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- Liu, Ke, et al.
(author)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases
- 2016
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In: Arthritis & Rheumatology. - : WILEY-BLACKWELL. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Journal article (peer-reviewed)abstract
- Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
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| 3. |
- Liu, Ke, et al.
(author)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome
- 2016
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Journal article (peer-reviewed)abstract
- OBJECTIVE:More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS:We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS:We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.
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- Harris, Valerie M., et al.
(author)
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Klinefelters syndrome (47,XXY) is in excess among men with Sjogrens syndrome
- 2016
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In: Clinical Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1521-6616 .- 1521-7035. ; 168, s. 25-29
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Journal article (peer-reviewed)abstract
- Primary Sjogrens syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelters syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47)0(Y, p = 0.0012 by Fishers exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fishers exact test p = NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA. Published by Elsevier Inc.
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| 7. |
- Li, He, et al.
(author)
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Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
- 2017
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In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:6
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Journal article (peer-reviewed)abstract
- Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
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| 8. |
- Rayner, Matt J., et al.
(author)
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Using miniaturized radiotelemetry to discover the breeding grounds of the endangered New Zealand Storm Petrel Fregetta maoriana
- 2015
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In: Ibis. - : Wiley. - 0019-1019. ; 157:4, s. 754-766
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Journal article (peer-reviewed)abstract
- Identification of breeding sites remains a critical step in species conservation, particularly in procellariiform seabirds whose threat status is of global concern. We designed and conducted an integrative radiotelemetry approach to uncover the breeding grounds of the critically endangered New Zealand Storm Petrel Fregetta maoriana (NZSP), a species considered extinct before its rediscovery in 2003. Solar-powered automated radio receivers and hand-held telemetry were used to detect the presence of birds on three island groups in the Hauraki Gulf near Auckland, New Zealand. At least 11 NZSP captured and radiotagged at sea were detected at night near Te Hauturu-o-Toi/Little Barrier Island with the detection of an incubating bird leading to the discovery of the first known breeding site for this species. In total, four NZSP breeding burrows were detected under mature forest canopy and three adult NZSP and two NZSP chicks were ringed. Telemetry data indicated NZSP showed strong moonlight avoidance behaviour over the breeding site, had incubation shifts of approximately 5days and had a breeding season extending from February to June/July, a different season from other Procellariiformes in the region. Radiotelemetry, in combination with rigorously collected field data on species distribution, offers a valuable technique for locating breeding grounds of procellariiform seabirds and gaining insights into breeding biology while minimizing disturbance to sensitive species or damage to fragile habitat. Our study suggests an avenue for other breeding ground searches in one of the most threatened avian Orders, and highlights the general need for information on the location of breeding sites and understanding the breeding biology in data-deficient birds.
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| 9. |
- Sharma, Rohan, et al.
(author)
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Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjogrens Syndrome
- 2017
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 69:11, s. 2187-2192
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Journal article (peer-reviewed)abstract
- Objective. Sjogrens syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of similar to 10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. Methods. We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. Results. Among similar to 2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among similar to 2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in similar to 1 in 25,000-50,000 live female births, while partial triplications are even rarer. Conclusion. Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.
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| 10. |
- Wang, Jing, et al.
(author)
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A major locus controls local adaptation and adaptive life history variation in a perennial plant
- 2018
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In: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 19
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Journal article (peer-reviewed)abstract
- Background: The initiation of growth cessation and dormancy represent critical life history trade offs between survival and growth and have important fitness effects in perennial plants Such adaptive life history traits often show strong local adaptation along environmental gradients but, despite then importance, the genetic architecture of these traits remains poorly understood.Results: We integrate whole genome re sequencing with environmental and phenotypic data from common garden experiments to investigate the genomic basis of local adaptation across a latitudinal gradient in European aspen (Populus tremula). A single genomic region containing the PtFT2 gene mediates local adaptation in the timing of bud set and explains 65% of the observed genetic variation in bud set This locus is the likely target of a recent selective sweep that originated right before or during colonization of northern Scandinavia following the last glaciation Field and greenhouse experiments confirm that variation in PtFT2 gene expression affects the phenotypic variation in bud set that we observe in wild natural populations.Conclusions: Our results reveal a major effect locus that determines the timing of bud set and that has facilitated rapid adaptation to shorter growing seasons and colder climates in European aspen. The discovery of a single locus explaining a substantial fraction of the variation in a key life-history trait is remarkable, given that such traits are generally considered to be highly polygenic. These findings provide a dramatic illustration of how loci of large effect for adaptive traits can arise and be maintained over large geographical scales in natural populations.
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