Estimating the causal effect of liability to disease on healthcare costs using Mendelian Randomization

Accurate measurement of the effects of disease status on healthcare costs is important in the pragmatic evaluation of interventions but is complicated by endogeneity bias. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We used a novel Mendelian Randomization analysis to model the causal impact on inpatient hospital costs of liability to six prevalent diseases and health conditions: asthma, eczema, migraine, coronary heart disease, Type 2 diabetes, and depression. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs on over 300,000 individuals. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex and methods robust to violations of the exclusion restriction. Results overall were imprecise and we could not rule out large effects of liability to disease on healthcare costs. In particular, genetic liability to coronary heart disease had substantial impacts on costs.     

Female waist-to-hip ratio,body mass index and sexual attractiveness in China

Men and women at Northwest University (n=751), Xi'an, China were asked to judge the attractiveness of photographs of female patients who had undergone micrograft surgery to reduce their waist-to-hip ratios (WHR). Micrograft surgery involves harvesting adipose tissue from the waist and reshaping the buttocks to produce a low WHR and an 'hourglass' female figure. This gynoid distribution of female body fat has been shown to correlate with measures of fertility and health. Significantly larger numbers of subjects, of both sexes, chose post-operative photographs, with lower WHRs, as more attractive than pre-operative photographs of the same women. Some patients had gained, and some had lost weight, post-operatively, with resultant changes in body mass index (BMI). However, these changes in BMI were not related to judgments of attractiveness. These results show that the hourglass female figure is rated as attractive in China, and that WHR, rather than BMI, plays a crucial role in such attractiveness judgments.     

Time discounting and the body mass index: Evidence from the Netherlands

In many Western countries, the relative weight of people -- measured by the body mass index (BMI) -- has increased substantially in recent years, leading to an increasing incidence of overweight and related health problems. As with many forms of risky behavior, it is plausible that overweight is related to the individual discount rate. Increases in credit card debts, the rise in gambling and the development of a more hedonic life style, suggest that the average discount rate has increased over time. An increase in time discounting may be a contributing factor in the rise in BMI. Applying a large set of indicators for the individual discount rate from a Dutch survey, this paper analyzes whether changes in time discounting can account for differences in body mass between individuals at a given point in time and whether changes in the average individual discount rate can explain the remarkable increase in BMI experienced in recent years in the Netherlands. We find some evidence for a link between time discounting and differences in BMI between people, but this relationship depends strongly on the choice of the proxy for the discount rate. Giving our hypothesis the best chance, we analyze the development of the time discounting proxies that are most strongly related to BMI. We find no evidence for a change of these proxies over time. Our main conclusion therefore is that overweight might be related to the way people discount future health benefits, but the increase in BMI is more likely explained by shifts in other parameters that determine the intertemporal decisions regarding the trade-off of current and future health and satisfaction.     

Patterns of subcutaneous fat deposition and the relationship between body mass index and waist-to-hip ratio: Implications for models of physical attractiveness

Body mass index (BMI) and waist-to-hip ratio (WHR) are two widely used anthropometric indices of body shape argued to convey different information about health and fertility. Both indices have also been shown to affect attractiveness ratings of female bodies. However, BMI and WHR are naturally positively correlated, complicating studies designed to identify their relative importance in predicting health and attractiveness outcomes. We show that the correlation between BMI and WHR depends on the assumed model of subcutaneous fat deposition. An additive model, whereby fat is added to the waist and hips at a constant rate, predicts a correlation between BMI and WHR because with increasing fat, the difference between the waist and hips becomes smaller relative to total width. This model is supported by longitudinal and cross-sectional data. We parameterised the function relating WHR to BMI for white UK females of reproductive age, and used this function to statistically decompose body shape into two independent components. We show that judgements of the attractiveness of female bodies are well explained by the component of curvaceousness related to BMI but not by residual curvaceousness. Our findings resolve a long-standing dispute in the attractiveness literature by confirming that although WHR appears to be an important predictor of attractiveness, this is largely explained by the direct effect of total body fat on WHR, thus reinforcing the conclusion that total body fat is the primary determinant of female body shape attractiveness.     

Patterns of eye movements when male and female observers judge female attractiveness, body fat and waist-to-hip ratio

Behavioural studies of the perceptual cues for female physical attractiveness have suggested two potentially important features: body fat distribution [the waist-to-hip ratio (WHR)] and overall body fat [often estimated by the body mass index (BMI)]. However, none of these studies tell us directly which regions of the stimulus images inform observers' judgments. Therefore, we recorded the eye movements of three groups of 10 male observers and three groups of 10 female observers, when they rated a set of 46 photographs of female bodies. The first sets of observers rated the images for attractiveness, the second sets rated for body fat and the third sets for WHR. If either WHR and/or body fat is used to judge attractiveness, then observers rating attractiveness should look at those areas of the body which allow assessment of these features, and they should look in the same areas when they are directly asked to estimate WHR and body fat. So we are able to compare the fixation patterns for the explicit judgments with those for attractiveness judgments and infer which features were used for attractiveness. Prior to group analysis of the eye-movement data, the locations of individual eye fixations were transformed into a common reference space to permit comparisons of fixation density at high resolution across all stimuli. This manipulation allowed us to use spatial statistical analysis techniques to show the following: (1) Observers' fixations for attractiveness and body fat clustered in the central and upper abdomen and chest, but not the pelvic or hip areas, consistent with the finding that WHR had little influence over attractiveness judgments. (2) The pattern of fixations for attractiveness ratings was very similar to the fixation patterns for body fat judgments. (3) The fixations for WHR ratings were significantly different from those for attractiveness and body fat.     

Effects of gestational weight gain and body mass index on obstetric outcome

Abstract It is already known that maternal overweight, obesity, and morbid obesity are associated with adverse obstetric and neonatal outcomes. To assess the prevalence of overweight and obesity, and the impact of body mass index (BMI) on maternal and neonatal outcomes in Turkey. The study population consisted of 698 singleton pregnancies whose height and weight follow up were performed from the first trimester of pregnancy and whose deliveries were monitored in Trabzon, Turkey in July 2014–June 2015. The data obtained during the study were evaluated using SPSS 21 package program. The differences in variables were assessed by Chi-square-test for categorical data or by One-way Anova test for continuous data. The results were evaluated at a confidence interval of 95% and at a significance level of p?<?0.05. According to the BMI of the women in the study, 68.8% were in normal weight, 20.6% were overweight, 3.9% were obese, and the majority was in the 20–29 age group and 8–15.9?kg. The rate of cesarean, instrumental delivery, induction, episiotomy, late breastfeeding, low apgar (<7 at 5?min), neonatal intensive care unit admission requirement, the newborn at 4000?g or more in overweight (BMI 25–29.9) and obese (BMI?≥?30) pregnancies was higher and the first and second phases of labor were longer (p?<?0.05). The study showed that as the pre-pregnancy body mass index and gestational weight gain increased the rates of cesarean section and interventional delivery increased and the neonatal need for neonatal intensive care unit increased.     

The effect of VDR gene polymorphisms and vitamin D level on blood pressure,risk of preeclampsia,gestational age,and body mass index

We investigated the influence of vitamin D receptor (VDR) polymorphisms and vitamin D level on the blood pressure and the risk of preeclampsia. In a case-control study, 200 pregnant women, including 100 individuals with preeclampsia along with 100 healthy pregnant women, were studied for VDR FokI, TaqI, and BmsI polymorphisms and serum 25 (OH)-D level using polymerase chain reaction-restriction fragment length polymorphism method and commercial kit, respectively. The mean level of 25 (OH)-D in preeclamptic patients was significantly lower (16.6 ± 4.2 ng/mL, P < 0.001) compared with controls (19.6 ± 3.8 ng/mL). Among all women, a significantly higher systolic blood pressure and before-pregnancy body mass index and also lower gestational age were observed in the presence of 25 (OH)-D level < 20 ng/mL compared with the 20 to 30 ng/mL. A significantly higher frequency of VDR FokI C allele in preeclamptic patients (83%) than controls (74%) was associated with a 1.72-fold increased risk of preeclampsia. In all the studied individuals, the systolic and diastolic blood pressures were significantly higher in the presence of the FokI CC genotype compared with the TC and TT+TC genotypes. Neither VDR Taq1 nor VDR BmsI was associated with the risk of preeclampsia. The haplotype FokI C, TaqI C and BmsI A (CCA) compared with haplotype CTG increased the risk of preeclampsia by 1.4-fold (P = 0.33). Our study suggests an association between VDR FokI polymorphism and an insufficient serum level of 25 (OH)-D with the risk of preeclampsia and also the influence of insufficient 25 (OH)-D level and VDR FokI polymorphism on maternal factors, including blood pressure.     

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

Background

As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation.

Results

The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10⁻¹⁶) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10⁻¹⁸).

Conclusion

Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-368) contains supplementary material, which is available to authorized users.     

Identification of a novel duplication CFTRdup2 and functional impact of large rearrangements identified in the CFTR gene

The aim of this study was to investigate associations of two candidate gene SNPs of the endocannabinoid receptor type 1 gene (CNR1) with overweight, obesity and obesity-related traits in Chinese retired women. The study subjects were a subsample of the Taizhou Retiree Women Cohort, consisting of 2812 retired women aged 50-64 years recruited from Taizhou, Jiangsu, China. Neither rs2023239 nor rs806381 polymorphism was significantly associated with body mass index-defined overweight and obesity or waist-to-hip-ratio-defined obesity. For obesity-related traits, rs2023239 was significantly associated with glutamate pyruvate transaminase (GPT) (median, 18.00 vs 17.00 for TT and TC genotypes, respectively, P=0.043). The rs806381 also showed significant association with triglyceride (TG) (mean±SD, 1.46±0.20 vs 1.53±0.20 for GA and GG+AA genotypes, respectively, P=0.013) under the dominant genetic model. In conclusion, the rs2023239 and rs806381 polymorphisms of CNR1 were not associated with increased overweight and obesity risk. But the rs2023239 polymorphism was significantly associated with GPT, and the rs806381 polymorphism was significantly associated with TG.     

Association of P213S polymorphism of the L-selectin gene with type 2 diabetes and insulin resistance in Chinese population

Aims

L-selectin belongs to selectin family of adhesion molecule and participates in the generation and development of type 2 diabetes (T2D). In this study, we evaluated the relationship between the P213S polymorphism of L-selectin gene and T2D and insulin resistance in the Chinese population.

Methods

We genotyped P213S polymorphism in 801 patients with T2D and 834 healthy controls in the Chinese population using polymerase chain reaction–ligase detection reaction (PCR–LDR) technique. Plasma glucose, insulin, lipid, blood urea nitrogen, creatinine and uric acid levels were measured by biochemical technique.

Results

The frequency of 213PP genotype and P allele of the L-selectin gene in patients with T2D was significantly higher than that in controls (P = 0.007; P = 0.019, respectively). The relative risk of allele P suffered from T2D was 1.191 times higher than that of allele S. Moreover, the levels of FPG and HOMA-IR of PP and PS genotype carriers were significantly higher than those of SS genotype carriers in the T2D group (P < 0.05).

Conclusion

These findings indicated that the P213S polymorphism of L‐selectin gene may contribute to susceptibility to T2D and insulin resistance in the Chinese population, and P allele appears to be a risk factor for T2D.     

Significant associations of the rs2943634 (2q36.3) genetic polymorphism with adiponectin, high density lipoprotein cholesterol and ischemic stroke

Background

rs2943634 C/A single nucleotide polymorphism (SNP), located in a non coding region of chromosome 2q36.3, has been associated with coronary artery disease in two genome wide association studies. Our goal was to investigate its relation with myocardial infarction (MI) and ischemic stroke (IS), as well as with 12 intermediate risk phenotypes, in a population-based prospective cohort study.

Methods

rs2943634 was genotyped in a case-cohort study including a random sample of 1891 individuals (subcohort) and all incident MI (n = 211) and IS (n = 144) cases during a mean follow-up of 8.2 ± 2.2 years, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 27,548 middle-aged men and women.

Results

rs2943634 minor allele (A) was associated in an additive fashion with lower risk of IS but not with MI [hazard ratio (HR) = 0.66; 95% confidence interval (CI): 0.50-0.87; P = 0.003; HR = 1.02; 95% CI: 0.82-1.28; P = 0.83 respectively, for the age and sex adjusted model]. Furthermore, it was related to slightly higher levels of plasma adiponectin [CC 6.94, CA 7.27, AA 7.86 μg/ml, P = 0.0002] and high density lipoprotein (HDL)-cholesterol (CC 52.08, CA 53.05 and AA 55.27 mg/dl, P = 0.002), based on additive models. Adjustment for adiponectin and HDL-cholesterol did not attenuate the association between the SNP and IS risk. In contrast, adjustment for adiponectin abolished the association between the SNP and HDL-cholesterol and adjustment for HDL-cholesterol attenuated the association between the SNP and adiponectin.

Conclusions

Our findings suggest that rs2943634 is associated with IS risk and with plasma levels of HDL-cholesterol and adiponectin in this German population. Further investigations are needed to confirm these results and to clarify the mechanisms underlying the association.