The X-chromosome and susceptibility to ankylosing spondylitis

Objective. Ankylosing spondylitis (AS) affects 0.25-1.0% of the population, and its etiology is incompletely understood. Susceptibility to this highly familial disease (λ(s) = 58) is primarily genetically determined. There is a significant sex bias in AS, and there are differences in recurrence risk to the offspring of affected mothers and fathers, suggesting that there may be an X-linked recessive effect. We undertook an X- chromosome linkage study to determine any contribution of the X-chromosome to AS susceptibility. Methods. A linkage study of the X-chromosome using 234 affected sibling pairs was performed to investigate this hypothesis. Results. No linkage of the X-chromosome with susceptibility to AS was found. Model- free multipoint linkage analysis strongly excluded any significant genetic contribution (λ ≥1.5) to AS susceptibility encoded on the X-chromosome (logarithm of odds [LOD] <-2.0). Smaller genetic effects (A ≥1.3) were also found to be unlikely (LOD <-1.0). Conclusion. The sex bias in AS is not explained by X-chromosome-encoded genetic effects. The disease model best explaining the sex bias in occurrence and transmission of AS is a polygenic model with a higher susceptibility threshold in females.

Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis

The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made.

Cardiovascular disease is increased prior to onset of rheumatoid arthritis but not osteoarthritis: The population-based Nord-Trøndelag health study (HUNT)

Introduction: Patients with rheumatoid arthritis (RA) have increased risk of cardiovascular (CV) events. We sought to test the hypothesis that due to increased inflammation, CV disease and risk factors are associated with increased risk of future RA development. Methods: The population-based Nord-Trøndelag health surveys (HUNT) were conducted among the entire adult population of Nord-Trøndelag, Norway. All inhabitants 20 years or older were invited, and information was collected through comprehensive questionnaires, a clinical examination, and blood samples. In a cohort design, data from HUNT2 (1995-1997, baseline) and HUNT3 (2006-2008, follow-up) were obtained to study participants with RA (n = 786) or osteoarthritis (n = 3,586) at HUNT3 alone, in comparison with individuals without RA or osteoarthritis at both times (n = 33,567). Results: Female gender, age, smoking, body mass index, and history of previous CV disease were associated with self-reported incident RA (previous CV disease: odds ratio 1.52 (95% confidence interval 1.11-2.07). The findings regarding previous CV disease were confirmed in sensitivity analyses excluding participants with psoriasis (odds ratio (OR) 1.70 (1.23-2.36)) or restricting the analysis to cases with a hospital diagnosis of RA (OR 1.90 (1.10-3.27)) or carriers of the shared epitope (OR 1.76 (1.13-2.74)). History of previous CV disease was not associated with increased risk of osteoarthritis (OR 1.04 (0.86-1.27)). Conclusion: A history of previous CV disease was associated with increased risk of incident RA but not osteoarthritis.

Non-major-histocompatibility-complex genetics of ankylosing spondylitis

There is strong evidence from twin and family studies indicating that a substantial proportion of the heritability of susceptibility to ankylosing spondylitis (AS) and its clinical manifestations is encoded by non-major-histocompatibility-complex genes. Efforts to identify these genes have included genomewide linkage studies and candidate gene association studies. One region, the interleukin (IL)-1 gene complex on chromosome 2, has been repeatedly associated with AS in both Caucasians and Asians. It is likely that more than one gene in this complex is involved in AS, with the strongest evidence to date implicating IL-1A. Identifying the genes underlying other linkage regions has been difficult due to the lack of obvious candidates and the low power of most studies to date to identify genes of the small to moderate magnitude that are likely to be involved. The field is moving towards genomewide association analysis, involving much larger datasets of unrelated cases and controls. Early successes using this approach in other diseases indicates that it is likely to identify genes in common diseases like AS, but there remains the risk that the common-variant, common-disease hypothesis will not hold true in AS. Nonetheless, it is appropriate for the field to be cautiously optimistic that the next few years will bring great advances in our understanding of the genetics of this condition.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Progress in the genetics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthropathy. In addition to being strongly associated with HLA-B27, a further 13 genes have been robustly associated with the disease. These genes highlight the involvement of the IL-23 pathway in disease pathogenesis, and indicate overlaps between the pathogenesis of AS, and of inflammatory bowel disease. Genetic associations in B27-positive and -negative disease are similar, with the main exception of association with ERAP1, which is restricted in association to B27-positive cases. This restriction, and the known function of ERAP1 in peptide trimming prior to HLA Class I presentation, indicates that HLA-B27 is likely to operate in AS by a mechanism involving aberrant peptide handling. These advances point to several potential novel therapeutic approaches in AS.

PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton

We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.

Suggestive linkage of 2p22-25 and 11q12-13 with low bone mineral density at the lumbar spine in the Irish population

Osteoporosis is a disease characterized by low bone mineral density (BMD) and poor bone quality. Peak bone density is achieved by the third decade of life, after which bone is maintained by a balanced cycle of bone resorption and synthesis. Age-related bone loss occurs as the bone resorption phase outweighs the bone synthesis phase of bone metabolism. Heritability accounts for up to 90% of the variability in BMD. Chromosomal loci including 1p36, 2p22-25, 11q12-13, parathyroid hormone receptor type 1 (PTHR1), interleukin-6 (IL-6), interleukin 1 alpha (IL-1α) and type II collagen A1/vitamin D receptor (COL11A1/VDR) have been linked or shown suggestive linkage with BMD in other populations. To determine whether these loci predispose to low BMD in the Irish population, we investigated 24 microsatellite markers at 7 chromosomal loci by linkage studies in 175 Irish families of probands with primary low BMD (T-score ≤ -1.5). Nonparametric analysis was performed using the maximum likelihood variance estimation and traditional Haseman-Elston tests on the Mapmaker/Sibs program. Suggestive evidence of linkage was observed with lumbar spine BMD at 2p22-25 (maximum LOD score 2.76) and 11q12-13 (MLS 2.55). One region, 1p36, approached suggestive linkage with femoral neck BMD (MLS 2.17). In addition, seven markers achieved LOD scores > 1.0, D2S149, D11S1313, D11S987, D11S1314 including those encompassing the PTHR1 (D3S3559, D3S1289) for lumbar spine BMD and D2S149 for femoral neck BMD. Our data suggest that genes within a these chromosomal regions are contributing to a predisposition to low BMD in the Irish population.

Genetics of ankylosing spondylitis

Ankylosing spondylitis is a common inflammatory rheumatic disease. Both susceptibility to and clinical manifestations of the disease are highly heritable. Although some genes, notably HLA-B27, have been implicated in susceptibility to the disease, the genetics of the condition are complex and many more genes involved in the condition await discovery.

Genetics of ankylosing spondylitis and rheumatoid arthritis: Where are we at currently, and how do they compare?

Both ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are common, highly heritable conditions, the pathogenesis of which are incompletely understood. Gene-mapping studies in both conditions have over the last couple of years made major breakthroughs in identifying the mechanisms by which these diseases occur. Considering RA, there is an over-representation of genes involved in TNF signalling and the NFκB pathway that have been shown to influence the disease risk. There is also considerable sharing of susceptibility genes between RA and other autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes, autoimmune thyroid disease and celiac disease, with thus far little overlap with AS. In AS, genes involved in response to IL12/IL23, and in endoplasmic reticulum peptide presentation, have been identified, but a full genomewide association study has not yet been reported.

Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population

Objective: Association between ankylosing spondylitis (AS) and two genes, ERAP1 and IL23R, has recently been reported in North American and British populations. The population attributable risk fraction for ERAP1 in this study was 25%, and for IL23R, 9%. Confirmation of these findings to ERAP1 in other ethnic groups has not yet been demonstrated. We sought to test the association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to AS among a Portuguese population. We also investigated the role of these genes in clinical manifestations of AS, including age of symptom onset, the Bath Ankylosing Spondylitis Disease Activity, Metrology and Functional Indices, and the modified Stoke Ankylosing Spondylitis Spinal Score. Methods: The study was conducted on 358 AS cases and 285 ethnically matched Portuguese healthy controls. AS was defined according to the modified New York Criteria. Genotyping of IL23R and ERAP1 allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests of genotypes as implemented in PLINK for dichotomous and quantitative variables respectively. A meta-analysis for Portuguese and previously published Spanish IL23R data was performed using the StatsDirect® Statistical tools, by fixed and random effects models. Results: A total of 14 nsSNPs markers (8 for IL23R, 5 for ERAPl, 1 for LN-PEP) were analysed. Three markers (2 for IL23R and 1 for ERAP1) showed significant single-locus disease associations, confirming that the association of these genes with AS in the Portuguese population. The strongest associated SNP in IL23R was rs1004819 (OR=1.4, p=0.0049), and in ERAP1 was rs30187 (OR=1.26, p=0.035). The population attributable risk fractions in the Portuguese population for these SNPs are 11% and 9.7% respectively. No association was seen with any SNP in LN-PEP, which flanks ERAP1 and was associated with AS in the British population. No association was seen with clinical manifestations of AS. Conclusions: These results show that IL23R and ERAP1 genes are also associated with susceptibility to AS in the Portuguese population, and that they contribute a significant proportion of the population risk for this disease.

The genetics of osteoporosis: Future diagnostic possibilities

The risk of developing osteoporosis is determined by the interaction of several mostly unknown genes and environmental factors. Genetic studies in osteoporosis have largely focussed on association studies of a small number of candidate genes, with few linkage studies performed, and large areas of the genome remaining unexplored. Identifying the genes involved in osteoporosis would be a major advance in our understanding of the causation of the disease, and lead to advances in diagnosis, risk prediction, and potentially preventive and therapeutic measures.

Genetics and the pathogenesis of ankylosing spondylitis

Purpose of review The field of genetic research in ankylosing spondylitis (AS) is advancing rapidly. The purpose of this review is to outline recent findings, particularly, in regard to genetic studies of the major histocompatibility complex (MHC) and the non-MHC genes IL23R, ERAP1, and killer cell immunologlobulin-like receptor (KIR) complex, in AS. Recent findings: Convincing evidence has been reported for the existence of further non-B27 MHC genes involved in AS. Strong, replicated association has been reported with IL23R and ERAP1 and AS. The IL23R finding strongly implicates the TH17 lymphocyte system in AS aetiopathogenesis. Suggestive evidence of a role for KIR gene polymorphism in AS exists, but definitive findings are awaited. Summary: The findings suggest that further genome-wide studies in large case-control cohorts are likely to be very productive in this disease. The IL23R findings and subsequent immunological investigations suggest that targeted intervention in the TH17 system is likely to have major therapeutic benefit, as it does in the genetically related diseases, inflammatory bowel disease and psoriasis.

Genetics of ankylosing spondylitis

Purpose of Review Over the past 3 years, several new genes and gene deserts have been identified that are associated with ankylosing spondylitis (AS). The purpose of this review is to discuss the major findings of these studies, and the answers they provide and questions they raise about the pathogenesis of this common condition. Recent Findings: Five genes/genetic regions have now definitively been associated with AS [the major histocompatibility complex (MHC), IL23R, ERAP1, 2p15 and 21q22]. Strong evidence to support association with the disease has been demonstrated for the genes IL1R2, ANTXR2, TNFSF15, TNFR1 and a region on chromosome 16q including the gene TRADD. There is an overrepresentation of genes involved in Th17 lymphocyte differentiation/activation among genes associated with AS and the related diseases inflammatory bowel disease and psoriasis, pointing strongly to this pathway as playing a major causative role in the disease. Increasing information about differential association of HLA-B27 subtypes with disease suggests a hierarchy of strength of association of those alleles with AS, providing a useful test as to the validity of different potential mechanisms of association of HLA-B27 with AS. The mechanism underlying the association of the gene deserts, 2p15 and 21q22, suggests the involvement of noncoding RNA in AS etiopathogenesis. Summary: The increasing list of genes identified as being definitely involved in AS provides a useful platform for hypothesis-driven research in the field, providing a potential alternative route to determining the underlying mechanisms involved in the disease to research focusing on HLA-B27 alone.

Parenting and the behavior problems of young children with an intellectual disability: Concurrent and longitudinal relationships in a population-based study

We examined parenting behaviors, and their association with concurrent and later child behavior problems. Children with an intellectual disability (ID) were identified from a UK birth cohort (N  =  516 at age 5). Compared to parents of children without an ID, parents of children with an ID used discipline less frequently, but reported a more negative relationship with their child. Among children with an ID, discipline, and home atmosphere had no long-term association with behavior problems, whereas relationship quality did: closer relationships were associated with fewer concurrent and later child behavior problems. Increased parent-child conflict was associated with greater concurrent and later behavior problems. Parenting programs in ID could target parent-child relationship quality as a potential mediator of behavioral improvements in children.