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- Westerberg, Per-Anton, et al.
(författare)
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Variation in the klotho gene is not associated with mortality risk among elderly men in MR OS Sweden
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:Suppl 1, s. S103-S104
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Polymorphisms in the Klotho (Kl) gene, which is central for vitamin D regulation by fibroblast growth factor 23 (FGF23), have been associated with longevity, coronary disease and stroke. The CC genotype of the single nucleotide polymorphism (SNP) rs577912 in the Kl-gene is associated with decreased Kl expression, as well as increased mortality in end stage renal disease. We examined if SNP in the Kl-gene was associated with mortality in the community derived cohort of 70 to 80 year old males of MrOS Sweden (N = 3014).High throughput genotyping of the KLOTHO SNPs was achieved by use of SequenomR MassEXTEND/Mass/ARRAY technology. 2738 subjects had a valid result for rs577912: CC 73.1% and CA + AA 26.9%. There were no differences in the serum levels of FGF23, phosphate, parathyroid hormone or renal function between genotypes CC and CA + AA. During a follow-up of a median of 4.5 years there were 337 deaths, 253 (12.6%) in the CC group and 84 (11.4%) in the CA + AA group. With log rank analysis there were no differences in mortality between the genotypes for all cause mortality (P = 0.39) or cardiovascular mortality (P = 0.60). None of the other SNPs in the Kl gene was associated with mortality in this cohort either.Conclusion:There is no association between the SNP rs577912 in the Kl-gene and mortality among elderly men.
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- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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