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The purpose of this study was to assess the informational content, readability, suitability and comprehensibility of websites offering educational information about monogenic diabetes available to patients. The top 20 results from 15 queries in four search engines were screened. Content analysis was performed by two independent coders. Readability was determined using Flesch-Kincaid grade level (FKGL) and Simplified Measure of Goobledygook (SMOG). The Comprehensibility Assessment of Materials (SAM + CAM) scale was utilized to evaluate website suitability and comprehensibility. Only 2% (N = 29) of 1200 screened websites met inclusion criteria. Content analysis showed that 16 websites presented information on at least the most common forms of MODY (1, 2 and 3), four addressed the utility of genetic counseling, and none included support resources for patients. All websites exceeded the consensus readability level (6th grade) as assessed by FKGL (10.1 grade) and SMOG (12.8 ± 1.5 grades). Although the majority (N = 20) of websites had an overall "adequate" to "superior" quality score (SAM + CAM score > = 40%), more than one-third scored "not suitable" in categories of content, literacy demand, graphics, and learning motivation. The online educational resources for monogenic diabetes have a high readability level and require improvement in ease of use and comprehensibility for patients with diabetes.

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI)., Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI., Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights., Results: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60)., Conclusions: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis -expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants., Competing Interests: Conflict of interest statement: S.E.L., J. Laramie, and R.G.T. were employees of Complete Genomics during this study. T.M.T. is an employee of Regeneron Pharmaceuticals. D.A. is an employee of Vertex Pharmaceuticals.

Background: Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization., Methods and Results: Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; P =3.5×10 -11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ≈7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5 . The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (β=-0.92±0.059 SD unit; P =9.6×10 -55 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null., Conclusions: APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants., (© 2017 American Heart Association, Inc.)

Background: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility., Methods: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches., Results: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years., Conclusions: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that accounts for at least 1 % of all cases of diabetes mellitus. MODY classically presents as non-insulin-requiring diabetes in lean individuals typically younger than 25 with evidence of autosomal dominant inheritance, but these criteria do not capture all cases and can also overlap with other diabetes types. Genetic diagnosis of MODY is important for selecting the right treatment, yet ~95 % of MODY cases in the USA are misdiagnosed. MODY prevalence and characteristics have been well-studied in some populations, such as the UK and Norway, while other ethnicities, like African and Latino, need much more study. Emerging next-generation sequencing methods are making more widespread study and clinical diagnosis increasingly feasible; at the same time, they are detecting other mutations in the same genes of unknown clinical significance. This review will cover the current epidemiological studies of MODY and barriers and opportunities for moving toward a goal of access to an appropriate diagnosis for all affected individuals.

Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease.

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cardiovascular disease, particularly coronary artery disease (CAD), is the leading cause of death in the United States. Dyslipidemia, including elevated low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and low high density lipoprotein cholesterol (HDL-C), is a well-established risk factor for CAD and is influenced by both genetic and lifestyle factors, including the diet and dietary fat in particular. Major strides in elucidating the genetic basis for dyslipidemia have been made in recent years, and the quest to clarify how genetic differences influence lipid response to dietary intervention continues. Some monogenic conditions such as famililal hypercholesterolemia and sitosterolemia already have customized dietary recommendations. Some promising associations have emerged for more polygenic dyslipidemia, but further studies are needed in large dietary intervention studies capturing increasing amounts of explainable genetic variation before recommendations can be made for clinical translation.

Context: Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP)., Interventions and Main Outcome Measures: We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions., Results: GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05)., Conclusions: Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin.

Background: Obesity is associated with low-grade chronic inflammation, and serum markers of inflammation are independent risk factors for cardiovascular disease (CVD). However, the molecular and cellular mechanisms that link obesity to chronic inflammation and CVD are poorly understood., Methods and Findings: Acute-phase serum amyloid A (A-SAA) mRNA levels, and A-SAA adipose secretion and serum levels were measured in obese and nonobese individuals, obese participants who underwent weight-loss, and persons treated with the insulin sensitizer rosiglitazone. Inflammation-eliciting activity of A-SAA was investigated in human adipose stromal vascular cells, coronary vascular endothelial cells and a murine monocyte cell line. We demonstrate that A-SAA was highly and selectively expressed in human adipocytes. Moreover, A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively). Serum A-SAA levels decreased significantly after weight loss in obese participants (p = 0.006), as well as in those treated with rosiglitazone (p = 0.033). The magnitude of the improvement in insulin sensitivity after weight loss was significantly correlated with decreases in serum A-SAA (r = -0.74; p = 0.034). SAA treatment of vascular endothelial cells and monocytes markedly increased the production of inflammatory cytokines, e.g., interleukin (IL)-6, IL-8, tumor necrosis factor alpha, and monocyte chemoattractant protein-1. In addition, SAA increased basal lipolysis in adipose tissue culture by 47%., Conclusions: A-SAA is a proinflammatory and lipolytic adipokine in humans. The increased expression of A-SAA by adipocytes in obesity suggests that it may play a critical role in local and systemic inflammation and free fatty acid production and could be a direct link between obesity and its comorbidities, such as insulin resistance and atherosclerosis. Accordingly, improvements in systemic inflammation and insulin resistance with weight loss and rosiglitazone therapy may in part be mediated by decreases in adipocyte A-SAA production.

Background: The relationship between parity and life span is uncertain, with evidence of both positive and negative relationships being reported previously. We evaluated this issue by using genealogical data from an Old Order Amish community in Lancaster, Pennsylvania, a population characterized by large nuclear families, homogeneous lifestyle, and extensive genealogical records., Methods: The analysis was restricted to the set of 2,015 individuals who had children, were born between 1749 and 1912, and survived until at least age 50 years. Pedigree structures and birth and death dates were extracted from Amish genealogies, and the relationship between parity and longevity was examined using a variance component framework., Results: Life span of fathers increased in linear fashion with increasing number of children (0.23 years per additional child; p =.01), while life span of mothers increased linearly up to 14 children (0.32 years per additional child; p =.004) but decreased with each additional child beyond 14 (p =.0004). Among women, but not men, a later age at last birth was associated with longer life span (p =.001). Adjusting for age at last birth obliterated the correlation between maternal life span and number of children, except among mothers with ultrahigh (>14 children) parity., Conclusions: We conclude that high parity among men and later menopause among women may be markers for increased life span. Understanding the biological and/or social factors mediating these relationships may provide insights into mechanisms underlying successful aging.

Context: Mature ghrelin has been shown to stimulate eating and to participate in the regulation of insulin signaling and glucose homeostasis. Its gene, GHRL, is located on chromosome 3 in a region where we have shown linkage to eating behavior, percentage body fat, and total and low-density lipoprotein cholesterol levels in subjects of the Amish Family Diabetes Study., Objective: Our objective was to determine whether mutations in GHRL might influence eating behavior and risk for metabolic syndrome, obesity, diabetes, and related traits., Design: We genotyped 856 Amish samples for three missense polymorphisms in GHRL, Arg51Gln, Leu72Met (rs696217), and Gln90Leu (rs4684677) and performed association analyses with eating behavior traits and metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines., Subjects: Our subjects were adult participants in the Amish Family Diabetes Study., Results: The allele frequencies of these variants were 0.03, 0.04, and 0.03, respectively. The prevalence of metabolic syndrome was lower among those carrying the 51Gln allele (3.8 vs. 15.8%; age- and sex-adjusted odds ratio = 0.22; P = 0.031). Hunger scores tended to be lower among 51Gln allele carriers but did not reach statistical significance (P = 0.07). The Leu72Met variant was also associated with increased prevalence of metabolic syndrome (23.2 vs. 13.4%; age- and sex-adjusted odds ratio = 2.57; P = 0.02) as well as higher fasting glucose, lower high-density lipoprotein, and higher triglyceride levels (P = 0.02, P = 0.007, and P = 0.04, respectively). The two variants were not in linkage disequilibrium with each other, suggesting independent effects. We conclude that mutations in GHRL may confer risk for the metabolic syndrome.

Context: We reported previously that Old Order Amish (OOA) women have fewer hip fractures and higher bone mineral density (BMD) than non-Amish Caucasian women., Objective: The objective of this study was to determine whether the high parity characteristic of OOA women contributes to their relative bone health. Previous data on the long-term effects of parity on BMD have yielded conflicting results with few data from very high parity populations. This observational study included participants in the Amish Family Osteoporosis Study, begun in 1997 to identify genetic and clinical determinants of osteoporosis in the OOA. We measured BMD by dual-energy x-ray absorptiometry at the spine, hip, and distal radius in 424 parous OOA women aged 40 and older (mean age, 57.7 +/- 12 yr; mean parity, 7.6 +/- 2.9)., Results: Increasing parity was associated with later menopause (P = 0.001) and modestly, but not significantly, higher body mass index (BMI) (P = 0.09). Increasing parity was associated with higher BMD at the total hip and trochanter (age-adjusted P = 0.02 and 0.03), no longer statistically significant after accounting for BMI. Among women aged 50-59 yr, parity was strongly associated with BMD even after accounting for age and BMI (age-adjusted P = 0.02), although this was not true for women younger than 50 or at least 60 yr old., Conclusions: We conclude that high parity is associated with increased hip BMD in OOA women, largely mediated by higher BMI. The parity-hip BMD association remained statistically significant after accounting for age and BMI only in women aged 50-59 yr, partially explained by a later menopausal age with high parity. The benefit of high parity on BMD appeared to be lost soon after the menopausal transition, and, therefore, these data provide evidence of neither a detrimental nor beneficial effect of high parity on long-term bone health.

Adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) are newly identified receptors for adiponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties. We screened for polymorphisms by performing sequence analysis on all eight exons, splice junctions, and approximately 2 kb of the 5' flanking regions of each receptor. We detected 5 single nucleotide polymorphisms (SNPs) in ADIPOR1 and 16 SNPs in ADIPOR2. We genotyped these SNPs in Amish subjects with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) to test for association with type 2 diabetes. Three intronic SNPs in ADIPOR1 were significantly associated with type 2 diabetes (P = 0.014-0.007; odds ratio [OR] 1.61-1.65) and in high linkage disequilibrium (r2 = 0.97-1.0). In ADIPOR2, we found that five SNPs delineated one large haplotype block (r2= 0.9-1.0) spanning >98 kb of the gene and promoter region, which was strongly associated with the combined type 2 diabetes/IGT trait (P < or = 0.001; OR 1.64-1.71). To our knowledge, these data provide the first evidence for association between variation in the adiponectin receptors and type 2 diabetes.

In vitro and in vivo studies suggest a role for betacellulin in islet neogenesis and regeneration. Since abnormalities in beta-cell function play a role in the development of type 2 diabetes, a mutation in the betacellulin gene could potentially contribute to the development of type 2 diabetes. Using RT-PCR, we initially determined that betacellulin was expressed in 9- to 24-week-old human fetal pancreas. We then screened the betacellulin gene for mutations in subjects with type 2 diabetes and identified seven polymorphisms in segments encompassing the 5' untranslated region (G-233C, A-226G), exon 1 (TGC19GGC, Cys7Gly), exon 2 (CTC130TTC, Leu44Phe), exon 4 (TTG370ATG, Leu124Met), intron 2 (T-31C), and intron 4 (C-4T). These polymorphisms were genotyped in an expanded set of diabetic case and control subjects. Among African Americans (n = 334), the frequency of the Gly7 allele in exon 1 was 31.9% in diabetic case subjects compared with 45.1% in nondiabetic control subjects (P = 0.0004). Allele frequencies for the other polymorphisms did not differ significantly between African-American case and control subjects. Additionally, there were no significant differences in allele frequencies between case and control subjects among the Caucasian sample (n = 426) for any of the seven polymorphisms, including the Gly7 variant. Further studies will be needed to understand the different roles that betacellulin polymorphisms play in susceptibility to type 2 diabetes in Caucasians and African Americans.

Lifespan is a complex phenotype determined by the interaction of genetic and environmental factors. This makes the identification of variants in genes that influence longevity challenging. We believe that the Old Order Amish (OOA) of Lancaster, Pennsylvania is an excellent population for studying the genetics of longevity. They are a closed population derived from a limited number of founders. They have large families and maintain extensive genealogic records dating to the 1700 s. They eschew modern technology; their lifestyle is little changed over the last 250 years. Homogeneity of environment and lifestyle factors across time and across the OOA population minimizes the influence that environmental factors have in determining the differences in lifespan between individuals. We hypothesize that this reduction in environmental variability will make it easier to identify the genetic factors that influence lifespan. In this article, we describe our strategy for identifying variants in genes that influence longevity in the Amish and present the results of our studies to date.

We performed a genome-wide linkage scan of plasma adiponectin levels in 569 nondiabetic participants in the Amish Family Diabetes Study. The highest logarithm of odds (LOD) score (2.13; P = 0.0009) occurred on chromosome 3q27 between markers D3S1602 and D3S1580, which flank APM1/ACDC, the adiponectin gene. The APM1 +2019 A/- insertion/deletion polymorphism in the 3' untranslated region (single nucleotide polymorphism [SNP] +2019; deletion allele frequency 0.30 in Amish) showed strong association with adiponectin levels in a dosage-dependent manner in a direction consistent with that reported in previous studies, with deletion heterozygosity increasing adiponectin levels by 1.3 +/- 0.5 microg/ml and deletion homozygosity increasing levels by 3.0 +/- 0.8 microg/ml (P < 0.0001). Two other SNPs, rs2241766 and rs1501299, showed moderate association. In a subset of 523 subjects genotyped for both SNP +2019 and rs2241766, including the APM1 SNP +2019 genotype as a covariate reduced the linkage signal at 3q27 by 1.26 LOD units (from 2.22 to 0.96) and including both SNPs reduced the signal by 1.51 LOD units (to 0.71). These findings, combined with a two-point LOD score of 2.35 for SNP +2019, provide evidence that variation in APM1 is responsible for linkage of adiponectin levels to 3q27 in the Old Order Amish.

Calsequestrin (CASQ)1 is involved in intracellular storage and release of calcium, a process that has been shown to mediate glucose transport in muscle. Its gene, CASQ1, is encoded on chromosome 1q21, a region that has been linked to type 2 diabetes in the Amish and several other populations. We screened all 11 exons, exon-intron junctions, and the proximal regulatory region of CASQ1 for mutations. We detected four novel single nucleotide polymorphisms (SNPs) (-1470C-->T, -1456delG, -1366insG, and 593C-->T). Ten informative SNPs within CASQ1 were genotyped in Amish subjects with type 2 diabetes (n = 145), impaired glucose tolerance (n = 148), and normal glucose tolerance (n = 358). Rs2275703 and rs617698 in introns 4 and 2 were significantly associated with type 2 diabetes (P = 0.008 and 0.04, respectively); three other SNPs showed borderline evidence for association to type 2 diabetes (P = 0.076-0.093). Furthermore, in nondiabetic subjects (n = 754), both rs2275703 and rs617698 were significantly associated with glucose area under the curve during an oral glucose tolerance test (P = 0.035 and 0.013, respectively). Haplotype analysis suggested that no haplotype could explain these associations better than rs2275703. These findings, coupled with similar findings in Utah Caucasians, suggest that sequence variation in CASQ1 may influence risk of type 2 diabetes.

Hepatocyte nuclear factor 4-alpha (HNF4A) is a transcription factor located on chromosome 20q13 that regulates expression of genes involved in glucose metabolism and homeostasis. Recently, two groups independently identified single nucleotide polymorphism (SNPs) in an alternate upstream promoter (P2) of HNF4A that were associated with type 2 diabetes in Ashkenazi Jews and Finns. We genotyped haplotype-tagging SNPs (htSNPs) across the two promoter regions and the coding region of HNF4A in individuals with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) from the Amish Family Diabetes Study (AFDS) to test for association with type 2 diabetes. In the P1 promoter region, we observed a significant association between the A allele of rs2425640 and type 2 diabetes (odds ratio [OR] 1.60, P = 0.03). Furthermore, the mean age of type 2 diabetes onset was, on average, 5.1 years earlier in those with the AA or GA genotype at SNP rs2425640 than in those with the GG genotype (57.8 vs. 62.9 years, P = 0.011). In the P2 promoter, the htSNP rs1884614 showed borderline association with both type 2 diabetes (OR 1.40, P = 0.09) and the combined type 2 diabetes/IGT trait (1.35, P = 0.07). In an expanded set of 698 nondiabetic AFDS subjects, we found association between rs1884614 and glucose area under the curve during an oral glucose tolerance test (additive model, P = 0.022; dominant model, P = 0.010). The results of this study provide evidence that variants in both the P1 and P2 promoters of HNF4A increase risk for typical type 2 diabetes.

Objective: Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM). The lamin A/C (LMNA) gene, mutations of which cause rare syndromes of severe insulin resistance and dyslipidemia, is located on chromosome 1q21-q24, a region linked to T2DM in several genome wide scans, including in the Old Order Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components., Methods and Results: We performed DNA sequence analysis of LMNA. Six single-nucleotide polymorphisms (SNPs) were identified: c.141889C>T (intron 3), c.141906G>T (intron 3), A287A (c.141253T>C; exon 5), c.140353G>A (intron 6), c.139418C>T (intron 8), and H566H (c. 138747C>T; exon 10). In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations. However, no differences in allele frequencies were observed for any SNP among participants with T2DM or impaired glucose homeostasis (IGH) and normoglycemic controls. Haplotype analysis showed that >87% of individuals carried 1 of 2 common LMNA haplotypes. There were no significant differences in haplotype frequencies among subjects with metabolic syndrome T2DM, IGH, and controls., Conclusions: Sequence variation in LMNA may confer modest susceptibility for development of metabolic syndrome and dyslipidemia in the Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components, we performed DNA analysis of polymorphisms in LMNA. The H566H polymorphism was associated with metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations in the Old Order Amish.

Elevated serum low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) and decreased high density lipoprotein cholesterol (HDL-C) levels are established risk factors for cardiovascular disease (CVD). To identify quantitative trait loci influencing lipid levels, we conducted genome-wide linkage analyses of total serum cholesterol (TSC), HDL-C, ln-transformed TG (LNTG) and LDL-C levels in 612 individuals from 28 families of the Amish Family Diabetes Study (AFDS). Subjects were genotyped for 373 microsatellite markers covering all 22 autosomes and the X chromosome at an average density of 9.7 centimorgans. All lipid traits exhibited moderate estimated heritability (h2 +/- S.E.): TSC, 0.63 +/- 0.11; HDL-C, 0.54 +/- 0.08; LNTG, 0.37 +/- 0.08; LDL-C, 0.62 +/- 0.10. The highest logarithm of the odds (LOD) score observed was 2.47 (P = 0.0003), at 3p25 for LDL-C. LOD scores exceeding 2.0 (P < 0.001) were also observed at 2p23 (LOD = 2.17) and 19p13 (LOD = 2.23) for LDL-C, and at 11q23 (LOD = 2.03) for LNTG. Three additional regions exhibited LOD scores greater than 1.5, corresponding to a P-value of <0.005. Many of the regions suggestively linked in this genome-wide scan contain genes encoding proteins with established roles in lipid metabolism, including apolipoproteins, peroxisome proliferater-activated receptor-gamma and the LDL receptor.

Unlabelled: The incidence of hip fracture was estimated in a community of Old Order Amish and compared with available data from non-Amish whites. Hip fracture rates were 40% lower in the Amish, and the Amish also experienced higher BMD., Introduction: Understanding the patterns of fracture risk across populations could reveal insights about bone health and lead to the earlier detection and prevention of osteoporosis. Toward this aim, we compared hip fracture incidence and bone mineral density (BMD) between an Old Order Amish (OOA) community, characterized by a rural and relatively active lifestyle, and non-Amish U.S. whites., Materials and Methods: All hospital admissions for hip fracture among OOA individuals in Lancaster County, PA, were identified between 1995 and 1998 from four area hospitals. Hip fracture incidence was calculated by cross-referencing an available Anabaptist genealogy database with communities located within these hospital service areas and compared with non-Amish whites obtained from National Hospital Discharge data. Additionally, BMD at the hip was compared between 287 Amish subjects and non-Amish whites from the National Health and Nutrition Examination Survey III survey., Results and Conclusions: OOA experienced 42% fewer hip fractures than would be expected had they experienced the same rate of hip fracture as observed in non-Amish whites (p < 0.01) and a higher mean BMD that was significant in women (p < 0.05) but not men. Further evaluation of lifestyle and/or genetic differences between Amish and non-Amish populations may shed insights into etiologic factors influencing hip fracture risk.

Autoimmune thyroiditis (AITD) is a common disorder characterized by circulating antibodies to epitopes of thyroid tissue and hypothyroidism (Hashimoto's thyroiditis or AITD-hypothyroidism), although many subjects with AITD are euthyroid. Current evidence suggests that AITD is familial and polygenic. We studied AITD in a homogeneous founder Caucasian population, the Old Order Amish of Lancaster County, Pennsylvania. We found autoimmune thyroiditis, defined by the presence of circulating antimicrosomal antibodies, to be relatively common in the Amish, with a prevalence of 22.7%. The prevalence of AITD-hypothyroidism was 9.2%. We performed a genome-wide linkage analysis with 373 short tandem repeat markers in 445 subjects from 29 families. We observed suggestive evidence of linkage of AITD to a locus on chromosome 5q11.2-q14.3 (LOD, 2.30; P = 0.0006 at 94 cM; closest marker, D5S428), a region that was previously reported to be linked to AITD-hypothyroidism in a Japanese study. AITD-hypothyroidism showed a more modest linkage peak to the same region (LOD, 1.46; P = 0.005). Possible linkage (nominal P < 0.01) to autoimmune thyroiditis and/or AITD-hypothyroidism was also detected in five other regions. We conclude that a gene on chromosome 5q11.2-q14.3 is likely to contribute to susceptibility to AITD in the Amish.

We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.

Background: Eating behavior and thus dietary intake affect the development of obesity-related diseases such as diabetes, hypertension, and hyperlipidemia., Objective: We investigated the genetic underpinnings of eating behavior., Design: We administered a standardized eating behavior inventory to 624 adults from 28 families participating in the Amish Family Diabetes Study. Three quantifiable components of eating behavior were measured: restraint, disinhibition, and hunger. Associations between eating behavior scores and physical characteristics were evaluated. Heritability analysis and a genome-wide multipoint linkage analysis were performed., Results: Eating behavior scores were associated with obesity and obesity-related phenotypes. Heritability estimates were 0.28 +/- 0.09 for restraint, 0.40 +/- 0.10 for disinhibition, and 0.23 +/- 0.09 for hunger (P < 0.001). The linkage analysis showed 4 regions of suggestive linkage. We observed suggestive evidence for linkage of restraint scores to 2 chromosomal regions, near markers D3S1304 [LOD (log of odds) = 2.5, P = 0.0003] and D6S276 (LOD = 2.3, P = 0.0006). We previously reported that D3S1304 is linked to a locus influencing percentage body fat in this same population (LOD = 1.6), suggesting that this behavioral phenotype may be secondary to obesity. The maximum LOD scores for disinhibition were 1.6 (P = 0.003) near marker D7S657 and 1.4 (P = 0.005) near marker D16S752. The maximum LOD score for hunger was 1.4 (P = 0.005) near marker D3S1278., Conclusion: Significant familial effects on eating behavior and suggestive genetic linkage were found in Amish adults.

Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regulated by the deiodinases of which type 2 is expressed in humans in skeletal muscle and brown adipose tissue, where its transcription is stimulated by the beta-3 adrenergic pathway. We performed molecular scanning of the human type 2 deiodinase (DIO2) gene and evaluated a novel variant for associations with obesity and insulin resistance, assessing both the main effect and interaction with the Trp64Arg beta-3--adrenergic receptor (ADRB3) variant. Molecular scanning of DIO2 in 50 obese Caucasians demonstrated a Thr92Ala variant. Association studies in 972 nondiabetic patients, 135 of whom underwent euglycemic-hyperinsulinemic clamps, showed that subjects with the Thr92Ala variant had lower glucose disposal rate (0.54 plus minus 0.02 mg center dot min(-1) center dot kg(-1) fat-free mass Ala92 homozygotes vs. 0.44 plus minus 0.02 Ala92 heterozygotes vs. 0.42 plus minus 0.04 Thr92 homozygotes, P = 0.0088). Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 plus minus 0.9 kg/m(2) vs. neither variant 33.1 plus minus 0.4 kg/m(2), P = 0.04 for interaction). To our knowledge, Thr92Ala is the first description of a missense mutation of DIO2. This variant strongly associates with insulin resistance and, in subjects with the Trp64Arg ADRB3 variant, an increased BMI, suggesting an interaction between these two common gene variants.