Pasi J. Eskola

Genetic Association Studies in Lumbar Disc Degeneration: A Systematic Review

Objective Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans. Methods A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990–2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines. Results Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat), COL11A1 (rs1676486), GDF5 (rs143383), SKT (rs16924573), THBS2 (rs9406328) and MMP9 (rs17576). Conclusions Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.

Genetic susceptibility of intervertebral disc degeneration among young Finnish adults

BackgroundDisc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD.MethodsWe investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging.ResultsOf the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89).ConclusionOur results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Depressive symptom profiles and glucose tolerance status

report of a medical diagnosis during follow-up. This definition had been previously validated. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) of depression across sex-specific quintiles of predicted CVD risk. Models were adjusted for age, adherence to the Mediterranean dietary pattern (low/moderate/high), physical activity (quintiles), total energy intake (quintiles), menopause due to natural causes (yes/no), living alone (yes/no), employment status (employed, unemployed, retired), marital status (married or not), and personality traits (competitiveness, relaxation, dependence). Over 151,125 person-years of follow-up, we identified 927 incident cases of depression. A higher predicted cardiovascular risk at baseline was significantly associated with higher risk of depression. Young adult participants (<40 years) in the highest quintile of CVD risk (mean risk: 0.30%) presented an adjusted HR of 1.47 (95% CI: 1.08-2.00) compared to those in the lowest quintile (mean risk: 0.05%). The second, third and fourth quintiles presented non-significant HRs of 1.05, 1.21, and 1.16, respectively. This association was even stronger for older participants ( 40 years): 1.65 (1.17-2.34) for the second quintile (mean risk: 0.54%), 1.68 (1.16-2.42) for the third quintile (mean risk: 0.85%), 1.85 (1.24-2.75) for the fourth quintile (mean risk: 1.43%), and 2.17 (1.33-3.54) for the fifth quintile (mean risk: 4.31%), all of them compared to the first quintile (mean risk: 0.31%). So, a higher predicted CVD risk was strongly associated with a higher future incidence of depression, both in younger and older adults. This finding may support the hypothesis that CVD and depression share common pathophysiological mechanisms. As an alternative, depression and CVD may share risk factors but not the mechanisms through which these risk factors act. Actually, there is a growing body of research on the bi-directional relationship between depression and metabolic syndrome, obesity or type 2 diabetes. The clinical implications of our findings are of great importance for public health and clinical practice. First, public health agencies may consider sharing efforts for the primary prevention of both depression and CVD, which may be synergic. Both CVD and depression are associated with a set of known and modifiable risk factors that it is worth to target from a public health perspective. Second, general practitioners should consider that both older and younger patients at higher risk of CVD may also be at higher risk of depression. Physicians can calculate the predicted cardiovascular risk using the Framingham risk score or other similar equations which are available in charts and user-friendly versions. Their interventions addressed to obtain improvements in these equations through changes in lifestyle are likely to also be an appropriate approach for the prevention of depression. Finally, the knowledge that lifestyle factors are not only increasing the risk of CVD but also that of depression, even at younger ages, needs to reach the general public. This take-home message may be useful to achieve greater changes in unhealthy habits throughout the life cycle in the population at large.

Long-term adolescent multi-site musculoskeletal pain is associated with psychological distress and anxiety

OBJECTIVE Although several studies have shown that adolescent musculoskeletal pain is associated with psychological problems in a cross-sectional setting, the associations of long-term musculoskeletal pain with psychological distress and anxiety are not known. METHODS The study included 1773 adolescents belonging to the Northern Finland Birth Cohort 1986. They received a postal questionnaire at the age of 16years and a follow-up questionnaire two years later. The first inquiry contained questions about the sites of musculoskeletal pain; the second had the same pain questions, along with measures of distress and anxiety. Risk ratios (RR) were assessed by log-linear regression analysis. RESULTS Multi-site musculoskeletal pain (in ≥2 body locations) at both 16 and 18years was common, reported by 53% of girls and 30% of boys. Multi-site pain at both ages, compared to those with multi-site pain neither at 16 nor 18years, was associated with psychological distress at the age of 18 among both girls (RR 1.8 95% CI 1.2-2.7) and boys (RR 3.5 95% CI 2.1-5.9). For anxiety, the corresponding relative risks were 1.5 (95% CI 1.0-2.2) and 1.8 (95% CI 1.4-2.3), respectively. For short-term multi-site pain (prevalent only at the age of 16 or 18), these relative risks were between 0.8 and 2.3. CONCLUSIONS Adolescents with long-term multi-site pain have higher levels of distress and anxiety than those without or with only short-term multi-site pain. Associations were found in both genders, but the relationship between pain and distress was more pronounced among boys. The associations had modest effect strength.

Depression and Insulin Resistance: Additional Support for the Novel Heuristic Model in Perimenopausal Depression

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ÖMPSQ-short score and determinants of chronic pain : cross-sectional results from a middle-aged birth cohort

BACKGROUND The Örebro Musculoskeletal Pain Screening Questionnaire (ÖMPSQ) was developed to identify patients at risk of developing work disability due to pain. So far, neither the ÖMPSQ or its short version (ÖMSPQ-short) have been tested in population-based samples. AIM We examined the associations between several well-known determinants for chronic pain and ÖMPSQ-Short Score. DESIGN Cross-sectional study. SETTING All measurements and tests were made at the University of Oulu. POPULATION Subjects belonging to the Northern Finland Birth Cohort 1966 answered a questionnaire at the age of 46 years (N.=5637). METHODS The questionnaire included the ÖMPSQ-short as well as questions about smoking, education, location, number of pain sites, and physical activity. In addition, body weight and height were measured in order to calculate the Body Mass Index. RESULTS In multivariate logistic regression analysis, reporting 4-5 pain sites (females OR 3.4; males 3.0), ≥6 pain sites (females OR 12.4; males 7.4) and current smoking (females 1.8; males 2.6) were associated with being classified into the ÖMPSQ high risk group. In females, also obesity (OR 1.6) and less than 9 years of education (2.7) were associated with higher ÖMPSQ Score. The frequency of physical activity was not associated with the ÖMPSQ Score. CONCLUSIONS High number of pain sites and smoking among both genders, and obesity and low education level among females is associated with higher ÖMPSQ scores. Therefore, the ÖMPSQ-short may be a working instrument for also screening the general population. CLINICAL REHABILITATION IMPACT Results of this study may improve the detection of patients at high risk of developing work disability due to pain.