Showing papers by "Ranjan Deka published in 2018"

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Abstract: Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

Abstract: The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand. Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis. For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 × 10−6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 × 10−6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (β = 0.012 mmol/l, pcorrected = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59). Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.

Impact of gestational weight gain and prepregnancy body mass index on the prevalence of large-for-gestational age infants in two cohorts of women with type 1 insulin-dependent diabetes: a cross-sectional population study.

Abstract: Objectives Despite improvements in treatment modalities, large-for-gestational age (LGA) prevalence has remained between 30% and 40% among infants of mothers with type 1 insulin-dependent diabetes mellitus (TIDM). Our objective was to estimate LGA prevalence and examine the association between gestational weight gain (GWG) and prepregnancy body mass index (BMI) with LGA among mothers with TIDM. Design Cross-sectional study. Setting Regional data in Cincinnati, Ohio, from the Diabetes in Pregnancy Program Project (PPG), a prospective cohort for the period 1978–1993; national data from Consortium on Safe Labor (CSL), a multicentre cross-sectional study for the period 2002–2008. Participants The study included 333 pregnancies in the PPG and 358 pregnancies in the CSL. Pregnancies delivered prior to 23 weeks’ gestation were excluded. Women with TIDM in the PPG were identified according to physician confirmation of ketoacidosis, and/or c-peptide levels, and by International Classification of Diseases, ninth version codes within the CSL. LGA was identified as birth weight >90th percentile according to gestational age, race and sex. Main outcome measures LGA at birth. Results Mean±SD maternal age at delivery was 26.4±5.1 years for PPG women and 27.5±6.0 years for CSL women, p=0.008. LGA prevalence did not significantly differ between cohorts (PPG: 40.2% vs CSL: 36.6%, p=0.32). More women began pregnancy as overweight in the later cohort (PPG (16.8%) vs CSL (27.1%), p Conclusions Normal-weight women with GWG within IOM guidelines experienced a lower LGA prevalence, supporting the importance of adherence to IOM guidelines for GWG to reduce LGA. High BMI and GWG may be hindering a reduction in LGA prevalence.

Assessing the Impact of Excessive Gestational Weight Gain Among Women With Type 1 Diabetes on Overweight/Obesity in Their Adolescent and Young Adult Offspring: A Pilot Study.

Abstract: Aims/hypothesis: We sought to determine the impact of intrauterine exposure to excessive gestational weight gain (GWG) on overweight/obesity in adolescent/young adult offspring of women with type 1 diabetes mellitus (TIDM). Methods: In 2008, a pilot study was conducted among 19 randomly-selected adolescent and adult offspring of mothers with TIDM who participated in the Diabetes in Pregnancy Program Project (DiP) between 1978 and 1995. Body mass index (BMI)-specific Institute of Medicine (IOM) guidelines for gestational weight gain (GWG) were defined as: 12.5-18.0 kilograms (kg) GWG; 11.5-16.0 kg GWG: 7.0-11.5 kg GWG; 5.0-9.0 kg GWG, for women classed as underweight, normal, overweight and obese according to pre-pregnancy BMI, respectively. Generalized estimating equations were used to estimate adjusted odds ratios (aOR, [95% confidence intervals, CI]) for overweight/obesity among offspring, related to IOM adherence, adjusting for pre-pregnancy BMI and mean maternal daily insulin units/kg body weight. Results: Mean age of offspring at follow-up was 20.3 ± 3.3 years, 12(63%) were male, 4(21%) Black and 12(63%) overweight/obese. There were 9(82%) overweight/obese offspring among the 11 mothers who exceeded IOM guidelines for GWG compared with 3(38%) overweight/obese offspring among the 8 mothers with GWG within guidelines. Exceeding vs. adhering to IOM guidelines (OR = 7.50, [95%CI: 0.92-61.0]) and GWG per kilogram (OR = 1.39, [95%CI: 0.98-1.97]) were associated with offspring overweight/obesity at follow-up. Conclusions/interpretation: Our pilot study suggests potential long-term implications of excessive GWG on metabolic health in offspring of mothers with TIDM, warranting future research examining the health impact of GWG in this population.

Genome-wide association studies in Samoans give insight into the genetic architecture of fasting serum lipid levels

Abstract: The current understanding of the genetic architecture of lipids has largely come from genome-wide association studies To date, few studies have examined the genetic architecture of lipids in Polynesians, and none have in Samoans, whose unique population history, including many population bottlenecks, may provide insight into the biological foundations of variation in lipid levels Here we performed a genome-wide association study of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2,849 Samoans, with validation genotyping for associations in a replication cohort comprising 1,798 Samoans and American Samoans We identified multiple genome-wide significant associations (P