.4 crashes per 100,000 farm population and for horse and buggy the crash rate was calculated as 89.4 crashes per 100,000 Amish population per year. This study suggests that road safety and public health programs should focus not only on farm equipment operators and horse and buggy drivers but on other motorists sharing the roadway with them.

Mitochondrial respiratory chain disorders in the Old Order Amish population.

The Old Order Amish populations in the US are one of the Plain People groups and are descendants of the Swiss Anabaptist immigrants who came to North America in the early eighteenth century. They live in numerous small endogamous demes that have resulted in reduced genetic diversity along with a high prevalence of specific genetic disorders, many of them autosomal recessive. Mitochondrial respiratory chain deficiencies arising from mitochondrial or nuclear DNA mutations have not previously been reported in the Plain populations. Here we present four different Amish families with mitochondrial respiratory chain disorders. Mutations in two mitochondrial encoded genes leading to mitochondrial respiratory chain disorder were identified in two patients. In the first case, MELAS syndrome caused by a mitochondrial DNA (mtDNA) mutation (m.3243A>G) was identified in an extended Amish pedigree following a presentation of metabolic strokes in the proband. Characterization of the extended family of the proband by a high resolution melting assay identified the same mutation in many previously undiagnosed family members with a wide range of clinical symptoms. A MELAS/Leigh syndrome phenotype caused by a mtDNA mutation [m.13513G>A; p.Asp393Asn] in the ND5 gene encoding the ND5 subunit of respiratory chain complex I was identified in a patient in a second family. Mutations in two nuclear encoded genes leading to mitochondrial respiratory chain disorder were also identified in two patients. One patient presented with Leigh syndrome and had a homozygous deletion in the NDUFAF2 gene, while the second patient had a homozygous mutation in the POLG gene, [c.1399G>A; p.Ala467Thr]. Our findings identify mitochondrial respiratory chain deficiency as a cause of disease in the Old Order Amish that must be considered in the context of otherwise unexplained systemic disease, especially if neuromuscular symptoms are present.

Three cases of Troyer syndrome in two families of Filipino descent.

Troyer syndrome is a complex hereditary spastic paraplegia (HSP) due to a mutation in SPG20 first reported in the Old Amish population. A genetic mutation in SPG20 is responsible for a loss of function of the protein spartin in this disease. Since its initial report, this syndrome has also been reported in Turkish and Omani families. Here we report the case of three patients of Filipino descent with Troyer syndrome. Whole exome sequencing (WES) identified a homozygous mutation c.364_365delAT which predicts p.Met122Valfs*2 in SPG20. This is the same mutation identified in affected patients from the Omani and Turkish families, and is the first report of this syndrome in the Filipino population. Although Troyer syndrome has characteristic phenotypic manifestations it is likely underdiagnosed due to its rarity and we expect that WES will lead to identifying this disease in other individuals. © 2016 Wiley Periodicals, Inc.

Amish Culture and Their Utilization of Burns and Wounds Ointment for the Treatment of Burns.

As indicated in the 2010 United States Religion Census, there are approximately 251,000 Amish people in the United States and Ontario. This census also demonstrated that a new Amish community is founded on average about every three-and-a-half weeks, suggesting that this religious culture is the fastest-growing religion throughout the United States. Because of the rapid growth of the Amish population, it is essential for health care workers to understand their background, cultural, and health care beliefs, especially in the treatment of burns. The purpose of this article is to examine the Amish background, cultural, and health care beliefs, specifically the utilization of burns and wounds ointment and burdock leaves in the treatment of burns.

The microbial environment and its influence on asthma prevention in early life

There is accumulating evidence to suggest that the environmental microbiome plays a significant role in asthma development. The very low prevalence of asthma in populations highly exposed to microbial environments (farm children and Amish populations) highlights its preventive potential. This microbial diversity might be necessary to instruct a well-adapted immune response and regulated inflammatory responses to other inhaled and ingested environmental elements, such as allergens, particles, and viruses. Like the internal gut microbiome, which is increasingly recognized as an important instructor of immune maturation, the external environmental microbiome might shape immune responses on the skin, airway mucosal surfaces, and potentially also the gut early in life. The diversity of the external microbial world will ensure that of the many maladapted pathways leading to asthma development, most, if not all, will be counterbalanced. Likewise, important contributors to asthma, such as allergen sensitization and allergic manifestations early in life, are being suppressed. Thus the facets of innate immunity targeted by microbes and their compounds and metabolites might be the master switch to asthma and allergy protection, which has been found in environments rich in microbial exposures.

What Kinds of Places Attract and Sustain Amish Populations?

AbstractThe Amish are one of the fastest growing ethnoreligious groups in rural America. They are not only growing in historic settlements but are also starting new settlements. This study synthesizes and tests hypotheses about Amish migration destinations and settlement sustainability. Specifically, hypotheses address factors related to population, agriculture, and proximity to other Amish. Findings suggest that the locations Amish settle have several defining characteristics including: low population density, nonmetropolitan county designation, context conducive to small‐scale farming (e.g., low farm acreage price, moderately rolling hills), vicinity to a small commercial center, low to negative population growth, and proximity to an existing Amish settlement. Some characteristics are showing increasing flexibility, such as a small‐scale farming context and proximity to a commercial center. Conversely, settling in areas with a growing population or at a distance from another Amish settlement contributes to a higher likelihood of community dissolution.

Heritability of complex white matter diffusion traits assessed in a population isolate.

Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries. Using Old Order Amish (OOA) population isolate with large family pedigrees and high environmental homogeneity, we compared the heritability of measures derived from three representative DWI methods targeting the corpus callosum WM and cingulate gyrus GM: diffusion tensor imaging (DTI), the permeability-diffusivity (PD) model, and the neurite orientation dispersion and density imaging (NODDI) model. These successively more complex models represent the diffusion signal modeling using one, two, and three diffusion compartments, respectively. We replicated the high heritability of the DTI-based fractional anisotropy (h(2) = 0.67) and radial diffusivity (h(2) = 0.72) in WM. High heritability in both WM and GM tissues were observed for the permeability-diffusivity index from the PD model (h(2) = 0.64 and 0.84), and the neurite density from the NODDI model (h(2) = 0.70 and 0.55). The orientation dispersion index from the NODDI model was only significantly heritable in GM (h(2) = 0.68). DWI measures from multicompartmental models were significantly heritable in WM and GM. DWI can offer valuable phenotypes for genetic research; and genes thus identified may reveal mechanisms contributing to mental and neurological disorders in which diffusion imaging anomalies are consistently found. Hum Brain Mapp 37:525-535, 2016. © 2015 Wiley Periodicals, Inc.

MG-137 Autosomal recessive disorders are common in the old order amish population of southwestern ontario

Background The Old Order Amish in Milverton, Ontario, represent a genetically isolated group which originated with 12 founding families in 1824. Due to inbreeding and founder effect, certain genetic disorders have become highly prevalent in Ontario Amish. Objective This study aims to describe the spectrum of genetic disorders observed in the Old Order Amish of Southwestern Ontario (population size ˜ 2500). Design and method Over the past 25 years, we have documented the clinical phenotype, and molecular aetiology of genetic disorders in Old Order Amish children. Results A disorder characterised by acute encephalopathy with fever, visual hallucinations, hearing loss, and retinal dystrophy was observed in 7 out of about 220 families, caused by mutation in the histidyl t-RNA synthetase (HARS) gene. Acute respiratory distress syndrome may lead to sudden death. This disorder was first reported in the Amish in Pennsylvania. Other disorders observed in the Ontario Amish but not in American Amish include endocrine-osteodysplasia syndrome (ICK), cerebral atrophy (TMPRSS4), cystinosis (CTNS), sodium diarrhoea (SPINT2), juvenile-onset glaucoma (CYP1B1), epidermolysis bullosa simplex, and Fraser syndrome (FRAS1). Lethal disorders include a central hypoventilation syndrome, a disorder with oligohydramnios and renal hypoplasia, and ichthyosis-microcephaly. In total, the causative mutations have been found for 8 disorders, while another 5 disorders are presumed autosomal recessive. Knowledge of these disorders enabled molecular diagnosis of a child affected concurrently with two conditions within 5 days of birth. Conclusion Awareness of genetic disorders common in this population will aid in early diagnosis and management, and avoid the diagnostic odyssey.

Mitochondrial respiratory chain disorders in the old order Amish population

Mitochondrial respiratory chain disorders in the old order Amish population

Doubling Time and Population Increase of the Amish

Current estimates of Amish population growth often cite a “doubling time” figure, but fail to substantiate the source from which the estimate was derived. As well, some estimates of population increase, such as by the Young Center for Anabaptist and Pietist Studies at Elizabethtown College, use net change in the number of church districts as a proxy to determine population change, rather than a more precise counting up of children and adults. Unfortunately, a direct “head count” of the Amish, and changes in this count overtime to create a doubling time estimate, would be very daunting, Until there is a valid database from which this can be accomplished, an alternative is to calculate doubling time based on net change in the number of households in various Amish settlements from one year to the next. In this article, end-of-year statistics submitted by scribes from hundreds of Amish settlements to a monthly periodical known as The Diary are used to estimate doubling time. Five time periods, each representing consecutive years from 2009 through 2014 for which the number of households for the same settlement is reported, are used to create a doubling time estimate. Altogether, there were 673 data-points for which consecutive year information about the same settlement was available. The article discusses possible limitations to using The Diary and households to calculate a doubling time, as well as the possible uses of an accurate doubling time estimate for research and

Transcription of the Human Microsomal Epoxide Hydrolase Gene (EPHX1) Is Regulated by PARP-1 and Histone H1.2. Association with Sodium-Dependent Bile Acid Transport.

Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in the metabolism of numerous xenobiotics as well as mediating the sodium-dependent transport of bile acids into hepatocytes. These compounds are involved in cholesterol homeostasis, lipid digestion, excretion of xenobiotics and the regulation of several nuclear receptors and signaling transduction pathways. Previous studies have demonstrated the critical role of GATA-4, a C/EBPα-NF/Y complex and an HNF-4α/CAR/RXR/PSF complex in the transcriptional regulation of the mEH gene (EPHX1). Studies also identified heterozygous mutations in human EPHX1 that resulted in a 95% decrease in mEH expression levels which was associated with a decrease in bile acid transport and severe hypercholanemia. In the present investigation we demonstrate that EPHX1 transcription is significantly inhibited by two heterozygous mutations observed in the Old Order Amish population that present numerous hypercholanemic subjects in the absence of liver damage suggesting a defect in bile acid transport into the hepatocyte. The identity of the regulatory proteins binding to these sites, established using biotinylated oligonucleotides in conjunction with mass spectrometry was shown to be poly(ADP-ribose)polymerase-1 (PARP-1) bound to the EPHX1 proximal promoter and a linker histone complex, H1.2/Aly, bound to a regulatory intron 1 site. These sites exhibited 71% homology and may represent potential nucleosome positioning domains. The high frequency of the H1.2 site polymorphism in the Amish population results in a potential genetic predisposition to hypercholanemia and in conjunction with our previous studies, further supports the critical role of mEH in mediating bile acid transport into hepatocytes.

A rare case report of Ellis Van Creveld syndrome in an Indian patient and literature review

Ellis Van Creveld syndrome (EVC) is a rare genetic disorder having autosomal recessive inheritance affecting the Amish population of Pennsylvania in USA with incidence of 1:244,000 for the general population. This syndrome consists of characteristic features such as bilateral postaxial polydactyly, chondroectodermal dysplasia, congenital heart defects and hypoplastic nails and teeth. There are few case reports of this syndrome reported in dental literature. We report a case of a 17 year old female presenting typical features of this syndrome and the oral findings of this patient which are the key diagnostic features.

Cartilage hair hypoplasia: characteristics and orthopaedic manifestations.

PurposeCartilage hair hypoplasia (CHH) is a rare metaphyseal chondrodysplasia characterized by short stature and short limbs, found primarily in Amish and Finnish populations. Cartilage hair hypoplasia is caused by mutations in the RMRP gene located on chromosome 9p13.3. The disorder has several characteristic orthopaedic manifestations, including joint laxity, limited elbow extension, ankle varus, and genu varum. Immunodeficiency is of concern in most cases. Although patients exhibit orthopaedic problems, the orthopaedic literature on CHH patients is scant at best. The objective of this study was to characterize the orthopaedic manifestations of CHH based on the authors’ unique access to the largest collection of CHH patients ever reported.MethodsThe authors examined charts and/or radiographs in 135 cases of CHH. We analyzed the orthopaedic manifestations to better characterize and further understand the orthopaedic surgeon’s role in this disorder. In addition to describing the clinical characteristics, we report on our surgical experience in caring for CHH patients.ResultsGenu varum, with or without knee pain, is the most common reason a patient with CHH will seek orthopaedic consultation. Of the cases reviewed, 32 patients had undergone surgery, most commonly to correct genu varum.ConclusionThis paper characterizes the orthopaedic manifestations of CHH. Characterizing this condition in the orthopaedic literature will likely assist orthopaedic surgeons in establishing a correct diagnosis and appreciating the orthopaedic manifestations. It is important that the accompanying medical conditions are appreciated and evaluated.Electronic supplementary materialThe online version of this article (doi:10.1007/s11832-015-0646-z) contains supplementary material, which is available to authorized users.

Association of OCT derived drusen measurements with AMD associated-genotypic SNPs in Amish population.

Purpose: To investigate the association of optical coherence tomography (OCT)-derived drusen measures in Amish age-related macular degeneration (AMD) patients with known loci for macular degeneration. Methods: Members of the Old Order Amish community in Pennsylvania ages 50 and older were assessed for drusen area, volume and regions of retinal pigment epithelium (RPE) atrophy using a Cirrus High-Definition OCT. Measurements were obtained in the macula region within a central circle (CC) of 3 mm in diameter and a surrounding perifoveal ring (PR) of 3 to 5 mm in diameter using the Cirrus OCT RPE analysis software. Other demographic information, including age, gender and smoking status, were collected. Study subjects were further genotyped to determine their risk for the AMD-associated SNPs in the SYN3, LIPC, ARMS2, C3, CFB, CETP, CFI and CFH genes using TaqMan genotyping assays. The association of genotypes with OCT measures were assessed using linear trend p-values calculated from univariate and multivariate generalized linear models. Results: 432 eyes were included in the analysis. Multivariate analysis (adjusted by age, gender and smoking status) confirmed the known significant association between AMD and macular drusen with the number of CFH risk alleles for the drusen area (the area increased 0.12 mm2 for a risk allele increase, p < 0.01), drusen volume (the volume increased 0.01 mm3 for a risk allele increase, p ≤ 0.05) and the area of RPE atrophy (the area increased 0.43 mm2 for a risk allele increase, p = 0.003). SYN3 risk allele G is significantly associated with larger area PR (the area increased 0.09 mm2 for a risk allele increase, p = 0.03) and larger drusen volume in the central circle (the volume increased 0.01 mm3 for a risk allele increase, p = 0.04). Conclusion: Among the genotyped SNPs tested, the CFH risk genotype appears to play a major role in determining the drusen phenotype in the Amish AMD population.

Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics.

Despite ample success in reducing coronary artery disease (CAD) risk through reduction of low-density lipoprotein cholesterol (LDL-C), there remains substantial residual risk.1–4 Recent prospective studies have demonstrated that elevated triglycerides (TGs) are independent predictors of CAD risk.5–9 Furthermore, TGs are strongly associated with incident CAD events in patients with low LDL-C levels treated with statin.10 Thus, triglyceride-rich lipoproteins (TRLs) offer a potentially orthogonal risk factor to LDL-C for lowering CAD risk, but only if TRLs are causally associated with atherosclerotic disease.11 Human genetics has the potential to reveal the causal relationships of biomarkers found to be associated with disease outcomes.12–15 For example, genetic variants associated with plasma LDL-C levels are consistently associated with CAD risk in the right direction,15–18 consistent with a causal relationship. Importantly, similar studies have causally implicated the key TG-regulating enzyme lipoprotein lipase (LPL) in CAD risk. A common gain-of-function LPL variant, S447X, confers an antiatherogenic lipid profile characterized by low levels of TGs, and in several studies, it has been associated with lower incidence of vascular disease or myocardial infarction (MI).19–25 Conversely, several loss-of-function (LOF) LPL variants associated with elevated TG levels have been reported to be associated with increased CAD risk.21,26 Furthermore, multiple genome-wide association studies in the last 5 years have identified common noncoding variants at the LPL gene locus associated with both TG and CAD risk in the same direction.27–29 Beyond LPL itself, common variants that influence TG levels are significantly associated with CAD risk even after adjusting for their effects on other lipid traits.30 Do et al30 surveyed 185 single-nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with ≥1 plasma lipid trait and identified a subset of …