Browsing by Author "Ralhan, S."

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Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India
(American Diabetes Association Inc., 2013) Saxena, R.; Saleheen, D.; Been, L.F.; Garavito, M.L.; Braun, T.; Bjonnes, A.; Young, R.; Ho, W.K.; Rasheed, A.; Frossard, P.; Sim, X.; Hassanali, N.; Radha, V.; Chidambaram, M.; Liju, S.; Rees, S.D.; Ng, D.P.-K.; Wong, T.-Y.; Yamauchi, T.; Hara, K.; Tanaka, Y.; Hirose, H.; McCarthy, M.I.; Morris, A.P.; Basit, A.; Barnett, A.H.; Katulanda, P.; Matthews, D.; Mohan, V.; Wander, G.S.; Singh, J.R.; Mehra, N.K.; Ralhan, S.; Kamboh, M.I.; Mulvihill, J.J.; Maegawa, H.; Tobe, K.; Maeda, S.; Cho, Y.S.; Ta
We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10-3) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10-4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 ? 10-8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10-3) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10-4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10-5 to < 10-7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. ? 2013 by the American Diabetes Association.
Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study
(Elsevier Ltd, 2016) Sapkota, B.R.; Hopkins, R.; Bjonnes, A.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.R.; Blackett, P.R.; Saxena, R.; Sanghera, D.K.
Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P < 10-4) using an independent replication sample (n = 2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [? = -0.13, p = 4.47 ? 10-9] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [? = 0.90; p = 1.36 ? 10-6] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p = 0.007) and CYP2R1 (p = 0.019) reported in Europeans and the DAB1 (p = 0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities. ? 2015 Elsevier Ltd. All rights reserved.
A low frequency variant within the GWAS locus of MTNR1B affects fasting glucose concentrations: Genetic risk is modulated by obesity
(2012) Been, L.F.; Hatfield, J.L.; Shankar, A.; Aston, C.E.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.R.; Mulvihill, J.J.; Sanghera, D.K.
Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), ?-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low ? 25 kg/m2 and high > 25 kg/m2) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (? = -0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (? = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation. ? 2011.
PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes mellitus risk in Asian Indian Sikhs: Pro12Ala still remains as the strongest predictor
(2010) Sanghera, D.K.; Demirci, F.Y.; Been, L.; Ortega, L.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.; Aston, C.E.; Mulvihill, J.J.; Kamboh, I.M.
We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated receptor-? transcripts 1 and 2 (PPARG1 and 2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes mellitus (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic controls were examined for association with T2D and other subphenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D (odds ratio, 0.13; 95% confidence interval, 0.03-0.56; P = .0007), no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the 2 marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of 1 "risk" (CGC) (P = .003, permutation P = .015) and 1 "protective" (CAC) (P = .001, permutation P = .005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala, as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (P = .262). In addition, 2-site haplotype analysis in the ADIPOQ locus using only 2 marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (P = .009, permutation P = .026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (P = .010), waist (P = .024), and hip (P = .021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to the risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine the true physiologic significance of these loci in T2D and obesity. ? 2010 Elsevier Inc. All rights reserved.
Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US
(2011) Been, L.F.; Ralhan, S.; Wander, G.S.; Mehra, N.K.; Singh, J.; Mulvihill, J.J.; Aston, C.E.; Sanghera, D.K.
Background: Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.Methods: We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.Results: Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 ? 10-4in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).Conclusions: Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through ? cell function. ? 2011 Been et al; licensee BioMed Central Ltd.