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Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

BackgroundTelomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS).MethodologyFive variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects.ResultsThe adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (β = -0.19±0.04 kbp, p = 0.001).ConclusionOur study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.

Abstract Background Systemic blood pressure, influenced by both genetic and environmental factors, is regulated via sympathetic nerve activity. We assessed the role of genetic variation in three subunits of the neuromuscular nicotinic acetylcholine receptor positioned on chromosome 2q, a region showing replicated evidence of linkage to blood pressure. Methods We sequenced CHRNA1, CHRND and CHRNG in 24 Amish subjects from the Amish Family Diabetes Study (AFDS) and identified 20 variants. We then performed association analysis of non-redundant variants (n = 12) in the complete AFDS cohort of 1,189 individuals, and followed by genotyping blood pressure-associated variants (n = 5) in a replication sample of 1,759 individuals from the Framingham Heart Study (FHS). Results The minor allele of a synonymous coding SNP, rs2099489 in CHRNG, was associated with higher systolic blood pressure in both the Amish (p = 0.0009) and FHS populations (p = 0.009) (minor allele frequency = 0.20 in both populations). Conclusion CHRNG is currently thought to be expressed only during fetal development. These findings support the Barker hypothesis, that fetal genotype and intra-uterine environment influence susceptibility to chronic diseases later in life. Additional studies of this variant in other populations, as well as the effect of this variant on acetylcholine receptor expression and function, are needed to further elucidate its potential role in the regulation of blood pressure. This study suggests for the first time in humans, a possible role for genetic variation in the neuromuscular nicotinic acetylcholine receptor, particularly the gamma subunit, in systolic blood pressure regulation.

Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4×10(-4)) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2 Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates. [ABSTRACT FROM AUTHOR]

The article presents a genome-wide association study of low-density lipoprotein cholesterol (LDL-C) levels and coronary artery calcification (CAC) in Amish individuals. A sample of 841 Amish individuals aged 20 to 80 years were studied, with replication in a second sample of 663. Scanning was performed for CAC in 1,018 of the individuals. The results reveal the presence of the mutation responsible for familial defective apolipoprotein B-100, a major determinant of LDL-C levels and CAC in the Amish.

Perilipins are lipid droplet-coating proteins that regulate intracellular lipolysis in adipocytes. A haplotype of two perilipin gene (PUN) single nucleotide polymorphisms, 13041A>G and 14995A>T, has been previously associated with obesity risk. Furthermore, the available data indicate that this association may be modified by sex. We hypothesized that this haplotype would associate with body fatness, aerobic fitness, and a number of cardiovascular (CV) risk factor phenotypes before and after a 6-mo endurance exercise training program in sedentary older Caucasians. The major haplotype group (13041A114995A; n = 57) had significantly lower body mass index (BMI) and body fatness compared with noncarriers of the AA haplotype (n = 44) before the training intervention. Training improved body composition in both groups, but fatness remained higher in noncarriers than AA carriers after training. This fat retention in noncarriers blunted their maximal oxygen uptake (VO2max) adaptation to training. Female noncarriers had substantially higher concentrations of several conventionally and NMR-measured HDL-C subfractions than male noncarriers before and after training, but only minimal differences were found between the sexes in the AA haplotype group. Haplotype group differences in baseline and after-training responses to an oral glucose tolerance test (OGTT) also differed by sex, as noncarrier men had the highest baseline area under the insulin curve (insulin AUC), but were the only group to significantly improve insulin AUC with training. The insulin sensitivity index and plasma glucose responses to the OGTT were more favorable in AA carriers than noncarriers before and after training. Overall, our findings suggest that PUN variation explains some of the interindividual differences in the response of obesity and CV phenotypes to exercise training. Furthermore, these data contribute to the growing under- standing of PUN as a candidate gene for human obesity and the cardiometabolic consequences of excess adiposity. [ABSTRACT FROM AUTHOR]

Postprandial triglyceridemia is an emerging risk factor for cardiovascular disease. However, most of the genes that influence postprandial triglyceridemia are not known. We evaluated whether a common nonsynonymous SNP rs1260326/P446L in the glucokinase regulatory protein ( GCKR) gene influenced variation in the postprandial lipid response after a high-fat challenge in seven hundred and seventy participants in the Amish HAPI Heart Study who underwent an oral high-fat challenge and had blood samples taken in the fasting state and during the postprandial phase at 1, 2, 3, 4, and 6 h. We found that the minor T allele at rs1260326 was associated with significantly higher fasting TG levels after adjusting for age, sex, and family structure ( Pa = 0.06 for additive model, and Pr = 0.0003 for recessive model). During the fat challenge, the T allele was associated with significantly higher maximum TG level ( Pa = 0.006), incremental maximum TG level ( Pa = 0.006), TG area under the curve ( Pa = 0.02) and incremental TG area under the curve ( Pa = 0.03). Our data indicate that the rs1260326 T allele of GCKR is associated with both higher fasting levels of TG as well as the postprandial TG response, which may result in higher atherogenic risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the study "Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer," which appeared in the 2013 issue of the periodical "Cell."

We performed a genome-wide association scan of T2D in the OOA using the Affymetrix 100K genotyping platform. The OOA are a genetically well-defined closed Caucasian founder population, and thus potential biases due to stratification are minimized in this population. We genotyped 116,204 single nucleotide polymorphisms in 124 genetically enriched T2D cases and 295 normal glucose tolerant (NGT) controls. We used the BRLMM genotype-calling algorithm, which yielded an average sample call rate of 95% (range: 90-99%). The SNP concordance rate for 11 duplicated QC samples was 97.5% and the cross-platform concordance rate for 33 samples genotyped for 61 overlapping SNPs on the Illumina platform was 98.0%. Following additional QC checks, 102,079 informative SNPs (MAF>2%) were included in our analyses. We performed a variance components case-control analysis using an additive model and adjusted for age, age², sex, and familial relationships. For rare SNPs (MAF: 2-5%) we used a dominant genetic model. We found that 150 SNPs were associated (nominal p<0.001) with T2D, more than would be expected by chance alone. We also assessed replication of our findings by performing quantitative trait association analyses of four oral glucose tolerance test (OGTT) traits (fasting insulin, insulin area under the curve, fasting glucose, glucose area under the curve) in 428 non-diabetic Amish samples. A total of 132 SNPs were associated with T2D (p<0.01) and at least 1 OGTT trait (p<0.01). SNPs showing evidence for internal replication map to 95 genes, several of which are excellent candidate genes for T2D. We also found that some T2D-associated SNPs mapped to replicated T2D linkage regions on chromosomes 1q21-125, 2q33-q37, 18p11, and 20q, lending additional support for their prioritization. In summary, we have conducted the first genome-wide association study of T2D in the OOA and identified several genes/regions that warrant further investigation. ADA-Funded Research [ABSTRACT FROM AUTHOR]

To identify candidate genes for type 2 diabetes (T2D), we performed a genome-wide association (GWA) analysis using the Affymetrix GeneChip® Mapping 100K Array set in 124 T2D cases and 295 normal glucose tolerant (NGT) controls enrolled in the Amish Family Diabetes Study (AFDS). Our analyses were based on 102,079 high quality informative SNPs. We performed a variance components case-control analysis using an additive model and adjusted for age, sex, and familial relationships. Our most significant result, rs2237457 (P=1.23e[sup -5]; OR= 1.64), mapped to the growth factor receptor-bound protein (GRB10) gene on chromosome 7p12.2. GRB10 is an adapter protein that negatively regulates insulin signaling. After genotyping 36 haplotype-tagging SNPs (htSNPs) across GRB10, rs2237457 remained the strongest T2D-associated SNP. The rs2237457 SNP tags a ∼33.3 kb linkage disequilibrium block encompassed by intron 5. The SNPs were also genotyped in an expanded set of 743 nondiabetic AFDS subjects. The T2D-risk allele for rs2237457 was significantly associated with higher glucose area under the curve (P=3.5e[sup -6]), providing evidence for internal replication. As an additional external replication, we genotyped rs2237457 in 192 Caucasian T2D cases recruited from the University of Maryland Joslin Diabetes Center and 234 Caucasian nondiabetic controls. Genotype frequencies differed significantly between cases and controls (P=0.03; OR=1.40). In conclusion, our analyses suggest that genetic variation in GRB10, a strong candidate gene for T2D susceptibility, is associated with T2D and related Waits. Support for this association is provided by an internal replication within the Amish and an external replication in a second more outbred Caucasian population, making GRB10 among the first potential T2D susceptibility loci to be identified using the GWA approach. ADA-Funded Research [ABSTRACT FROM AUTHOR]

Perilipins are lipid droplet-coating proteins that regulate intracellular lipolysis in adipocytes. A haplotype of two perilipin gene (PLIN) single nucleotide polymorphisms, 13041A>G and 14995A>T, has been previously associated with obesity risk. Furthermore, the available data indicate that this association may be modified by sex. We hypothesized that this haplotype would associate with body fatness, aerobic fitness, and a number of cardiovascular (CV) risk factor phenotypes before and after a 6-mo endurance exercise training program in sedentary older Caucasians. The major haplotype group (13041A/14995A; n = 57) had significantly lower body mass index (BMI) and body fatness compared with noncarriers of the AA haplotype (n = 44) before the training intervention. Training improved body composition in both groups, but fatness remained higher in noncarriers than AA carriers after training. This fat retention in noncarriers blunted their maximal oxygen uptake (Vo(2 max)) adaptation to training. Female noncarriers had substantially higher concentrations of several conventionally and NMR-measured HDL-C subfractions than male noncarriers before and after training, but only minimal differences were found between the sexes in the AA haplotype group. Haplotype group differences in baseline and after-training responses to an oral glucose tolerance test (OGTT) also differed by sex, as noncarrier men had the highest baseline area under the insulin curve (insulin AUC), but were the only group to significantly improve insulin AUC with training. The insulin sensitivity index and plasma glucose responses to the OGTT were more favorable in AA carriers than noncarriers before and after training. Overall, our findings suggest that PLIN variation explains some of the interindividual differences in the response of obesity and CV phenotypes to exercise training. Furthermore, these data contribute to the growing understanding of PLIN as a candidate gene for human obesity and the cardiometabolic consequences of excess adiposity.

Obesity and type 2 diabetes are closely related, multifactorial metabolic conditions characterized by alterations in energy metabolism and glucose homeostasis, respectively. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that regulates genes involved in lipid and glucose homeostasis, including the adipocyte-specific fatty acid-binding protein (FABP4). In turn, FABP4 binds fatty acids and transports them to the nucleus where the FABP4/fatty acid complex activates PPARgamma in a positive feedback loop. In this study, we tested the hypothesis that the polymorphisms, FABP4-376 and PPARgamma Pro12Ala, interactively influence insulin sensitivity and body composition in nondiabetic, Hispanic and non-Hispanic white males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS). Although the individual sites were not statistically significantly associated with any of the outcomes, we found statistically significant interaction terms in 2-way analysis of covariance (ANCOVA) models for homeostasis model assessment of insulin resistance (HOMA-IR) (P =.014) and lean mass (P =.019). While the PPARgamma Pro12Ala site was the only statistically significant predictor of fat mass in the 2-way model (P =.012), the FABP4 and PPARgamma main effect terms individually became stronger when considered in one model compared with the analysis of each polymorphism separately. These findings provide evidence that FABP4 and PPARgamma work together to influence a biologic pathway affecting insulin sensitivity and body composition, illustrating the importance of investigating the joint effect of genes in determining susceptibility for complex disease.