Development and validation of a prediction model for incident hand osteoarthritis in the HUNT study.

OBJECTIVE: To develop and externally validate prediction models for incident hand osteoarthritis (OA) in a large population-based cohort of middle aged and older men and women. DESIGN: We included 17,153 men and 18,682 women from a population-based cohort, aged 35-70 years at baseline (1995-1997). Incident hand OA were obtained from diagnostic codes in the Norwegian National Patient Register (1995-2018). We studied whether a range of self-reported and clinically measured predictors could predict hand OA, using the Area Under the receiver-operating Curve (AUC) from logistic regression. External validation of an existing prediction model for male hand OA was tested on discrimination in a sample of men. Bootstrapping was used to avoid overfitting. RESULTS: The model for men showed modest discriminatory ability (AUC = 0.67, 95% CI 0.62-0.71). Adding a genetic risk score did not improve prediction. Similar discrimination was observed in the model for women (AUC = 0.62, 95% CI 0.59-0.64). Prediction was not improved by adding a genetic risk score or hormonal and reproductive factors. Applying external validation, similar results were observed among men in HUNT (The Nord-Trøndelag Health Study) as in the developmental sample (AUC = 0.62, 95% CI 0.57-0.65). CONCLUSION: We developed prediction models for incident hand OA in men and women. For women, the model included body mass index (BMI), heavy physical work, high physical activity and perceived poor health. The model showed moderate discrimination. For men, we have shown that a prediction model including BMI, education and information on sleep can predict incident hand OA in several populations with moderate discriminative ability.

The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT study.

BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.

The causal role of smoking on the risk of hip or knee replacement due to primary osteoarthritis: a Mendelian randomisation analysis of the HUNT study.

OBJECTIVE: Smoking has been associated with a reduced risk of hip and knee osteoarthritis (OA) and subsequent joint replacement. The aim of the present study was to assess whether the observed association is likely to be causal. METHOD: 55,745 participants of a population-based cohort were genotyped for the rs1051730 C > T single-nucleotide polymorphism (SNP), a proxy for smoking quantity among smokers. A Mendelian randomization analysis was performed using rs1051730 as an instrument to evaluate the causal role of smoking on the risk of hip or knee replacement (combined as total joint replacement (TJR)). Association between rs1051730 T alleles and TJR was estimated by hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were adjusted for age and sex. RESULTS: Smoking quantity (no. of cigarettes) was inversely associated with TJR (HR 0.97, 95% CI 0.97-0.98). In the Mendelian randomization analysis, rs1051730 T alleles were associated with reduced risk of TJR among current smokers (HR 0.84, 95% CI 0.76-0.98, per T allele), however we found no evidence of association among former (HR 0.97, 95% CI 0.88-1.07) and never smokers (HR 0.97, 95% CI 0.89-1.06). Neither adjusting for body mass index (BMI), cardiovascular disease (CVD) nor accounting for the competing risk of mortality substantially changed the results. CONCLUSION: This study suggests that smoking may be causally associated with the reduced risk of TJR. Our findings add support to the inverse association found in previous observational studies. More research is needed to further elucidate the underlying mechanisms of this causal association.

Early menarche and chronic widespread musculoskeletal complaints--Results from the HUNT study.

BACKGROUND: There is a predominance of chronic widespread musculoskeletal complaints (WMSC) among women. Previous studies suggest an association between hormonal factors and pain. However, it is not known whether earlier age at menarche is associated with higher prevalence of chronic WMSC. The aim of this study was to investigate the association between age at menarche and chronic WMSC. METHODS: Data from a cross-sectional study of inhabitants ≥20 years in Nord-Trøndelag County (Helseundersøkelsen i Nord-Trøndelag -HUNT), conducted in 1995-1997 (HUNT 2) were used. The study population comprised 32,673 women with valid information of age at menarche (exposure) and chronic WMSC (outcome data). RESULTS: In total, 8986 (27.5%) women reported WMSC. The overall prevalence of WMSC was 29.7% among those with menarche ≤12 years and 26.7% among those with menarche >12 years. The prevalence of chronic WMSC was consistently higher for those with early age at menarche in all age groups. The crude odds ratio for chronic WMSC, when comparing women with age at menarche ≤12 years to women with age at menarche >12 years, was 1.16 (95% CI: 1.10-1.22). The corresponding odds ratio was 1.26 (95% CI: 1.19-1.34) when adjusted for age, education, body mass index (BMI), smoking, alcohol consumption, depression, systolic blood pressure (SBP) and parity. CONCLUSION: In this cross-sectional study, there was an association between early age at menarche and chronic WMSC later in life, but the difference in absolute risk was low (3%).

Migraine and frequent tension-type headache are not associated with multiple sclerosis in a Norwegian case-control study.

BACKGROUND: Inconsistent results have been obtained with regard to headache comorbidity in multiple sclerosis (MS). OBJECTIVE: Investigate the one-year prevalence of migraine and tension-type headache (TTH) in Norwegian MS patients and relate this to clinical parameters. METHODS: A questionnaire concerning headache was administered to 756 MS patients and 1090 controls and used to determine the one-year prevalence of migraine and frequent TTH. RESULTS: No significant differences were seen between patients and controls or between patients with different disease course. Less migraine was observed in patients with Expanded Disability Status Scale score (EDSS) ≥4.0. CONCLUSIONS: This case-control study does not support an association between migraine or TTH and MS.

Blood pressure as a risk factor for headache and migraine: a prospective population-based study.

BACKGROUND AND PURPOSE: During the past decade, several population-based studies have found an inverse association between blood pressure (BP) and headache. However, most of them have a cross-sectional design or lack a validated definition of a headache-free population at baseline. Therefore, additional population-based studies using a clearly defined headache-free population and a prospective design are warranted. METHODS: Data from two large epidemiological studies, the Nord-Trondelag Health Survey 1995-1997 (HUNT 2) and 2006-2008 (HUNT 3), were used to evaluate the association between BP (systolic, diastolic and pulse pressure) at baseline and headache (migraine and tension type headache) at follow-up. RESULTS: An inverse relationship was found between all three BP measures at baseline in HUNT 2 and any headache in HUNT 3, more evident for systolic BP [odds ratio (OR) 0.90 per 10 mmHg increase in systolic BP, 95% confidence interval (CI) 0.87-0.93, P < 0.001] and pulse pressure (OR 0.84 per 10 mmHg increase in pulse pressure, 95% CI 0.80-0.89, P < 0.001) than for diastolic BP (OR 0.92 per 10 mmHg increase in diastolic BP, 95% CI 0.87-1.00, P = 0.036). The most robust finding, evident for both sexes, was that increased pulse pressure was linked to decreased prevalence of both migraine and tension type headache. CONCLUSION: An inverse relationship between BP and subsequent development of headache was confirmed in this large-scale population-based cohort study. Nevertheless, further research is needed to investigate the underlying mechanisms explaining these findings.

Candidate-gene association study searching for genetic factors involved in migraine chronification.

INTRODUCTION: Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. METHODS: We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p values < 0.05 were forwarded to the replication stage containing 531 patients with CM or HFM. RESULTS: Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. DISCUSSION: We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.

OS046. Genome-wide association scans identify novel maternalsusceptibility loci for preeclampsia.

INTRODUCTION: We have successfully utilized a family-based study design to localize several positional candidate preeclampsia susceptibility genes to chromosomes 2q22(ACVR2A,LCT,LRP1B,RND3,GCA),5q (ERAP2) and 13q(TNFSF13B). We now report on our continued positional cloning efforts using an alternative genome-wide association (GWA) mapping strategy in large Caucasian case-control cohorts from Australia and Norway. OBJECTIVES: To identify maternal genetic risk loci for preeclampsia. METHODS: The unrelated Australian samples (545 cases,547 controls) were genotyped using Illumina BeadChip technology (700K loci) and have been analyzed using PLINK. All unrelated Norwegian samples were genotyped across several Illumina BeadChip substrates and consist of 847 cases (700K loci) and 638 controls. The Norwegian control samples originate from other HUNT studies pertaining to migraine (n=95,700K loci), lung cancer (n=89,370K loci) and normal brain pathology (n=454,2.5M loci). To analyze a concordant set of 2.5-3 million genotypes across all Norwegian samples we are currently using MaCH to impute those loci not directly genotyped. The Norwegian GWA data will be analyzed in SOLAR utilizing empirical kinship estimates to account for any distant relatedness. RESULTS: 1078 Australian samples (538 cases,540 controls) and 648, 175 SNPs passed our quality control metrics. Two SNP associations (rs7579169,p=3.6×10(-7); rs12711941,p=4.3×10(-7)) satisfied our genome-wide significant threshold (p<5.1×10(-7)). These SNPs reside less than 15kb downstream from the 3 terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. Sequencing of the INHBB locus in our patient cohort identified a third intergenic SNP to significantly associate with preeclampsia (rs7576192,p=1.5×10(-7)). These three SNPs confer risk (OR>1.56) and are in strong linkage disequilibrium with each other (r(2)>0.9) but not with any other genotyped SNP ±200kb. The analysis of the Norwegian GWAS is underway. CONCLUSION: The Australian GWAS has identified a novel preeclampsia risk locus on chromosome 2q. The INHBB gene closest to our SNP associations is a plausible positional candidate susceptibility gene. There is a substantive body of evidence implicating inhibins, activins and other members of the TGF-ßsuperfamily to have a role in the development of preeclampsia. The biological connection between ACVR2A and INHBB leads us to speculate that our linkage-based and GWA-based study designs, respectively, have identified a key biological pathway involved in susceptibility to preeclampsia.

Headache, migraine and cardiovascular risk factors: the HUNT study.

BACKGROUND: Migraine with aura (MA) has been found to be a risk factor for cardiovascular disease including ischaemic stroke and myocardial infarction. Studies have also reported a higher prevalence of unfavourable cardiovascular risk factors amongst migraineurs, but results have been conflicting as to whether this is restricted to MA or also holds true for migraine without aura (MO). This study aims to examine the relation between headache and cardiovascular risk factors in a large cross-sectional population-based study. METHODS: A total of 48,713 subjects (age ≥ 20 years) completed a headache questionnaire and were classified according to the headache status in the Nord-Trøndelag Health Study in Norway 1995-1997 (HUNT 2). Framingham 10-year risk for myocardial infarction and coronary death could be calculated for 44,098 (90.5%) of these. Parameters measured were blood pressure, body mass index, serum total and high-density lipoprotein cholesterol. RESULTS: Compared to controls, Framingham risk score was elevated in non-migraine headache sufferers (OR 1.17, 95% CI 1.10-1.26), migraineurs without aura (OR 1.17, 95% CI 1.04-1.32) and most pronounced amongst migraineurs with aura (OR 1.54, 95% CI 1.21-1.95). Framingham risk score consistently increased with headache frequency. For non-migrainous headache and MO, the increased risk was accounted for by the lifestyle factors smoking, high BMI and low physical activity, whilst such factors did not explain the elevated risk associated with MA. CONCLUSIONS: Both MA, MO and non-migrainous headache are associated with an unfavourable cardiovascular risk profile, but different mechanisms seem to underlie the elevated risk in MA than in the other headache types.

A re-evaluation of the phonological similarity effect in adults' short-term memory of words and nonwords.

The phonological similarity effect (PSE) was studied in two tasks of serial recall, in one task of serial recognition and one item identification task. PSE occurred only in the former three tasks involving memory of order when study items were words and nonwords with an associative connectedness to long-term memory. Nonwords that, according to a reaction time assessment of associative value, were less well connected to long-term memory mechanisms, were not sensitive to phonological similarity. These results are discussed in relation to contemporary models of short-term memory that explain the PSE as a result of confusions of items that are similarly encoded in a phonological layer. This layer is identified as a higher-level phonological space that is accessed by words and nonwords of high associative value and not by nonwords of low associative value.