Genetics of otosclerosis: finally catching up with other complex traits?

Otosclerosis is a relatively common cause of hearing impairment, characterized by abnormal bone remodeling of the middle and inner ear. In about 50-60% of the patients, the disease is present in a familial form. In most of these families, otosclerosis seems to be caused by a small number of genetic factors (oligogenic) while only in a small number of families the disease seems to be truly monogenic. In the remaining patients a complex genetic form of otosclerosis is present. Several studies have aimed to identify the genetic factors underlying otosclerosis, which has led to the identification of eight published loci for monogenic otosclerosis, as well as several genes and one chromosomal region (11q13.1) with a clear association with otosclerosis. Implementation of next-generation sequencing (NGS) in otosclerosis research has led to the identification of pathogenic variants in MEPE, ACAN and SERPINF1, although the pathogenic role of the latter is under debate. In addition, a recent GWAS can be considered a breakthrough for otosclerosis as it identified several strong associations with otosclerosis and suggested new potential candidate genes. These recent findings are important for unraveling the genetic architecture of otosclerosis. More future studies will help to understand the complete pathogenesis of the disease.

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis.

In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3'-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

Mitonuclear genomics challenges the theory of clonality in Trypanosoma congolense: Reply to Tibayrenc and Ayala.

We recently published the first genomic diversity study of Trypanosoma congolense, a major aetiological agent of Animal African Trypanosomiasis. We demonstrated striking levels of SNP and indel diversity in the Eastern province of Zambia as a consequence of hybridization between divergent trypanosome lineages. We concluded that these and earlier findings in T. congolense challenge the predominant clonal evolution (PCE) model. In a recent comment, Tibayrenc and Ayala claim that there are many features in T. congolense supporting their theory of clonality. While we can follow the reasoning of the authors, we also identify major limitations in their theory and interpretations that resulted in incorrect conclusions. First, we argue that each T. congolense subgroup should be analysed independently as they may represent different (sub)species rather than "near-clades". Second, the authors neglect major findings of two robust population genetic studies on Savannah T. congolense that provide clear evidence of frequent recombination. Third, we reveal additional events of introgressive hybridization in T. congolense by analysing the maxicircle coding region using next-generation sequencing analyses. At last, we pinpoint two important misinterpretations by the authors and show that there are no spatially and temporally widespread clones in T. congolense. We stand by our earlier conclusions that the clonal framework is unlikely to accurately model the population structure of T. congolense. Other theoretical frameworks such as Maynard Smith's epidemic model may better represent the complex ancestry seen in T. congolense, where clones delimited in space and time arise against a background of recombination.

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study.

Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3-0.4% in the European population. Clinical symptoms usually occur between the second and fifth decade of life. Different studies have been performed to unravel the genetic architecture of the disease. Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes. In this study, seven candidate genes from the GWAS were resequenced using single molecule molecular inversion probes (smMIPs). smMIPs were used to capture the exonic regions and the 3' and 5' untranslated regions (UTR). Discovered variants were tested for association with the disease using single variant and gene-based association analysis. The single variant results showed that 13 significant variants were associated with otosclerosis. Associated variants were found in five of the seven genes studied here, including AHSG, LINC01482, MARK3, SUPT3H and RELN. Conversely, burden testing did not show a major role of rare variants in the disease. In conclusion, this study was able to replicate five out of seven candidate genes reported in the previous GWAS. This association is likely mainly driven by common variants.

Giant-cell arteritis in the southern United States. An 11-year retrospective study from the Texas Gulf Coast.

Giant-cell arteritis (GCA) and polymyalgia rheumatica are systemic disorders that reportedly affect primarily white women older than age 50 years. We conducted an 11-year chart review to determine the relative occurrence and pattern of demographic involvement of GCA in the Gulf Coast region of the United States. Of 101,239 computer-coded entries for individual patients aged 40 years or older, 60 charts listed GCA as a differential diagnosis. Twenty-seven patients had temporal GCA; 21 temporal artery biopsy specimens were identified. Two patients had associated systemic GCA (one with aortitis). A striking finding was that 13 of the 27 patients were black women (about 50% of the entire study population). The group with GCA and polymyalgia rheumatica (17 patients) had a significantly higher mean erythrocyte sedimentation rate than the group with "pure" GCA. Jaw claudication and blindness were rare. We concluded that temporal GCA seems relatively uncommon in the Gulf Coast region and in the southern United States as a whole. Furthermore, GCA seems rare in Hispanics (only one patient identified). Nonetheless, this is the first report to document a proportionally high occurrence of GCA in black patients in this part of the country.

Isolation of Mycoplasma pneumoniae from synovial fluid samples in a patient with pneumonia and polyarthritis.

A patient with a long history of arthritis developed pneumonia. Two weeks into her hospital course, the patient developed effusions in her knee and wrist that yielded cultures positive for Mycoplasma pneumoniae. To our knowledge, this is the third reported case of M pneumoniae isolation from a joint and the first report of isolation of M pneumoniae from two joints in a patient without hypogammaglobulinemia. The evidence suggests that in individuals with atypical pneumonia and joint effusions, M pneumoniae should be considered as a source of infection.

A community-based epidemiologic study of health sequelae of exposure to hydrofluoric acid.

An accident at an oil refinery in Texas City, Texas, released around 40,000 lb of hydrogen fluoride, exposing the community to the highly toxic and corrosive substance. A population-based epidemiologic study was conducted to evaluate the impact of the accident on the health of the community. Exposure assessment was done using a multipronged approach through a door-to-door survey of 10,811 individuals. A symptom survey resulting in 1994 completed interviews was conducted with a stratified random sample selected from the exposure study database. The sampling was balanced with respect to age, gender, and predisposition across the three ordinal exposure categories. The results show a strong dose relationship (P < 10(-4)) between the exposure and symptoms reported following the accident and 2 years later, most notably breathing and eye symptoms. However, substantial improvement in health was reported over the 2-year period regardless of the level of exposure. Problems of recall bias and behavioral sensitization are considered and it is recognized that the study may have overestimated the effect. It is also recognized that the study may not have completely unraveled the relative importance of exposure and host response in health outcome, since the two were probably conflated in the exposure measure. Nevertheless, the independence of predisposition and reported level of exposure, the magnitude of effect and its consistency, the unmistakable dose response, the large sample size, and the mutual corroboration of various findings make it difficult to dismiss the interpretation that the hydrofluoric acid exposure indeed caused health problems in the community that continued for at least 2 years after the accident.

Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants.

OBJECTIVE: To determine whether ethnic factors influence the presentation, serologic expression and immunogenetics of systemic sclerosis (SSc), patients from 3 ethnic groups were compared for clinical features, SSc-associated autoantibodies, and human leukocyte antigen (HLA) class II alleles. METHODS: Fifty-four Hispanics, 28 African Americans, and 79 whites from Texas with recent-onset (less than 5 years) SSc enrolled in a prospective longitudinal study were assessed for sociodemographic, clinical, immunologic, immunogenetic, behavioral, and psychologic parameters using validated instruments and standard laboratory techniques. Serologic and immunogenetic characteristics from these patients and larger retrospective SSc cohorts of the same ethnic groups also were examined. RESULTS: Hispanics and African Americans in the prospective cohort were more likely to have diffuse skin involvement, skin pigmentary changes, digital ulcers, pulmonary hypertension (African Americans), and an overall lower sociodemographic status than whites, who had more facial telangiectasia and hypothyroidism. In the larger combined prospective and retrospective groups of SSc patients, whites were likely to have more anticentromere antibodies (ACA) and African Americans more anti-U1-ribonucleoprotein (RNP) and anti-U3-RNP (fibrillarin) autoantibodies. HLA-DQB1*0301 was significantly associated with SSc per se in all 3 ethnic groups; HLA-DRB1*11 correlated with the anti-topoisomerase I antibody response, and HLA-DRB1*01, DRB1*04, and DQB1*0501 with ACA. CONCLUSIONS: Important sociodemographic, clinical, and serologic differences exist between whites, African Americans, and Hispanics, despite shared genetic (HLA class II) predisposing factors. The impact of these differences on prognosis remain to be determined.

Functional status and health-related quality of life of elderly osteoarthritic patients treated with celecoxib.

BACKGROUND: This study evaluates the impact of celecoxib on functional status, health-related quality of life (HRQOL), and safety of elderly patients (> or =70 years) with osteoarthritis (OA) of the knee and/or hip. METHODS: Data were pooled from three prospective, randomized, multicenter, double-blind, parallel group trials, each having a 12-week treatment period. Multicenter studies were conducted in the United States and Canada. Data for patients diagnosed with active OA of the knee and/or hip in a flare state who were 70 years of age and older were included in the comparison of therapeutic doses of celecoxib or naproxen versus placebo (N = 768). Elderly patients from each of the three trials who were randomly assigned to groups treated with a placebo. 200 mg/day of celecoxib, 400 mg/ day of celecoxib, or 1000 mg/day of naproxen were included in this analysis. The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status. The Short Form-36 was used as a general measure of HRQOL. Safety was assessed according to the incidence and type of adverse reactions as reported by the patients and the rate of withdrawal due to adverse events. RESULTS: At the end of the treatment period, patients in the celecoxib groups had significant improvement in both functional status and HRQOL in comparison with the placebo group. The effects of total daily doses of 200 mg of celecoxib, 400 mg of celecoxib, and 1000 mg of naproxen on functioning and HRQOL were not found to be significantly different from each other. The incidence of serious adverse events and withdrawal from the studies due to adverse events were similar in the celecoxib groups as they were in the placebo group. Overall, the naproxen group reported a significantly higher incidence of gastrointestinal adverse events than did the placebo and the 200-mg-daily celecoxib groups. CONCLUSIONS: This study showed that celecoxib and naproxen significantly improved functional status and HRQOL in elderly patients compared with those treated with a placebo. Celecoxib-treated patients were also found to experience safety and tolerability similar to that of the placebo-treated patients.

A double-blind, placebo-controlled study of acetylsalicylic acid (ASA) in trained runners.

Acetylsalicylic acid (ASA) is a short-acting oral inhibitor of the cyclooxygenase enzyme. Ingestion of ASA is associated with a decrease in prostaglandins, including those of the E2 series, as well as prostacyclin, and thromboxane. Consumption of therapeutic doses is associated with decreased pain and inflammation and is therefore used in a variety of inflammatory conditions. Platelet aggregation is also inhibited. Because of these observations, and the fact that platelet aggregation has been noted to be altered during exercise, the effects of ASA on exercise tolerance was of interest. We studied 17 healthy male volunteers who regularly ran as a source of exercise. During the study they ingested either 650 mg of ASA or placebo 30 min before running 2 miles (3.2 km). Outcome of the double-blind crossover study was measured by the time required to run a 2-mile distance. No differences between ASA or placebo were noted in the subjects. These data suggest that 650 mg of ASA as a premedication has little effect on exercise performance in normal endurance runners. However, whether ASA may affect pain after exercise or whether other dosage intervals would be more beneficial needs further study.

Rheumatic disorders in adults under 50. Guidelines for differential diagnosis.

Rheumatic disorders are not uncommon in patients between 20 and 50 years of age, and the differential diagnosis may be difficult. However, after a careful history and thorough physical examination, the cause usually becomes apparent. Laboratory findings alone should not be relied on for diagnosis. Because the impact on younger adults may be devastating and the potential disability may be present for many years, these patients represent an important challenge for any practicing physician.

Does rheumatoid factor always mean arthritis?

Rheumatoid arthritis is a clinical syndrome, and the diagnosis requires the presence of pain, swelling, and tenderness in the joints. In the absence of these features, identification of rheumatoid factor in the serum is of little use. Because rheumatoid factor is an immune complex, it is a marker of immune activation and, therefore, may be present in the circulation of persons with a variety of inflammatory conditions that stimulate the immune system. Also, 5% of the healthy population have significant titers of rheumatoid factor in their serum.

Ankylosing spondylitis. An optimistic outlook.

Although a rare disorder, ankylosing spondylitis is often considered in the differential diagnosis of low back pain. The disease primarily affects young white men and is characterized by early morning stiffness in the lower back that typically improves with activity. Patients often have tenderness over one or both sacroiliac joints and limited spinal mobility. With large doses of nonsteroidal antiinflammatory drugs and prompt physical therapy, disability may be kept to a minimum and survival is near normal.

Polymyalgia rheumatica and temporal arteritis. Related conditions with differing therapies.

Polymyalgia rheumatica and temporal arteritis are entities seen chiefly in older adults. Polymyalgia rheumatica is characterized by muscle and joint aches and an elevated erythrocyte sedimentation rate, and it responds rapidly to low-dose corticosteroid therapy. Temporal arteritis is a vasculitic process, the diagnosis of which must be established by invasive procedures. Higher doses of steroids are necessary to treat it, and the potential for steroid-induced side effects is high.

Clinical efficacy and safety of Naprelan versus Naprosyn in the treatment of rheumatoid arthritis.

A double-blind, randomized study compared the efficacy and safety of a controlled-release naproxen sodium formulation (Naprelan, Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) 1,000 mg once daily; a conventional naproxen formulation (Naprosyn, Syntex Laboratories, Inc., Palo Alto, California) 500 mg BID; and placebo given for 12 weeks to 348 patients with rheumatoid arthritis (RA). This was followed by an open-label study to evaluate the safety of naprelan 1,000 mg once daily for an additional 9 months. In the double-blind phase of this study, the safety and efficacy of Naprelan 1,000 mg once daily were compared with those of Naprosyn 500 mg twice daily and placebo in 348 patients with RA. At the end of 12 weeks of treatment, Naprelan and Naprosyn were numerically superior to placebo in 3 of the 4 primary efficacy variables--physician's global assessment, patient's global assessment, and number of painful joints. Differences between Naprelan and placebo reached statistical significance for the patient's global assessment at Week 12 (Visit 7). Significantly more Naprosyn- than placebo-treated patients had at least 1 severe digestive system adverse event (AE); 1 drug-related AE; or 1 drug-related, digestive-system AE. There was no statistically significant difference in the number of AEs experienced by Naprelan-treated patients compared with those who received placebo. A total of 240 patients enrolled in the Naprelan open-label phase. As would be expected, patients initially treated with placebo showed significant improvement after starting Naprelan. Those initially receiving Naprelan or Naprosyn also maintained their improvement. The AE profile with Naprelan was similar to that reported in the double-blind phase. It was concluded that Naprelan 1,000 mg once daily was as effective as Naprosyn 500 mg BID in the treatment of RA and was particularly effective in relieving pain later in the day. The controlled-release formulation may also offer safety benefits.

Anti-inflammatory drugs reduce age-related decreases in brain volume in cognitively normal older adults.

Previous studies have indicated a decreased risk for developing Alzheimer's disease in anti-inflammatory (AI) drug users. Yet few studies have determined whether AI drug use provides a protective effect against normal age-related changes in the brains of older adults. Regional volume changes in gray and white matter were assessed cross-sectionally using optimized voxel-based morphometry in 36 females taking AI drugs as arthritis or pain medication and 36 age- and education-matched female controls. Although mean gray and white matter volume differences between AI drug users and the non-AI group were small, AI drug use interacted with age, such that the non-AI group showed significantly greater age-related volume changes in regions of both gray and white matter compared to the AI drug users. These regions included the superior and medial frontal gyri, middle and inferior temporal gyri, fusiform and parahippocampal gyri, and occipital gray matter as well as temporal, parietal, and midbrain white matter. The results are consistent with the notion that AI drugs provide protection against age-related changes in brain volume. It is possible that inflammation plays a role in volume decreases associated with normal aging, and that suppressing the inflammatory response moderates this decrease.