Gene polymorphism of IL-6 and MMP-3 decreases passive range of motion after rotator cuff repair

Objectives: Post-operative stiffness is common after rotator cuff repair, given the difference in susceptibility and severity, the genetic factors may be involved. Interleukin 6 (IL-6) and Matrix metalloproteinases 3 (MMP-3) were previous found as key cytokines in the pathologies of adhesive capsulitis. The present study aims to investigate whether variants within the IL-6 and MMP-3 gene contributed to post-operative stiffness in a Chinese Han population. Methods: A total of 188 patients diagnosed with rotator cuff tears treated with mini-open surgery were enrolled in this study, among which 87 patients were diagnosed as post-operative stiffness and the remaining 101 patients as controls. All subjects were genotyped for IL-6 and MMP-3 SNPs. Results: The rs1800796 of IL-6 and rs679620 of MMP-3 were found significantly associated with increased susceptibility and severity of post-operative stiffness. Conclusion: The rs1800796 SNP of IL-6 and rs650108 SNP of MMP-3 were associated with increased risk of post-operative stiffness susceptibility and severity. This finding can be used in guiding the rehabilitation procedure after rotator cuff surgery, in another word, those with the genetic susceptibility factors should receive a more radical rehabilitation procedure and those without the susceptibility factors can be more conservative.     

Association of serum osteoprotegerin and osteoprotegerin gene polymorphism with subclinical carotid artery atherosclerosis and disease activity in rheumatoid arthritis patients

Aim of the workTo investigate the association of single nucleotide polymorphism (SNP) (rs2073618) of the OPG gene and of serum OPG with subclinical carotid atherosclerosis in RA patients.Patients and methodsEighty RA patients with no previous history of a cardiovascular disease were studied and forty healthy controls were enrolled in the study. Carotid atherosclerosis was evaluated by high-resolution B-mode ultrasound and the carotid intimal medial thickness (CIMT) measured. rs2073618 OPG genotyping was performed by polymerized chain reaction (PCR) and serum OPG concentrations were measured. The high sensitive C reactive protein (hs-CRP), rheumatoid factor (RF) titer and anti-cyclic citrullinated peptide (anti-CCP) were assessed. The disease activity score (DAS28) was evaluated.ResultsThe patients mean age was54.1 ± 6.2 years, disease duration of 12.5 ± 8.5 years and were 72 females and 8 males. Increased IMT was found in 38 patients, 40 age and sex matched controls were included. Patients with atherosclerosis (n = 38) had longer disease duration, higherDAS28, hs-CRP, RF titer and anti-CCP. The serum OPG levels were higher in patients with atherosclerosis (1106.4 ± 1157.1 ng/l) compared to those without (658.3 ± 151.1 ng/l)(p = 0.001). Serum OPG significantly correlated with disease duration (r = 0.42, p = 0.005), DAS28 (r = 0.53, p = 0.001), hs-CRP (r = 0.41, p = 0.007), anti-CCP (r = 0.47, p = 0.003) and mean CIMT (r = 0.37, p = 0.02). The frequencies of CC, CG and GG genotypes were comparable between those with and without atherosclerosis (39.5%, 50%, 10.4% vs 42.9%, 47.6% and 9.5% respectively).Conclusionrs2073618 OPG gene may not be associated with subclinical atherosclerosis, although the serum level could be a reliable marker for disease activity and for early detection of carotid artery atherosclerosis in RA.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population

In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6–7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship''s variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec.     

A genetic association study of D-dimer levels with 50 K SNPs from a candidate gene chip in four ethnic groups

Introduction

D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

Materials and Methods

We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

Results

Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0 × 10^− 6. The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer.

Conclusions

Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.     

Extensive X-linked adaptive evolution in central chimpanzees

Surveying genome-wide coding variation within and among species gives unprecedented power to study the genetics of adaptation, in particular the proportion of amino acid substitutions fixed by positive selection. Additionally, contrasting the autosomes and the X chromosome holds information on the dominance of beneficial (adaptive) and deleterious mutations. Here we capture and sequence the complete exomes of 12 chimpanzees and present the largest set of protein-coding polymorphism to date. We report extensive adaptive evolution specifically targeting the X chromosome of chimpanzees with as much as 30% of all amino acid replacements being adaptive. Adaptive evolution is barely detectable on the autosomes except for a few striking cases of recent selective sweeps associated with immunity gene clusters. We also find much stronger purifying selection than observed in humans, and in contrast to humans, we find that purifying selection is stronger on the X chromosome than on the autosomes in chimpanzees. We therefore conclude that most adaptive mutations are recessive. We also document dramatically reduced synonymous diversity in the chimpanzee X chromosome relative to autosomes and stronger purifying selection than for the human X chromosome. If similar processes were operating in the human-chimpanzee ancestor as in central chimpanzees today, our results therefore provide an explanation for the much-discussed reduction in the human-chimpanzee divergence at the X chromosome.