Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive ...indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting ~10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10...) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 ...IU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10...). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10...), GNAQ (rs10512065, p = 2.0 x 10...), TG (rs2252696, p = 2.2 x 10...), POU1F1 (rs1976324, p = 3.9 x 10...), PDE4D (rs27178, p = 8.3 x 10...), and TSHR (rs4903957, p = 8.6 x 10...) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction. (ProQuest: ... denotes formulae/symbols omitted.)
The South African clawed toad, Xenopus laevis, is a versatile laboratory model of vertebrate development. To study the role of insulin during embryogenesis, we have recently cloned preproinsulin ...cDNAs from this species. Unexpectedly, we identified two preproinsulin cDNAs corresponding to two different nonallelic genes that code for similar but distinctly different insulins. We now report the isolation, amino acid sequence, and characterization of both of these insulins from pancreatic extracts of adult toads, confirming that both Xenopus preproinsulin genes are expressed. Xenopus insulins represent the first amphibian insulins to be characterized. Xenopus insulin I and Xenopus insulin II are more similar to each other than they are to insulins of other species. In addition, Xenopus insulins are more similar to mammalian and bird insulins, than they are to fish insulins, implying a closer evolutionary link to terrestrial vertebrates than to most aquatic vertebrates. A homogeneous preparation of Xenopus insulin I showed high reactivity in a pork insulin RIA. Xenopus insulin I was approximately 2-fold more potent than pork insulin in binding to insulin receptors on human IM-9 lymphocytes and 1.5-fold more potent than pork insulin in stimulating glucose oxidation in rat adipocytes. We were unable to purify Xenopus insulin II sufficiently for immunological and biological characterization.
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association ...analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene NRXN3 (rs10146997, p = 6.4×10-7). The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10-8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) p = 7.4×10-6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2×10-5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations ...observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5' end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from -8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers -8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size.
Peroxisome proliferator-activated receptor gamma (PPARgamma)-2 is a member of the nuclear hormone receptor superfamily that is expressed predominantly in adipocytes and is thought to have a role in ...energy homeostasis, adipogenesis, and insulin sensitivity. A functional single nucleotide polymorphism (SNP) that predicts a proline to alanine substitution (Pro12Ala) within the coding region of this gene has previously been associated with obesity and type 2 diabetes in several populations. In this study, we identified several novel SNPs in the promoter region of PPARgamma2 and genotyped them, along with the previously identified Pro12Ala SNP. In 241 nondiabetic Pima subjects, the Pro12Ala was associated with whole-body insulin action (P = 0.05), hepatic insulin action (P = 0.03), and fasting plasma insulin concentrations (P = 0.01). One of the promoter SNPs positioned within a putative E2 box was in high linkage disequilibrium (/D'/ = 0.98) with the Pro12Ala. This promoter SNP was similarly associated with whole-body insulin action (P = 0.04) and hepatic insulin action (P = 0.05), but not fasting plasma insulin concentrations. Functional studies in transfected 3T3-L1 cells demonstrated that this single base substitution in the putative E2 box significantly altered transcriptional activity from a luciferase reporter construct. These data indicate that this promoter SNP, via its effect on PPARgamma2 expression, may also have functional consequences on PPARgamma2-activated pathways, and perhaps both the promoter SNP and the Pro12Ala contribute to PPARgamma2-related phenotypes.
Recent research suggests that the Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with diabetes- and obesity-related traits, and that its effects may ...be modified by obesity status. We characterized this variant in a population-based sample of 1,441 middle-aged African-American individuals with respect to diabetes-, obesity-, and other cardiovascular-related traits, both cross-sectionally and prospectively. The overall frequency of Ala12 was 1.9% (95% CI 1.5-2.5%), significantly lower than in Caucasian populations. Consistent with previous findings in Caucasians, African Americans with type 2 diabetes tended to be less likely to have the Pro/Ala genotype than those without (odds ratio OR 0.64, 95% CI 0.34-1.20); however, this OR was not statistically significant. Among nonobese individuals, the Pro/Ala genotype was associated with significantly lower ln(insulin) (P = 0.001), lower ln(HOMA-IR) (homeostasis model assessment of insulin resistance) (P = 0.002), higher fasting glucose-to-insulin ratio (P = 0.005), and lower diastolic blood pressure (P = 0.02). Among overweight individuals (BMI 25-29.9 kg/m(2)), the Pro/Ala genotype was associated with greater BMI (P = 0.02), waist-to-hip ratio (P = 0.01), and waist circumference (P = 0.04). Among obese individuals, there was no association between any of the diabetes- or obesity-related traits and the Pro12Ala PPAR-gamma2 variant. We conclude that among nonobese African Americans, the Pro/Ala genotype is associated with markers of greater insulin sensitivity.
Identifying genetic variants that influence human height will further our understanding of skeletal growth and development. A number of rare genetic variants have been convincingly and reproducibly ...associated with height in Mendelian syndromes, and common variants in
HMGA2
were recently found to be associated with variation in height in the general population
1
. Here, we report genome-wide association analyses of 6,669 individuals from Finland and Sardinia, using genotyped and imputed markers, and follow-up in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated
2
GDF5-BFZB
locus are responsible for variation in height (estimated additive effect of 0.44 cm, overall p<10
−15
). Our results suggest a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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