P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,
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Transcript of P. Chandrasekaran , A. Shet, K. Ramesh, P.K.Bhavani,
High prevalence of PLIN gene & Metabolic risk factors among
Children initiating Antiretroviral therapy in south India
P. Chandrasekaran, A. Shet, K. Ramesh, P.K.Bhavani, R. Srinivasan, G. Sanjeeva, P. Gangadevi, E. Suresh,
C. Chandrasekar, C. Wanke, S. SwaminathanNational Institute for Research in Tuberculosis (ICMR), India
Introduction• Antiretroviral therapy
– Overall reduction of morbidity & mortality – lead to development of Metabolic syndrome /
HIV Associated Lipodystrophy Syndrome (HALS)
• Similar exposure to drugs, diet, socioeconomic status, not every child on ART develops HALS
• Host Genetic factors
Host Genetic factors & HALS• Polymorphisms in APOA5
APOC3, APOE & CETP• Perilipin gene (PLIN), major
protein coating intracellular lipid droplets , modulates adipocyte lipolysis
Arnedoa M et al.. Pharmacogenetics and Genomics 2007, Ordovas JM et al. Curr Opin Lipidol 2007; 18: 152Qi L et al. Clin Genet 2004;
• Minor allele at PLIN 11482 (G>A) is associated with higher risk of metabolic syndrome
- Higher TGL / Lower HDL-c / Higher insulin resistance• No Indian Studies
India “HALS” study• Prospective study • To determine the incidence
& risk factors of dyslipidemia, insulin resistance & body shape changes
• Children 2-12 years, initiating ART (2NRTI + 1 NNRTI)
• NIRT, Chennai & SJRI, B’lore
Objectives
• To assess the baseline risk factors of metabolic syndrome, namely blood lipid profile, glucose, insulin resistance and waist: hip ratio, among children before they initiate first-line antiretroviral therapy
• To look for the presence of polymorphisms of specific gene PLIN - associated with metabolic syndrome - in these children
Data collection• Anthropometry, body circumferences & skinfold
thickness • 24-hour dietary recall and Food security • Fasting blood for Serum lipids, Glucose, Insulin, high-
sensitivity C-reactive protein (hs-CRP) • CD4 cell count & HIV-1 viral load • PLIN Gene polymorphisms RT- PCR• Homeostatic model assessment-Insulin resistance
(HOMA-IR) estimated using the formula [fasting glucose (mg/dL) X insulin (uU/mL)]/405
Study population
• 218 Children living with HIV infection – mean age: 8 + 3 years (2-12years)– mean body weight : 18 + 6 kgs– mean CD4%: 15% (1-54%)– median viral load : 179,136 copies/ml (46,090 – 574,494)
• 60% WHO Clinical Stage III or above • 16% co-infected with Tuberculosis
Study population• 97% through Vertical Transmission
– Only 35% mothers diagnosed antenatal• 61% were vaccinated up-to-date
• 40% households food insecure– 15% in foster-care
• Triple drug therapy, with 2NRTI + 1NNRTI – Regimen containing d4T : 48 / AZT :154 / ABC 16
Nutritional IndicatorsNo. of Children
(n=218)Percentage
Stunting (HAZ < -2SD) 122 56%
Underweight (WAZ < -2SD) 129 59%
Wasting (WHZ < -2SD) 38 17%
• Stunting or chronic malnutrition reflects past shortage of food intake or chronic illness - negatively and irreversibly affects linear growth, organ growth & cognition
• Underweight – composite indicator of both past & present under nutrition (measure of MDG)
Risk Factors of Metabolic Syndrome 1. Fasting Blood Lipids
Parameters (mg/dl) Mean (SD) (n=218) Normal Range
Total Cholesterol 130 (35) 150-200
LDL-Cholesterol 78 (28) 100 – 129
HDL-cholesterol 29 (11) 40 - 60
Sr.Triglycerides 142 (71) 10 - 150
• Hypocholesterolemia seen in majority of CLHIV• 87% of children having low HDL-c• Serum Triglycerides > 150 mg/dl seen in 37% CLHIV• Waist: Hip ratio 0.96 (WNL)
Risk Factors of Metabolic Syndrome 2. Insulin Resistance
Blood Parameters Mean (SD) (n=218) Normal Range
Fasting Glucose 84.0 (14) 60 – 110Serum Insulin 8.2 (13) 5 – 20
C-reactive Protein 2.0 (3.1) <3.0 low riskHOMA-IR 1.8 (2.3) < 3.5
• HOMA-IR > 3.5 in 13% of children at baseline • hs-CRP of 3-10 mg/dl in 22%
- indicators of high risk for metabolic syndrome
3a. PLIN Gene PolymorphismsPLIN 11482G>A (rs894160) (n=189)
Parameters GG (n=86)Mean (SD)
GA + AA (n=103)Mean (SD)
P value
Age (years) 7.2 (3) 7.5 (3) 0.42Weight (kgs) 17.9 (6) 17.8 (6) 0.95Waist circum. 52.4 (7) 52.4 (7) 0.99
Triglycerides (mg/dl) 132.5 (69) 156.2 (78) 0.03Tot. Cholesterol 129.1 (38) 127.3 (28) 0.71HDL-c (mg/dl) 28.3 (11) 28.2 (11) 0.99
• PLIN 11482 minor allele (GA+AA) associated with significant higher sr. triglycerides level at baseline
Discussion• Even before ART initiation, risk factors for
Metabolic syndrome seen in HIV-infected ART-naive children in South India
– serum triglycerides > 150mg/dl : 81 children (37%)– HDL-cholesterol < 40mg/dl: 189 children (87%)– HOMA-IR > 3.5 : 29 children (13%) – hs-CRP 3-10mg/dl : 22% of children
Discussion• In our cohort of CLHIV, minor allele A at PLIN4
11482G>A, which is associated with increased risk of MS, seen in 55% (103/189) of children – At baseline, among those with raised triglycerides,
68% (50/74) had minor allele A– Among those with normal TGL 46% (53/113) had
minor allele A at PLIN4 11482G>A
• PLIN 6209T>C, PLIN13041A>G did not find any association in our cohort
Conclusion• Despite background of food insecurity and
malnutrition, substantial number of HIV-infected ART-naive children are at high risk for development of Metabolic Syndrome
• Given the relatively large number of carriers of genetic risk variants in this group, children with advanced disease need to be closely monitored for the development of MS, once ART is initiated
• Prevent long-term morbidities. Study is ongoing
AcknowledgementsTufts University, Boston• Dr. Christine A Wanke,• Dr. Jose OrdovasSt. John’s Research Institute, B’lore• Dr. Anita ShetIndira Gandhi Hospital, Bangalore• Dr. GN Sanjeeva
Ro1 AI084390
• All study participants• ART centre Medical Officers