Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence ...for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P = 5.8 × 10(-9)), RELA (rs1049728, P = 2.7 × 10(-16)), and SH2B3 (rs3184504, P = 2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.
von Willebrand factor (VWF) is an essential component of hemostasis and has been implicated in thrombosis. Multimer size and the amount of circulating VWF are known to impact hemostatic function. We ...associated 78 VWF single nucleotide polymorphisms (SNPs) and haplotypes constructed from those SNPs with VWF antigen level in 7856 subjects of European descent. Among the nongenomic factors, age and body mass index contributed 4.8% and 1.6% of VWF variation, respectively. The SNP rs514659 (tags O blood type) contributed 15.4% of the variance. Among the VWF SNPs, we identified 18 SNPs that are associated with levels of VWF. The correlative SNPs are either intronic (89%) or silent exonic (11%). Although SNPs examined are distributed throughout the entire VWF gene without apparent cluster, all the positive SNPs are located in a 50-kb region. Exons in this region encode for VWF D2, D′, and D3 domains that are known to regulate VWF multimerization and storage. Mutations in the D3 domain are also associated with von Willebrand disease. Fifteen of these 18 correlative SNPs are in 2 distinct haplotype blocks. In summary, we identified a cluster of intronic VWF SNPs that associate with plasma levels of VWF, individually or additively, in a large cohort of healthy subjects.
Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare ...genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins
Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are ...almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10
). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10
) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.
Parathyroid hormone (PTH) is one of the principal regulators of calcium homeostasis, crucial for normal functioning of the kidneys, bones, heart, and nervous system. Different pathologic conditions ...can affect serum PTH level resulting in hyperparathyroidism or hypoparathyroidism. Our study assessed the association of previously reported polymorphisms with the level of PTH (expressed in pg/mL) among individuals with different pathologic conditions affecting PTH level.
We searched Web of Science, MEDLINE, and Scopus to identify relevant articles published up to July 2017. The search yielded 6967 publications of which 44 fulfilled the inclusion criteria. We conducted meta-analyses for calcium-sensing receptor gene (CaSR) rs1801725 polymorphism in patients with primary hyperparathyroidism and vitamin D receptor gene (VDR) rs1544410 polymorphism in patients with end-stage renal disease (ESRD).
None of the polymorphisms were significantly associated with PTH levels in the overall population. In subgroup analysis by ethnicity for VDR rs1544410 gene polymorphism, we found significant differences under dominant model (SMD: -0.18 -0.32, -0.05, P < .01) and AA versus GG comparison (SMD: -0.29 -0.52, -0.06, P < .01) in Asian patients with ESRD, while nominally significant results (P < .05) were observed for AG versus GG and AA versus GG comparisons in European individuals with ESRD.
Scientific evidence of genetic association of serum PTH level among individuals with different pathologic conditions remains deficient and published results provide weak evidence. Further well-conducted studies on larger sample sets designed according to evidence-based principles are warranted to assure clinically applicable findings.
Thyroid volume of Hashimoto's thyroiditis (HT) patients varies in size over the course of disease and it may reflect changes in biological function of thyroid gland. Patients with subclinical ...hypothyroidism predominantly have increased thyroid volume whereas patients with more pronounced hypothyroidism have smaller thyroid volumes. Suggested mechanism for thyroid atrophy is thyrocyte death due to apoptosis. We performed the first genome-wide association study (GWAS) of thyroid volume in two groups of HT patients, depending on levothyroxine (LT4) therapy, and then meta-analysed across. Study included 345 HT patients in total and 6 007 322 common autosomal genetic variants. Underlying hypothesis was that genetic components that are involved in regulation of thyroid volume display their effect in specific pathophysiologic conditions of thyroid gland of HT patients. We additionally performed immunohistochemical analysis using thyroid tissues and analysed differences in expression levels of identified proteins and apoptotic marker between HT patients and controls. We found genome-wide significant association of two loci, both involved in apoptosis, with thyroid volume of HT patients: rs7212416 inside apoptosis-antagonizing transcription factor AATF (P = 8.95 × 10
) and rs10738556 near chromatin-remodeling SMARCA2 (P = 2.83 × 10
). In immunohistochemical analysis we observed that HT patients with homozygous AATF risk genotypes have decreased AATF expression (0.46-fold, P < 0.0001) and increased apoptosis (3.99-fold, P = 0.0001) in comparison to controls. HT patients with heterozygous SMARCA2 genotypes have decreased SMARCA2 expression, albeit without reaching statistical significance (1.07-fold, P = 0.5876), and significantly increased apoptosis (4.11-fold, P < 0.0001). By two lines of evidence we show that two highly plausible genetic loci, AATF and SMARCA2, may be involved in determining the thyroid volume of HT patients. The results of our study significantly add to the current knowledge of disturbed biological mechanisms in thyroid gland of HT patients.
Thyroid antibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are key markers of Hashimoto's thyroiditis (HT), the most common autoimmune thyroid disorder. Genetic determinants of ...thyroid antibodies are still poorly known, especially as they were not studied in patients with thyroid diseases. We performed the first genome-wide association analysis of thyroid antibodies in 430 HT patients that may be considered as population extremes for thyroid antibodies distribution. We detected two suggestively associated genetic variants with TgAb, rs6972286 close to ANKRD7 and LSM8 (P = 2.34 × 10
) and rs756763 inside CA10 (P = 6.05 × 10
), and one with TPOAb, rs12507813 positioned between TRIM61 and TRIM60 (P = 4.95 × 10
). Bivariate analysis resulted with three suggestively associated genetic variants that predispose to both antibodies: rs13190616 inside RP11-138J23.1 (P = 2.01 × 10
), rs561030786 close to DUBR (P = 7.33 × 10
) and rs12713034 inside FSHR (P = 7.66 × 10
). All identified genomic regions have a substantial literature record of involvement with female-related traits, immune-mediated diseases and personality traits that are all characterized by increased thyroid antibody levels. Our findings demonstrate the existence of genetic overlap between thyroid autoimmunity in HT and different non-thyroid diseases characterized by the presence of thyroid antibodies. We also suggest that genetic variants that regulate antibody levels may differ between HT patients and individuals with normal thyroid function.
Abstract
Introduction
Thyroid peroxidase (TPO) and thyroglobulin (Tg) are main components of the thyroid gland and play an essential role in thyroid hormone synthesis. The development of antibodies ...to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) is the major diagnostic hallmark and early indicator of autoimmune thyroid disease. TPOAb and TgAb are under strong genetic influence; however, genetic factors that determine thyroid antibody positivity are largely unknown.
Materials and Methods
To identify novel loci associated with TPOAb and/or TgAb positivity, we performed a genome-wide meta-analysis in a total of 2613 individuals from Croatia. Participants with elevated plasma TPOAb and/or TgAb were defined as cases (N = 619) and those with TPOAb and TgAb within reference values were defined as controls (N = 1994).
Results
We identified 2 novel loci, of which 1 is located within the YES1 gene (rs77284350, P = 1.50 × 10–8), and the other resides within the IRF8 gene (rs16939945, P = 5.04 × 10–8).
Conclusions
Although the observed variants were associated with TPOAb and TgAb positivity for the first time, both YES1 and IRF8 were previously linked to susceptibility to other autoimmune diseases, and represent plausible biological candidates. This study adds to the knowledge of genetics underlying thyroid antibodies and provides a good basis for further research.
Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ ...cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.
Parathyroid hormone (PTH) is one of the principal regulators of calcium homeostasis. Although serum PTH level is mostly accounted by genetic factors, genetic background underlying PTH level is ...insufficiently known. Therefore, the aim of this study was to identify novel genetic variants associated with PTH levels.
We performed GWAS meta-analysis within two genetically isolated Croatian populations followed by replication analysis in a Croatian mainland population and we also combined results across all three analyzed populations. The analyses included 2596 individuals. A total of 7,411,206 variants, imputed using the 1000 Genomes reference panel, were analysed for the association. In addition, a sex-specific GWAS meta-analyses were performed.
Polymorphisms with the lowest P-values were located on chromosome 4 approximately 84 kb of the 5' of RASGEF1B gene. The most significant SNP was rs11099476 (P = 1.15 × 10
). Sex-specific analysis identified genome-wide significant association of the variant rs77178854, located within DPP10 gene in females only (P = 2.21 × 10
). There were no genome-wide significant findings in the meta-analysis of males.
We identified two biologically plausible novel loci associated with PTH levels, providing us with further insights into the genetics of this complex trait.
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