Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes.

AIMS/HYPOTHESIS: MODY is believed to be caused by at least 13 different genes. Five rare mutations at the BLK locus, including only one non-synonymous p.A71T variant, were reported to segregate with diabetes in three MODY families. The p.A71T mutation was shown to abolish the enhancing effect of BLK on insulin content and secretion from pancreatic beta cell lines. Here, we reassessed the contribution of BLK to MODY and tested the effect of BLK-p.A71T on type 2 diabetes risk and variations in related traits. METHODS: BLK was sequenced in 64 unelucidated MODY samples. The BLK-p.A71T variant was genotyped in a French type 2 diabetes case-control study including 4,901 cases and 4,280 controls, and in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) and SUVIMAX (Supplementation en Vitamines et Mineraux Antioxydants) population-based cohorts (n = 6,905). The variant effects were assessed by logistic and linear regression models. RESULTS: No rare non-synonymous BLK mutations were found in the MODY patients. The BLK p.A71T mutation was present in 52 normoglycaemic individuals, making it very unlikely that this loss-of-function mutation causes highly penetrant MODY. We found a nominal association between this variant and increased type 2 diabetes risk, with an enrichment of the mutation in the obese diabetic patients, although no significant association with BMI was identified. CONCLUSIONS/INTERPRETATION: No mutation in BLK was found in our MODY cohort. From our findings, the BLK-p.A71T mutation may weakly influence type 2 diabetes risk in the context of obesity; however, this will require further validation.

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight.

AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. METHODS: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. RESULTS: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1 rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037). CONCLUSIONS/INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.

A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals.

BACKGROUND: In Europeans, 45 genetic risk variants for coronary artery disease (CAD) have been identified in genome-wide association studies. We constructed a genetic risk score (GRS) of these variants to estimate the effect on incidence and clinical predictability of myocardial infarction (MI) and CAD. METHODS: Genotype was available from 6041 Danes. An unweighted GRS was constructed by making a summated score of the 45 known genetic CAD risk variants. Registries provided information (mean follow-up = 11.6 years) on CAD (n = 374) and MI (n = 124) events. Cox proportional hazard estimates with age as time scale was adjusted for sex, BMI, type 2 diabetes mellitus and smoking status. Analyses were also stratified either by sex or median age (below or above 45 years of age). We estimated GRS contribution to MI prediction by assessing net reclassification index (NRI) and integrated discrimination improvement (IDI) added to the European SCORE for 10-year MI risk prediction. RESULTS: The GRS associated significantly with risk of incident MI (allele-dependent hazard ratio (95%CI): 1.06 (1.02-1.11), p = 0.01) but not with CAD (p = 0.39). Stratification revealed association of GRS with MI in men (1.06 (1.01-1.12), p = 0.02) and in individuals above the median of 45.11 years of age (1.06 (1.00-1.12), p = 0.03). There was no interaction between GRS and gender (p = 0.90) or age (p = 0.83). The GRS improved neither NRI nor IDI. CONCLUSION: The GRS of 45 GWAS identified risk variants increase the risk of MI in a Danish cohort. The GRS did not improve NRI or IDI beyond the performance of conventional European SCORE risk factors.

Impact of size at birth and prematurity on adult anthropometry in 4744 middle-aged Danes - The Inter99 study.

Low birth weight is related to increased risk of developing cardiovascular disease and type 2 diabetes in adult life. Since obesity is closely associated with type 2 diabetes and cardiovascular disease, the relationship between size at birth and adult anthropometry is of interest as a mediator of the relationship between birth weight and metabolic diseases. The aim of this study was, therefore, to examine the effect of size at birth and prematurity on measures of adult anthropometry taking adult socio-economic status and lifestyle variables into account. Midwife records with information on mother's age and parity as well as weight, length and maturity at birth were traced in 4744 Danes born between 1939 and 1970. Measures of adult anthropometry (weight, height, body mass index (BMI), waist circumference, hip circumference and waist/hip ratio) had previously been recorded together with information on socio-economic factors, lifestyle and parental diabetes status. Mother's age, parity and diabetes status were associated with offspring birth weight. Size at birth was positively associated with adult height and weight, but only weakly associated with BMI and not associated with waist/hip ratio when adjusted for socio-economic and lifestyle factors. Infants born preterm were less growth restricted at birth and grew to be taller and heavier compared with term infants born small for gestational age. Altogether, this study does not find evidence that obesity or a central fat distribution is mediating the relationship between low birth weight and risk of cardiovascular disease or type 2 diabetes in later life.

Relations in families with a mentally retarded child from the perspective of the siblings.

Nowadays most handicapped children in Sweden live with their families. In this study some of the consequences of the normalisation of their lives are analysed, focusing on young siblings of mentally retarded children. Sixteen siblings, aged 5-11, were tested with the Family Relations Test and Kvebaek Family Sculpture Technique, as were siblings in a control group in which each child was chosen to match a sibling in the target group with respect to age and family constellation. The results show few differences between the two groups. According to the Family Relations Test, however, the emotional involvement in the eldest non-retarded sibling differs statistically significant from that of the corresponding child in the control group and especially so with respect to negative incoming feelings. Young siblings also show a tendency to unconsciously place the mentally retarded child at larger distances from themselves than they place the other siblings with respect to the Kvebaek Family Sculpture Technique. The results indicate that siblings of mentally retarded children have another frame of reference when judging family relations compared with that of the children in the control group. Thus siblings of mentally retarded children seem to adapt to change in the family because of the mentally retarded child and qualitatively alter their thinking in relation to the family members.

Specific phase related patterns of trunk muscle activation during lateral lifting and lowering.

AIM: Lateral bending of the trunk has been demonstrated to be a risk factor in connection with injuries to the spine and its surrounding tissues. Adequate co-ordination of muscle controlling movement and stabilization of the trunk is essential to avoid injury. However, little is yet known about the responses of the lumbar trunk muscles during lateral lifting and lowering. The present investigation was therefore designed to study these responses. METHODS: In six subjects performing lateral lifting and lowering of different loads (0-40 kg) held laterally in one hand, the activities of eight trunk muscles were recorded using intramuscular electrodes. In addition, the angular motion of the trunk from side to side was measured from video recordings. Electromyographic amplitudes on both the contra- and ipsi-lateral sides (ipsi = towards the loaded hand) were analysed in relation to defined phases of trunk motion. RESULTS: Three periods of trunk muscle activation were generally observed, two from the contralateral muscles at the beginning and end of the motion and one from the ipsilateral muscles during the mid-part of the motion. The activities of the contralateral muscles increased, whereas the activities of the ipsilateral muscles decreased with increasing load. The degree of bilateral co-activation was greater in ventral than in dorsal muscles, in lowering compared with lifting, and in no-load or low-load compared with heavy load conditions. CONCLUSION: The co-ordination of trunk muscle activations during side-to-side trunk movements is dependent on trunk position and load. It is speculated that ventral muscles, particularly the oblique and transverse abdominal muscles, are relatively more involved than the other trunk muscles in trunk stabilization, especially in connection with lowering of a light hand-held load.

Intramuscular EMG from the hip flexor muscles during human locomotion.

The purpose was to investigate the activation pattern of five major hip flexor muscles and its adaptation to changing speed and mode of progression. A total of 11 healthy subjects performed walking and running on a motor-driven treadmill at speeds ranging from 1.0 to 6.0 m s-1. Intramuscular fine-wire electrodes were used to record myoelectric signals from the iliacus, psoas, sartorius, rectus femoris and tensor fascia latae muscles. The basic pattern, with respect to number of activation periods, remained the same irrespective of speed and mode of progression. However, differences in the relative duration and timing of onset of activation occurred between individual muscles. Over the speed range in walking, a progressively earlier onset was generally seen for the activation period related to hip flexion. Changes in EMG amplitude were measured in the iliacus and psoas muscles and showed a marked increase and difference between walking and running at speeds above 2.0 m s-1. Thus, the alternating flexion-extension movements at the hip during locomotion appear to be governed by a rather fixed 'neural program' which normally only needs minor modulations to accomplish the adjustments accompanying an increase in speed of progression as well as a change from walking to running.

Relative EMG levels in training exercises for abdominal and hip flexor muscles.

The main purpose of our study was to compare systematically EMG levels in sub-maximal training exercises for the trunk and hip flexor muscles with those voluntarily attainable in corresponding situations. Six healthy subjects performed three types of standardized training exercises, whose static positions, movement velocity and range of motion were reproduced during maximal voluntary isokinetic strength tests. EMG was recorded with wire electrodes from the iliacus muscle and with surface electrodes from the rectus femoris, sartorius, rectus abdominis, obliquus externus and internus muscles. The relative EMG values demonstrated a task dependency which could differ between individual muscles. The maximal voluntary activation levels were relatively constant across conditions. Exceptions were present, particularly for the rectus femoris and iliacus muscles. These findings highlight the consequences of using different methods of normalizing EMG. The relative EMG values presented may serve as guidelines when selecting training exercises for specific trunk and hip flexor muscles in sports and rehabilitation.

Abdominal and hip flexor muscle activation during various training exercises.

The purpose of this study was to provide objective information on the involvement of different abdominal and hip flexor muscles during various types of common training exercises used in rehabilitation and sport. Six healthy male subjects performed altogether 38 different static and dynamic training exercises trunk and hip flexion sit-ups, with various combinations of leg position and support, and bi- and unilateral leg lifts. Myoelectric activity was recorded with surface electrodes from the rectus abdominis, obliquus externus, obliquus internus, rectus femoris, and sartorius muscles and with indwelling fine-wire electrodes from the iliacus muscle. The mean electromyogram amplitude, normalised to the highest observed value, was compared between static and dynamic exercises separately. The hip flexors were highly activated only in exercises involving hip flexion, either lifting the whole upper body or the legs. In contrast, the abdominal muscles showed marked activation both during trunk and hip flexion sit-ups. In hip flexion sit-ups, flexed and supported legs increased hip flexor activation, whereas such modifications did not generally alter the activation level of the abdominals. Bilateral, but not unilateral, leg lifts required activation of abdominal muscles. In trunk flexion sit-ups an increased activation of the abdominal muscles was observed with increased flexion angle, whereas the opposite was true for hip flexion sit-ups. Bilateral leg lifts resulted in higher activity levels than hip flexion sit-ups for the iliacus and sartorius muscles, while the opposite was true for rectus femoris muscles. These data could serve as a basis for improving the design and specificity of test and training exercises.

EMG activities of the quadratus lumborum and erector spinae muscles during flexion-relaxation and other motor tasks.

OBJECTIVE: The aim of this study was to provide new information on the myoelectrical activation of the quadratus lumborum, the deep lateral and the superficial medial lumbar erector spinae, the psoas, and the iliacus muscles in various motor tasks. DESIGN: An intramuscular electromyographic study was performed. BACKGROUND: The contribution of individual deep trunk muscles to the stability of the lumbar spine is relatively unknown in different tasks, including the flexion-relaxation phenomenon. METHODS: Seven healthy subjects participated. Fine-wire electrodes were inserted with a needle guided by ultrasound. RESULTS: The highest activity observed for quadratus lumborum and deep lateral erector spinae occurred in ipsilateral trunk flexion in a side-lying position and for superficial medial erector spinae during bilateral leg lift in a prone position. Quadratus lumborum and deep lateral erector spinae were activated when the flexion-relaxation phenomenon was present for superficial medial erector spinae, i.e. when its activity ceased in the latter part of full forward flexion of the trunk, held relaxed and kyphotic. CONCLUSIONS: In general, the activation of the investigated muscles showed a high degree of task specificity, where activation of a certain muscle was not always predictable from its anatomical arrangement and mechanical advantage.