Alex J. MacGregor

Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins

OBJECTIVE Twin concordance data for rheumatoid arthritis (RA) on their own provide only limited insight into the relative genetic and environmental contribution to the disease. We applied quantitative genetic methods to assess the heritability of RA and to examine for evidence of differences in the genetic contribution according to sex, age, and clinical disease characteristics. METHODS Data were analyzed from 2 previously published nationwide studies of twins with RA conducted in Finland and the United Kingdom. Heritability was assessed by variance components analysis. Differences in the genetic contribution by sex, age, age at disease onset, and clinical characteristics were examined by stratification. The power of the twin study design to detect these differences was examined through simulation. RESULTS The heritability of RA was 65% (95% confidence interval [95% CI] 50-77) in the Finnish data and 53% (95% CI 40-65) in the UK data. There was no significant difference in the strength of the genetic contribution according to sex, age, age at onset, or disease severity subgroup. Both study designs had power to detect a contribution of at least 40% from the common family environment, and a difference in the genetic contribution of at least 50% between subgroups. CONCLUSION Genetic factors have a substantial contribution to RA in the population, accounting for approximately 60% of the variation in liability to disease. Although tempered by power considerations, there is no evidence in these twin data that the overall genetic contribution to RA differs by sex, age, age at disease onset, and disease severity.

Epidemiology of back disorders: prevalence, risk factors, and prognosis

Purpose of reviewThis article reviews some of the advances that have taken place in understanding back disorders, with a particular emphasis on low back pain, as this area has been most represented in the literature in the preceding year (September 2003 to September 2004). Recent findingsEpidemiological studies continue to provide insights into the prevalence of back pain and have identified many individual, psychosocial, and occupational risk factors for its onset. Psychological factors have an important role in the transition from acute to chronic pain and related disability. Recent advances show that there is a significant genetic effect on severe low back pain in the community. Data emerging from candidate gene studies show an association between lumbar disc disease and mutations of genes encoding the α-2 and α-3 subunits of collagen IX. SummaryBack pain is among the most common conditions for which patients seek medical care. Interventions based on behavioral and cognitive principles and exercise programs are effective in improving disability in chronic back pain. Although progress has been made in understanding the role of genetic mutations in disorders such as lumbar disc disease, further investigation of the interaction between genetic and environmental factors such as physical stress is needed.

Genetic and environmental influences on migraine: a twin study across six countries.

Migraine is a common neurovascular brain disorder that is manifested in recurrent episodes of disabling headache. The aim of the present study was to compare the prevalence and heritability of migraine across six of the countries that participate in GenomEUtwin project including a total number of 29,717 twin pairs. Migraine was assessed by questionnaires that differed between most countries. It was most prevalent in Danish and Dutch females (32% and 34%, respectively), whereas the lowest prevalence was found in the younger and older Finnish cohorts (13% and 10%, respectively). The estimated genetic variance (heritability) was significant and the same between sexes in all countries. Heritability ranged from 34% to 57%, with lowest estimates in Australia, and highest estimates in the older cohort of Finland, the Netherlands, and Denmark. There was some indication that part of the genetic variance was non-additive, but this was significant in Sweden only. In addition to genetic factors, environmental effects that are non-shared between members of a twin pair contributed to the liability of migraine. After migraine definitions are homogenized among the participating countries, the GenomEUtwin project will provide a powerful resource to identify the genes involved in migraine.

Genetic Contribution to Bone Metabolism, Calcium Excretion, and Vitamin D and Parathyroid Hormone Regulation

A classical twin study was performed to assess the relative contribution of genetic and environmental factors to bone metabolism, calcium homeostasis, and the hormones regulating them. It was examined further whether the genetic effect is menopause dependent. The subjects were 2136 adult twins (98.3% female): 384 monozygotic (MZ) and 684 dizygotic (DZ) twin pairs. The intraclass correlations were calculated, and maximum likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in MZ twin pairs. The heritabilities (95% CIs) obtained from model fitting for hormones regulating bone metabolism and calcium homeostasis were parathyroid hormone (PTH), 60% (54–65%); 25‐hydroxyvitamin D [25(OH)D]; 43% (28–57%), 1,25‐hydroxyvitamin D [1,25(OH)], 65% (53–74%); and vitamin D binding protein 62% (56–66%). The heritabilities (95% CIs) for markers of bone formation also were assessed; bone‐specific alkaline phosphatase (BSAP), 74% (67–80%), and osteocalcin, 29% (14–44%); marker of bone resorption deoxypyridinoline (DPD), 58% (52–64%); and measure of calcium homeostasis 24 h urine calcium, creatinine (Cr), 52% (41–61%). The magnitude of genetic influence differed with menopause for most variables. This study provides evidence for the importance of genetic factors in determining bone resorption and formation, calcium excretion, and the hormones regulating these processes. It shows for the first time a clear genetic effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion. The genes controlling bone hormones and markers are likely to be useful therapeutic and diagnostic targets.

Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study

Objective Low back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population. Material and Methods A cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18–84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition. Results The major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (p<0.001) associated with non-specific LBP. The single most important risk factor was the amount of LDD. After adjustment for other risk factors, the individuals who exhibited advanced LDD (90% vs 10%) had 3.2 higher odds of manifesting LBP. The data also showed a significant (p<0.001) genetic correlation between the LBP and LDD measurements, suggesting that approximately 11–13% of the genetic effects are shared by LDD and LBP. Conclusions The main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.

Testing the fetal origins hypothesis in twins: the Birmingham twin study

Aims/hypothesis. To test whether the link between birthsize and raised blood pressure or glucose tolerance is due to genetic or intrauterine factors, we studied whether differences in birthweight between pairs of monozygous and dizygous twins are associated with adult differences in blood pressure and glucose tolerance.¶Methods. A sample of 58 monozygous and 140 dizygous twins were identified from a register of births in Birmingham, United Kingdom, between 1950 and 1954. The twins had their blood pressure measured and underwent an oral glucose tolerance test.¶Results. There were no statistically significant associations between birthweight, length or ponderal index, and either blood pressure or glucose tolerance in the twins. Although there were substantial within-pair differences in birthweight between monozygous and dizygous twin pairs, these differences did not correlate with the adult outcomes. Monozygous correlations, however, for both blood pressure and glucose tolerance were statistically significantly higher than dizygous correlations and a quantitative genetic model suggested statistically significant heritability for these traits. In contrast correlations of birthsize were similar in monozygous and dizygous pairs suggesting only a small genetic component in determining fetal size.¶Conclusion/interpretation. Our results show that birthsize in twins does not predict adult blood pressure or glucose tolerance. We also suggest that shared genetic determinants for fetal growth and adult outcomes are not likely to be prevalent or powerful. [Diabetologia (2001) 44: 33–39]

90-day mortality after 409,096 total hip replacements for osteoarthritis, from the National Joint Registry for England and Wales: a retrospective analysis.

BACKGROUND Death within 90 days after total hip replacement is rare but might be avoidable dependent on patient and treatment factors. We assessed whether a secular decrease in death caused by hip replacement has occurred in England and Wales and whether modifiable perioperative factors exist that could reduce deaths. METHODS We took data about hip replacements done in England and Wales between April, 2003, and December, 2011, from the National Joint Registry for England and Wales. Patient identifiers were used to link these data to the national mortality database and the Hospital Episode Statistics database to obtain details of death, sociodemographics, and comorbidity. We assessed mortality within 90 days of operation by Kaplan-Meier analysis and assessed the role of patient and treatment factors by Cox proportional hazards model. FINDINGS 409,096 primary hip replacements were done to treat osteoarthritis. 1743 patients died within 90 days of surgery during 8 years, with a substantial secular decrease in mortality, from 0·56% in 2003 to 0·29% in 2011, even after adjustment for age, sex, and comorbidity. Several modifiable clinical factors were associated with decreased mortality according to an adjusted model: posterior surgical approach (hazard ratio [HR] 0·82, 95% CI 0·73-0·92; p=0·001), mechanical thromboprophylaxis (0·85, 0·74-0·99; p=0·036), chemical thromboprophylaxis with heparin with or without aspirin (0·79, 0·66-0·93; p=0·005), and spinal versus general anaesthetic (0·85, 0·74-0·97; p=0·019). Type of prosthesis was unrelated to mortality. Being overweight was associated with lower mortality (0·76, 0·62-0·92; p=0·006). INTERPRETATION Postoperative mortality after hip joint replacement has fallen substantially. Widespread adoption of four simple clinical management strategies (posterior surgical approach, mechanical and chemical prophylaxis, and spinal anaesthesia) could, if causally related, reduce mortality further. FUNDING National Joint Registry for England and Wales.

Association between birth weight and adult blood pressure in twins: historical cohort study

Abstract Objectives: To evaluate the associations in twins between within pair differences in birth weight and subsequent blood pressures as adults thereby removing the impact of potential parental confounding variables. Design: Historical cohort study. Setting: St Thomass UK adult twin register, June 1992 to September 1995. Participants: 492 pairs of female twins (mean age 54 years). Main outcome measures: Mean within pair differences in adult blood pressure in each of four strata of within pair differences in birth weight (0, 1-500 g, 501-1000 g, >1000 g). Differences in blood pressure were analysed before and after adjustment for potential confounders between adult twins, after exclusion of those twin pairs including at least one twin taking antihypertensive drugs, and by zygosity. Results: Reported mean birth weights of heavier and lighter twins were 2.51 (SD 0.61)v 2.12 (0.59) kg respectively. A graded inverse relation between strata of within pair differences in birth weight and differences in adult blood pressure was apparent, with an adjusted blood pressure range of 8.7/5.1 mm Hg across the four strata (test for trend: systolic, P=0.05; diastolic, P=0.09). After excluding those women taking antihypertensive drugs the significance of the association was similar (systolic, P=0.04; diastolic, P=0.10). When differences in blood pressure were stratified for zygosity similar but non-significant trends were apparent. Conclusion: It would seem that birth weight is inversely associated with adult blood pressure and that this association is independent of parental confounding variables probably including, in view of the findings in monozygotic twins, genetic factors. The observed blood pressure differences are likely to result from retarded intrauterine growth due to placental dysfunction rather than inadequate maternal nutrition. Key messages Among adult twins, blood pressures tend to be lower among those twins who were heavier at birth Strata of within pair birthweight differences of twins show a graded inverse relation with adult blood pressure differences Monozygotic and dizygotic twins show a similar inverse association between birthweight differences and adult blood pressure differences The inverse association between birth weight and adult blood pressure is independent of parental confounding variables

Twins: novel uses to study complex traits and genetic diseases

The challenge faced by research into the genetic basis of complex disease is to identify genes of small relative effect against a background of substantial genetic and environmental variation. This has focused interest on a classical epidemiological design: the study of twins. Through their precise matching for age, the common family environment and background environmental variation, studying diseases in non-identical twins provides a means to enhance the power of conventional strategies to detect genetic influence through linkage and association. The unique matching of identical twins provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact.

Risk of Wrist Fracture in Women Is Heritable and Is Influenced by Genes That Are Largely Independent of Those Influencing BMD

Using a classical twin design study, we estimated the genetic contribution to liability of wrist fracture in women to be statistically and clinically significant. BMD is highly heritable, but statistical models showed very little overlap of shared genes between the two traits.