New Mexican Hispanic smokers have lower odds of COPD and less decline in lung function than non-hispanic whites

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1 New Mexican Hispanic smokers have lower odds of COPD and less decline in lung function than non-hispanic whites Shannon Bruse, Akshay Sood, Hans Petersen, Yushi Liu, Shuguang Leng, Juan C. Celedón, Frank Gilliland, Bartolomé Celli, Steven A. Belinsky, Yohannes Tesfaigzi ONLINE DATA SUPPLEMENT

2 Methods Random Sampling Approach for Matching on Smoking Intensity Further analyses were performed which matched the NHW and Hispanic sample on smoking intensity, then evaluated the association between ethnicity and COPD (GOLD). Smoking intensity was calculated as packs smoked per day while smoking or cumulative pack-years. The matching strategy was as follows: The Hispanic sample was divided into quartiles based on smoking intensity. NHW within the range of the quartiles set by the Hispanic sample were then randomly sampled, resulting in a NHW and Hispanic sample of the same size and with the same smoking intensity. To avoid a sampling bias, random sampling was repeated 1000 times, and for each random sampling the data was modeled using logistic regression to assess the association between ethnicity and COPD (GOLD). Verification for the Estimates for Genetic Ancestry The LSC contains a small number of Native American and African-American individuals with significant admixture (based on pilot STRUCTURE runs). Accurately estimating ancestral proportions using STRUCTURE is challenging if there are very few representatives of the parental population. Therefore, the final STRUCTURE runs were seeded using publicly available genotype data from Native American and African populations. We used the HapMap Yoruban sample containing 37 of the AIM SNPs genotyped in 153 individuals (1), and 14 AIM SNPs genotyped in 50 Pima and Maya individuals contained in the CEPH human diversity panel (2). Genotype data for the Yoruban and Pima/Maya populations was downloaded from the SPSmart database, from the HapMap and CEPH Stanford and Michigan datasets (3).

3 References E1. HapMap Homepage, Internet. Available from Nov. 11. E2. Cann HM, de Toma C, Cazes L, Legrand MF, Morel V, Piouffre L, Bodmer J, Bodmer WF, Bonne-Tamir B, Cambon-Thomsen A, Chen Z, Chu J, Carcassi C, Contu L, Du R, Excoffier L, Ferrara GB, Friedlaender JS, Groot H, Gurwitz D, Jenkins T, Herrera RJ, Huang X, Kidd J, Kidd KK, Langaney A, Lin AA, Mehdi SQ, Parham P, Piazza A, Pistillo MP, Qian Y, Shu Q, Xu J, Zhu S, Weber JL, Greely HT, Feldman MW, Thomas G, Dausset J, Cavalli-Sforza LL. A human genome diversity cell line panel. Science (New York, NY 2002;296: E3. Amigo J, Salas A, Phillips C, Carracedo A. Spsmart: Adapting population based snp genotype databases for fast and comprehensive web access. BMC Bioinformatics 2008;9:428.

4 Table E1: AIM SNPs used in study and allele frequencies in relevant populations Stanford HapMap (release #28) CEPH AIM SNP Alleles Reference Allele YRI* CHB* CEU* Pima/Maya rs AC C NA** rs CG C NA rs AC A rs CG C NA rs AG A NA rs AG A rs AG A rs CG C NA rs AT A NA rs CG C NA rs CT C NA rs CG G NA rs CT C rs CT C NA rs AG G NA rs AG G rs CT C NA rs AG A rs CT T NA rs CG C NA rs CT NA NA NA NA NA rs CT T rs CT T rs AG A NA rs25095 AG A NA rs AG A NA rs CG G NA rs3055 CT T NA rs CG G NA rs AG G rs AG A NA rs AG NA NA NA NA NA rs AC C rs AT A NA rs CT NA NA NA NA NA rs CT NA NA NA NA NA rs AG G NA rs AT T NA rs AG A NA rs CG G NA rs AG G NA rs AG G rs AG G rs AG NA NA NA NA NA rs CT T NA rs AC C rs CT T rs CG G NA Note 1: YRI=Yoruban, CHB=Han Chinese, CEU=European, PM=Pima/Maya Note 2: NA=Data not available from SPSmart database

5 Table E2: Delta values* of AIM SNPs in relevant populations AIM SNP YRI-CEU YRI-CHB YRI-PM CEU-CHB CEU-PM rs NA 0.10 NA rs NA 0.00 NA rs rs NA 0.48 NA rs NA 0.22 NA rs rs rs NA 0.23 NA rs NA 0.07 NA rs NA 0.34 NA rs NA 0.49 NA rs NA 0.20 NA rs rs NA 0.17 NA rs NA 0.05 NA rs rs NA 0.22 NA rs rs NA 0.59 NA rs NA 0.22 NA rs NA NA NA NA NA rs rs rs NA 0.03 NA rs NA 0.08 NA rs NA 0.28 NA rs NA 0.05 NA rs NA 0.68 NA rs NA 0.26 NA rs rs NA 0.64 NA rs NA NA NA NA NA rs rs NA 0.11 NA rs NA NA NA NA NA rs NA NA NA NA NA rs NA 0.10 NA rs NA 0.16 NA rs NA 0.24 NA rs NA 0.30 NA rs NA 0.13 NA rs rs rs NA NA NA NA NA rs NA 0.12 NA rs rs rs NA 0.41 NA Note 1: YRI=Yoruban, CHB=Han Chinese, CEU=European, PM=Pima/Maya Note 2: NA=Data not available from SPSmart database *Delta values are the absolute values of allele frequency differences between two populations, and are a measure of the informativeness of each AIM SNP.

6 Table E3: Odds ratios for predictors of COPD (LLN) in univariate and multivariable analysis of Hispanic (n=369) and NHW (n=1,580) individuals Univariate Multivariable Lower Upper Lower Upper Categorical OR p-value OR p-value Hispanic Ethnicity < Male Gender Not current smoking Education<HS Height (in) Pack years (10 yrs) < <0.001 BMI (kg/m 2 ) < <0.001 Age (10 yrs) < <0.001 *Total n=1,949; analysis includes all Hispanic and NHW with available baseline data

7 Table E4: Prevalence ratios for COPD (GOLD) using self-reported ethnicity in analysis of Hispanic (n=369) and NHW (n=1,580) individuals Categorical PR Univariate Lowe Upper r p- value PR Multivariable Lower Upper p-value Hispanic Ethnicity < <0.001 Male Gender < <0.001 Not currently smoking Education<HS Height (in) < Pack years (10 yrs) < <0.001 BMI (kg/m 2 ) < <0.001 Age (10 yrs) < <0.001 *Total n=1,949; analysis includes all Hispanic and NHW with available baseline data Table E5: Odds ratios for predictors of moderate to severe COPD in multivariable analysis of Hispanic (n=369) and NHW (n=1,580) individuals Multivariable, GOLD Stage 2-4 Categorical OR Lower Upper p-value Hispanic ethnicity <0.001 Male Gender Not current smoking Education<HS Height (in) Pack years (10 yrs) <0.001 BMI (kg/m 2 ) <0.001 Age (10 yrs) <0.001 *Total n=1,949; analysis includes all Hispanic and NHW with available baseline data **GOLD Stage 0 and 1 were defined as unaffected; GOLD Stage 2-4 were defined as affected

8 Table E6. Odds ratios for predictors of COPD (GOLD) in multivariable, gender stratified analyses Males (n=453) Females (n=1496) Categorical OR Lowe Upper Lower Upper p-value OR r p-value Hispanic Ethnicity <0.001 Not current smoking Education<HS Height (in) Pack years (10 yrs) < <0.001 BMI (kg/m 2 ) <0.001 Age (10 yrs) < <0.001 *Total n=453 for analysis of males; total n=1496 for analysis of females Table E7. Point estimates for predictors of ml per year decline of absolute FEV 1 in univariate and multivariable analysis in self-identified Hispanic (n=171) and NHW (n=895) individuals Univariate Multivariable Categorical PE Lower Upper p-value PE Lower Upper p- value Hispanic Ethnicity Male Gender Not smoking at baseline Education<HS Height (per in) <0.001 Pack years (10 yrs) BMI (per kg/m2) Age (10 yrs) <0.001 Baseline FEV1 (100mL) < <0.001 *Total n=1,066; analysis includes all Hispanic and NHW with available longitudinal data **Positive value represents less decline and negative value represents greater decline

9 Table E8: STRUCTURE estimated Native American proportions as a predictor selfidentified ethnicity as a predictor of categorical and quantitative pulmonary outcomes for Hispanic (n=305) relative to NHW (n=1404) individuals Categorical Outcomes OR* CI p -value COPD (LLN) COPD (GOLD) <0.001 Chronic Bronchitis Quantitative Outcomes PE SE p-value FEV1 % predicted FEV1/FVC <0.001 *Total n=1,709 for each outcome analyzed; analysis includes all Hispanic and NHW with available baseline and AIM data **Represents the odds ratio or point estimate for Hispanics compared to NHWs ***Odds ratios and point estimates for each outcome presented are derived from multivariable analysis as outlined in Methods Table E9. Point estimates for predictors of ml per year decline of absolute FEV 1 in univariate and multivariable analysis of Hispanic (n=169) and NHW (n=891) individuals Univariate Lower Upper p- value Multivariable Lower Upper p-value Categorical PE PE NA Genetic Ancestry 72.94** ** Male Gender Not smoking at baseline Education<HS Height (per in) Pack years (10 yrs) BMI (per kg/m2) Age (10 yrs) <0.001 Baseline FEV1 (100mL) < <0.001 *Total n=1060; analysis includes all Hispanic and NHW with available longitudinal and AIM data ** This point estimates for ml per year decline represents the reduction in decline when NA genetic ancestry proportion is increased by 0.32; this is the mean difference in NA genetic ancestry between Hispanics and NHW

10 Table E10: Odds ratios of COPD (GOLD) in self-identified Hispanics only subset with high (n=152) and low (n=153) Native American genetic ancestry** Multivariable Categorical OR Lower Upper p-value High NA genetic ancestry** Male Gender Not current smoking Education<HS Height (in) Pack years (yrs) BMI (kg/m 2 ) Age (yrs) <0.001 *Total n=305; analysis includes all Hispanics with available baseline and AIM data **Hispanics were dichotomized into high and low Native American (NA) genetic ancestry with mean NA genetic ancestry as the cut point

11 Figure E1 The clusters were likely defining European (blue), African (red), and Native American (green) ancestral populations. As a control for this assumption, the allele frequencies in each STRUCTURE-defined cluster (from runs not seeded with Yoruban and Pima/Maya data) were compared with allele frequencies in African, European, and Native American populations in the HapMap and CEPH datasets (Figure S1). Comparison of allele frequencies of 14 SNPs in these three ancestry groups as found in public genotype data (HapMap and CEPH) (Figure S1, part A) and from STRUCTURE-defined clusters (Figure S1, part B) were similar, supporting the assumption that African, European, and Native American proportions were correctly estimated. Modest differences between allele frequencies in STRUCTURE clusters and the CEPH and HapMap populations are expected given the small and highly admixed African American and Native American samples used in our unseeded STRUCTURE runs. Figure E1: Comparison of allele frequencies in STRUCTURE defined population clusters with HapMap data. Unseeded STRUCTURE runs were performed using all 48 AIM SNPs. The 14 AIM SNPs with publicly available Pima/Maya genotype data were assessed for correlation of allele frequencies between cluster defined populations and HapMap and CEPH genotype data. (A) Allele frequencies for public genotype data were obtained from Yoruban Nigerian (YRI), Pima/Maya, and European (CEU) populations. (B) Allele frequencies from STRUCTURE defined clusters were obtained from runs not seeded with Yoruban or Pima/Maya genotype data, and are assumed to represent European, African, and Native American genetic ancestry.