Matching on Race and Ethnicity in Case-Control Studies as a Means of Control for Population Stratification

Chokkalingam, Anand P.; Aldrich, Melinda C.; Bartley, Karen; Hsu, Ling‐I; Metayer, Catherine; Barcellos, Lisa F.; Wiencke, John K.; Buffler, Patricia A.; Selvin, Steve

doi:10.4172/2161-1165.1000101

Cited by 9 publications

(18 citation statements)

References 11 publications

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“…In addition, the extent of genetic admixture was assessed using a series of 80 ancestry informative markers for a subset of the cases and controls included in this study. 48 Estimates of genetic ancestry (percent of European, Amerindian, and African ancestry) were determined with these ancestry informative markers, and comparison of these estimates between cases and controls showed no significant differences (data not shown). 48 Potential selection biases resulting in systematic differences between cases and controls should be considered.…”

Section: Discussionmentioning

confidence: 99%

“…48 Estimates of genetic ancestry (percent of European, Amerindian, and African ancestry) were determined with these ancestry informative markers, and comparison of these estimates between cases and controls showed no significant differences (data not shown). 48 Potential selection biases resulting in systematic differences between cases and controls should be considered. In the NCCLS, population-based controls are selected from the statewide birth registry among all children born within the study region.…”

Section: Discussionmentioning

confidence: 99%

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HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Urayama

Chokkalingam

Metayer

et al. 2012

Blood

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The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only nonHispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Urayama

Chokkalingam

Metayer

et al. 2012

Blood

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“…We have previously demonstrated the validity of self-reported ethnicity as a measure of genetic ancestry in CCLS (24). …”

Section: Methodsmentioning

confidence: 99%

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution

et al. 2015

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Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases=1464, Ncontrols=3279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European-ancestry (OR=2.99; P=1.51×10−9) and Hispanic children (OR=2.77; P=3.78×10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial=0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.

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“…However, the effect is likely to be minimal in the CCLS due to the careful matching of race and ethnicity obtained from the subjects (52). Further, we used a principal components analysis (PCA) to successfully reduce the effects of potential population stratification (genomic control factor λ = 1.02) ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

Hsu

Chokkalingam

Briggs

et al. 2015

Cancer Causes Control

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Background Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on: IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early life infections (presence of older siblings, daycare attendance, and ear infections). Methods Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study (CCLS) were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated for each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early life infections using logistic regression models that included an interaction term. Results Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified; rs7780012, OR=0.50, 95% confidence interval (CI): 0.35-0.71 (p=0.004); rs7089424, OR=2.12, 95% CI: 1.70-2.65 (p=1.16 x 10-9); rs4982731, OR=1.69, 95% CI: 1.37-2.08 (p=2.35 x 10-6), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early life infections with ALL risk was not observed. Conclusions Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Impact Results implicate the ARID5B, CEBPE and IKZF1 genes in the pathogenesis of childhood ALL.

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Matching on Race and Ethnicity in Case-Control Studies as a Means of Control for Population Stratification

Cited by 9 publications

References 11 publications

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

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