Hagit Hochner

The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12–13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12–13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.

Associations of Maternal Prepregnancy Body Mass Index and Gestational Weight Gain With Adult Offspring Cardiometabolic Risk Factors The Jerusalem Perinatal Family Follow-Up Study

Background— Accumulating evidence demonstrates that both maternal prepregnancy body mass index (mppBMI) and gestational weight gain (GWG) are associated with adult offspring adiposity. However, whether these maternal attributes are related to other cardiometabolic risk factors in adulthood has not been comprehensively studied. Methods and Results— We used a birth cohort of 1400 young adults born in Jerusalem who had extensive archival data and clinical information at 32 years of age to prospectively examine the associations of mppBMI and GWG with adiposity and related cardiometabolic outcomes. Greater mppBMI, independently of GWG and confounders, was significantly associated with higher offspring BMI, waist circumference, systolic and diastolic blood pressures, insulin, and triglycerides and with lower high-density lipoprotein cholesterol. For example, the effect sizes were translated to nearly 5 kg/m2 higher mean BMI, 8.4 cm higher waist circumference, 0.13 mmol/L (11.4 mg/dL) higher triglycerides, and 0.10 mmol/L (3.8 mg/dL) lower high-density lipoprotein cholesterol among offspring of mothers within the upper mppBMI quartile (mppBMI >26.4 kg/m2) compared with the lower quartile (mppBMI <21.0 kg/m2). GWG, independently of mppBMI, was positively associated with offspring adiposity; differences of 1.6 kg/m2 in BMI and 2.4 cm in waist were observed when offspring of mothers in the upper (GWG >14 kg) and lower (GWG <9 kg) quartiles of GWG were compared. Further adjustment for offspring adiposity attenuated the observed associations to the null. Conclusions— Maternal size both before and during pregnancy is associated with cardiometabolic risk factors in young adult offspring. The associations appear to be driven mainly by offspring adiposity. Future studies that explore mechanisms underlying the intergenerational cycle of obesity are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions.

Association between number of children and mortality of mothers: results of a 37-year follow-up study

PURPOSE To examine the association between parity and long-term, all-cause mortality and mortality owing to specific causes in women. METHODS This prospective population-based study included 40,454 mothers who gave birth in Western Jerusalem, Israel, to 125,842 children and were followed for an average of 37 years after the birth of their first child. Cox proportional hazards models were used to evaluate long-term total and specific-cause mortality of women by their parity. RESULTS We found a U-shaped relationship between the number of offspring and risk of all-cause mortality in mothers. After adjustment for sociodemographic characteristics and maternal health and obstetric conditions, higher mortality rates were observed for mothers of 1 child (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.04-1.4), mothers of 5 to 9 children (HR, 1.21; 95% CI, 1.09-1.33), and mothers of 10 or more children (HR, 1.49; 95% CI, 1.12-1.99) compared with mothers of 2 to 4 children. Mortality risk from specific causes including coronary disease, circulatory disease, and cancer were increased for multiparous women. CONCLUSIONS In this long-term follow-up study, there was an association between number of children and mortality risk for mothers. These findings suggest that maternal pregnancies and postnatal characteristics as reflected by number of children may have consequences for long-term maternal health.

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.

Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13.

Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders characterised by adult-onset, slowly progressive distal and proximal muscle weakness and typical muscle pathology. Previously, we have mapped the gene responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the interval to one single YAC clone of 1 Mb in size. As a further step towards the identification of the HIBM gene, we have constructed a detailed physical and transcriptional map of this region. A high resolution BAC contig that includes the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed. This contig allowed the precise localisation of 25 genes and ESTs to the proximal region of chromosome 9. The expression pattern of those mapped genes and ESTs was established by Northern blot analysis. In the process of refining the HIBM interval, 13 new polymorphic markers were identified, of which 11 are CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map provides an important integration of physical and transcriptional information corresponding to chromosome 9p12-p13, which is expected to facilitate the cloning and identification not only of the HIBM gene, but also other disease genes which map to this region.

Establishment of the genomic structure and identification of thirteen single-nucleotide polymorphisms in the human RECK gene

The human RECK gene, mapped at 9p13→p12, is known as a tumor suppressor gene and as a key regulator of extracellular matrix integrity and angiogenesis. We have established the entire genomic structure of this gene, which spans more than 87 kb and consists of 21 exons and 20 introns, and identified thirteen single nucleotide polymorphisms (SNPs). Four SNPs were identified in the coding region of the gene (exons 1, 9, 13 and 15), and the remaining nine in introns 5, 8, 10, 12, 15 and 17. The availability of the genomic organization of the RECK gene and the identification of polymorphisms throughout its entire genome will facilitate the evaluation of its role in several disorders and also contribute to the assignment of genes to the several diseases mapped to this chromosomal region.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the ‘missing heritability’ of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug–gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug–single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Plasma vitamin D is associated with fasting insulin and homeostatic model assessment of insulin resistance in young adult males, but not females, of the Jerusalem Perinatal Study

OBJECTIVE To examine cross-sectional relationships between plasma vitamin D and cardiometabolic risk factors in young adults. DESIGN Data were collected from interviews, physical examinations and biomarker measurements. Total plasma 25-hydroxyvitamin D (25(OH)D) was measured using LC-tandem MS. Associations between 25(OH)D and cardiometabolic risk factors were modelled using weighted linear regression with robust estimates of standard errors. SETTING Individuals born in Jerusalem during 1974-1976. SUBJECTS Participants of the Jerusalem Perinatal Study (n 1204) interviewed and examined at age 32 years. Participants were oversampled for low and high birth weight and for maternal pre-pregnancy obesity. RESULTS Mean total 25(OH)D concentration among participants was 21·7 (sd 8·9) ng/ml. Among males, 25(OH)D was associated with homeostatic model assessment of insulin resistance (natural log-transformed, β=-0·011, P=0·004) after adjustment for BMI. However, these associations were not present among females (P for sex interaction=0·005). CONCLUSIONS We found evidence for inverse associations of 25(OH)D with markers of insulin resistance among males, but not females, in a healthy, young adult Caucasian population. Prospective studies and studies conducted on other populations investigating sex-specific effects of vitamin D on cardiometabolic risk factors are warranted.

Associations of maternal pre‐pregnancy and gestational body size with offspring longitudinal change in BMI

Studies demonstrate associations between changes in obesity‐related phenotypes and cardiovascular risk. Although maternal pre‐pregnancy BMI (mppBMI) and gestational weight gain (GWG) may be associated with adult offspring adiposity, no study has examined associations with obesity changes. Associations of mppBMI and GWG with longitudinal change in offsprings BMI (ΔBMI) were examined, and whether associations are explained by offspring genetics was assessed.

Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.

To study the risk factors associated with breast cancer in women younger than 40 years, a cohort study (The Jerusalem Perinatal Study) of 42 822 female offspring born in hospitals in West Jerusalem during 1964–1976 was carried out. Hazard ratios of potential parental and perinatal risk factors for early breast cancer were measured. The overall incidence of breast cancer was 5.2/100 000 person–years. The highest incidence was found among Jewish women of West Asian ancestry (8.6/100 000 person–years), specifically those whose maternal grandfathers were born in Iraq, Iran or Afghanistan (9.5/100 000 person–years). Using Cox models we found independent risk factors for early breast cancer to be paternal age (relative risk/year=1.06, 95% confidence interval=1.02–1.10, P=0.005), and ancestry from Iraq/Iran/Afghanistan (relative risk=3.1, 95% confidence interval=1.50–6.52, P=0.002). The study confirms a previously observed effect of advanced paternal age on the occurrence of early breast cancer and identifies a novel population group at increased risk for the disease. The excess risk of early breast cancer associated with ancestry from Iraq, Iran and Afghanistan suggests involvement of genetic determinants, environmental exposures and/or lifestyle factors and mandates further investigation.