Nir Sharon

Phenotypic and genetic variation in leptin as determinants of weight regain

Aims:Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention.Subjects and methods:In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the ‘weight loss phase’ (0–6 months) and the ‘weight maintenance/regain phase’ (7–24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP).Results:Mean weight reduction was −5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7–24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (β=−0.222, P-value=0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (β=0.505, P-value<0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (β=−0.131, P-value<0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1–4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval −1.1 to 1.4)); P-value<0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P=0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%.Conclusion:Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.

Obesity and Blood Pressure in 17-Year-Old Offspring of Mothers with Gestational Diabetes: Insights from the Jerusalem Perinatal Study

Objective. Gestational diabetes mellitus (GDM) influences fetal development and offsprings metabolic risk. We evaluated this association in 17-year-old offspring adjusting for birth weight (BW) and prepregnancy maternal BMI (mBMI). Study Design. The JPS birth cohort contains extensive data on 92,408 births from 1964 to 1976. Offsprings BMI and blood pressure (BP) were obtained from military records. For a subcohort born between 1974 and 1976, prepregnancy mBMI was available. Offspring were classified as born to mothers with GDM (n = 293) or born to mothers without recorded GDM (n = 59,499). Results. GDM offspring had higher mean BMI and systolic and diastolic BP compared to no-recorded-GDM offspring. After adjusting for BW, GDM remained significantly associated with offspring BMI and diastolic BP (β = 1.169 and 1.520, resp.). In the subcohort, when prepregnancy mBMI was entered to the models, it markedly attenuated the associations with GDM. Conclusions. Maternal characteristics have long-term effects on cardiometabolic outcomes of their offspring aged 17 years.

Beginning IVF Treatments After Age 30 Increases the Risk of Breast Cancer: Results of a Case–Control Study

Abstract:  The long‐term risks of in vitro fertilization (IVF) treatment remain unclear. This study was designed to determine breast cancer risk factors in women who underwent IVF, and to establish characteristics of these tumors. Records of 7,162 consecutive women who underwent IVF at a single center between 1984 and 2002 were linked with the Israel Cancer Registry to identify women who developed breast cancer. IVF‐related parameters were compared between 28 breast cancer patients who had undergone IVF (IVF BC) and for whom complete IVF data were available with 140 women who underwent IVF and did not develop breast cancer (IVF non‐BC). Tumor parameters were compared between 38 patients who developed breast cancer after IVF and 114 age‐matched breast cancer patients who did not undergo IVF (non‐IVF BC). Age over 30 at the time of first IVF treatment, even after controlling for age at first birth, was the only parameter significantly associated with increased breast cancer risk (RR = 1.24, p = 0.02, 95% CI = 1.03–1.48). There were no differences between IVF‐BC and IVF non‐BC patients in all other IVF‐related parameters. The only statistically significant difference in tumors developing in IVF‐BC patients compared with non‐IVF BC patients was in grade distribution, particularly for grade II tumors. However, the significance of such a difference is unclear. Women who start IVF after the age of 30 appear to be at increased risk of developing breast cancer. The characteristics of breast tumors in women who underwent IVF are no different than in patients without previous exposure to IVF.

Cholesteryl Ester transfer Protein (CETP) Genetic Variation and Early Onset of Non-Fatal Myocardial Infarction

Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early‐onset non‐fatal MI risk in a population‐based case‐control study from western Washington State.

Estrogen receptor beta gene variant is associated with vascular dementia in elderly women.

OBJECTIVE Alzheimers disease (AD) and vascular dementia (VaD) are the main causes of dementia. Postmenopausal estrogen deficiency was suggested as a contributor to cognitive decline; however, replacement therapy failed to prove beneficial in its prevention or therapy. Sequence variants in the estrogen receptor alpha gene (ESR1) and beta gene (ESR2) may alter the effects of estrogen. METHODS This is a case-control association study of sporadic AD, VaD, and single-nucleotide polymorphisms in ESR1 (rs2234693 and rs9340799), the TA dinucleotide repeat in the ESR1 promoter, and the rs4986938 single-nucleotide polymorphism in ESR2. Two hundred forty-six women (118 AD, age 83 +/- 7; 60 VaD, age 82 +/- 6; and 68 cognitively intact, age 81 +/- 7) residing in nursing homes were studied. The association of genotypes and AD or VaD was determined by logistic regression analysis adjusted for age and ethnic origin. RESULTS An association of VaD and ESR2 rs4986938 was found. Carriers of each A allele had a 1.7 increased risk compared to carriers of the G allele (odds ratio 1.71, 95% confidence interval 1-2.95). The ApoE epsilon 4 allele was associated with AD (odds ratio 3.35, confidence interval 1.44-7.82), but not with VaD. No association of AD or VaD with ESR1 genotypes or haplotypes was detected. CONCLUSIONS The ESR2 rs4986938 polymorphism is associated with susceptibility for VaD in elderly Jewish women. These results need to be confirmed in replicate studies in other populations.

Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease.

SummaryObjectives:Fabry disease is a multisystem disorder with phenotypic heterogeneity only partially explained by genotype. Elevated interleukin-6 (IL-6) plasma levels and C-reactive protein (CRP) serum levels are associated with increased risk and worse outcome of ischaemic events, a serious prognostic sign in Fabry disease.Methods:56 patients (34 hemizygous males, 22 females; 5 children) were studied. A promoter polymorphism −174G > C of the IL-6 gene associated with serum IL-6 levels was compared with the Mainz Severity Score Index (MSSI) in patients with Fabry disease. CRP levels and polymorphism 1059 G > C were evaluated as markers of inflammation to ascertain the possibility of an inflammatory mechanism of IL-6. Nonparametric ANOVA, Fisher’s exact, Bonferroni, and Hardy–Weinberg (HW) statistics were used.Results:Mean age of adults = 42 (range 26–58) years; 29 patients received enzyme therapy (ERT). Mean total MSSI = 26.7 (range 14.2–39.2) points, i.e. moderate disease, but females were lower (total 23.4 ± 12.6 vs 32.2 ± 13.6). Controls but not patients were in HW equilibrium. Significant correlation existed between all sub-scores of the MSSI and IL-6 genotypes in females but only with three MSSI sub-scores for males. The IL-6 C/C genotype was significantly correlated with the neurological, general and total MSSI sub-scores, generally twofold higher. There were no statistically significant correlations with CRP levels/polymorphisms and MSSI sub-scores nor with IL-6 polymorphisms. CRP levels decreased after ERT in patients with IL-6 G/G or G/C genotypes but increased in patients with C/C (p = 0.003).Conclusions:The prevalence of the IL-6 C allele significantly influences MSSI, i.e. clinical severity, especially in females. This is unrelated to IL-6 as a pro-inflammatory marker as demonstrated by lack of correlations with CRP levels and genotypes. IL-6 −174 polymorphic C allele may be a prognostic marker in Fabry disease, especially in females.

Effects of the single nucleotide polymorphism at MDM2 309 on breast cancer patients with/without BRCA1/2 mutations

BackgroundA germ line single nucleotide polymorphism (SNP) in the first intron of the gene encoding MDM2 at position 309, an important modulator of p53, has been described. BRCA1/2 mutation have been associated with increased rates of breast cancers with mutated P53. It was shown that the presence of MDM2 309 SNP correlated with younger cancer onset age in individuals with a p53 mutations. The differential effects of this SNP were also linked to estrogen receptor activation. Here we report on our study of 453 Ashkenazi breast cancer patients of whom 180 were positive for the known Ashkenazi BRCA1/2 mutationsMethodsDNA from breast cancer patients was obtained for analysis of one of the three common BRCA1/2 mutations and MDM2 SNP309. Data regarding cancer onset and death ages was obtained from our database and Statistical analysis was performed using the SPSS® statistical package (SPCC Inc., Chicago, IL), and JMP® software (SAS Institute, Cary, NC).ResultsThe percentage of MDM2 SNP309 in control and BRCA 1/2 population which is similar to that reported for other Jewish Ashkenazi populations at 52.2% for the heterozygotes and 25.0% for MDM2SNP309G/G and 22.8% for MDM2SNP309T/T.There was not a statistical significant difference in median age of disease onset in the different MDM2 SNP309 subgroups of the BRCA1/2 carriers. When we further divided the group into under and above 51 years old ( presumed menopause age) in the BRCA1 positive subset we found that there were less patients of the MDM2SNP309 G/G versus the MDM2SNP309 T/T in the over 51 patient group (p = 0.049). This result has been obtained in a relatively small subgroup and is of borderline statistical significance. Interestingly, in the BRCA1/2 mutation carriers, we found a survival advantage for patients harboring the SNP309 G/G genotype (p = 0.0086) but not for the 272 patients not harbouring this mutations.ConclusionMDM2SNP309G/G main effect on BRCA1/2 positive mutation carriers is linked to its effect on patients survival. Further research is needed in order to understand the reason for this difference.

Leptin, Insulin, and Obesity-related Phenotypes: Genetic Influences on Levels and Longitudinal Changes

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity‐related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8–10 years apart. We estimated that polygenes explained 30–50% of the adjusted leptin and insulin levels and 30–70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h2 = 0.45) and small‐to‐moderate heritability estimates for changes in insulin and other obesity‐related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20–30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20–25% of the additive genetic variance in insulin—anthropometric pairs of variables.

Genetic polymorphisms of vitamin D receptor (VDR) in Fabry disease

Fabry disease, an X-linked inborn error of metabolism, is characterized by multi-organ involvement including cardiac signs of left ventricular hypertrophy and abnormal intima-medial (IMT) thickening of arteries, progressive renal failure, neurological involvement, and more. The vitamin D receptor (VDR) and an enzyme producing vitamin D3 result in an autocrine loop with direct effects on blood vessels. The purpose of this study is to assess VDR polymorphisms (BsmI, FokI, ApaI, and TaqI) relative to clinically important disease parameters using a disease-specific severity score (MSSI) and haplotype analysis. There were statistically significant differences between females (43% of 74 patients) and males in MSSI total scores, and in general and neurologic sub-scores. There appears to be a protective effect of the TaqI tt genotype so that there were significantly lower scores in clinical categories between those with the tt genotype versus those with the TT genotype. Multivariate models of haplotypes with MSSI scores reveal that T-A-f-B and t-a-F-b haplotypes of the VDR gene polymorphisms are significantly associated with variation in the Fabry phenotype. Despite the limitations of using the MSSI score as a clinical correlate, these results are provocative and further studies in larger cohorts with more males are recommended.

Very high birth weight of offspring is associated with an increased risk of leukemia in their mothers: Results of a population-based cohort study

Although the association between birth weight and childhood leukemia is well described, the relation between a childs birth weight and parental risk of leukemia is unknown. We linked data from the Jerusalem Perinatal Study to the Israel Cancer Registry to ascertain the incidence of leukemia in mothers and fathers in relation to their offsprings birth weight. Birth weight >or=4500 g in any of the offspring was associated with a >3-fold risk of leukemia in mothers, but not fathers. Potential mechanisms include shared exposures of high birth weight infants and their mothers, possibly to radiation or growth factors, or genetic pathways leading to both high birth weight and leukemia.