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Does excess weight affect gout risk differently among genetically predisposed individuals? Sex-specific prospective cohort findings over >26 years


Chio Yokose (1,2); Natalie Mccormick (1,2,3); Na Lu, (3,4); Amit D. Joshi, Mbbs (5); Hyon K. Choi (1,2,3,4)



1. Division Of Rheumatology, Allergy, And Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Ma, USA
2. Clinical Epidemiology Program, Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Ma, USA
3. Arthritis Research Canada, Richmond, British Columbia, Canada
4. Channing Division Of Network Medicine, Department Of Medicine, Brigham And Women’s Hospital, Harvard Medical School, Boston, Ma, USA
5. Clinical And Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Ma, USA



: Global burden of gout has increased substantially, particularly among women.1,2 Addressing obesity, a major modifiable risk factor for gout, may alleviate this burden; however, there is also a significant genetic contribution to gout risk according to the genome-wide association studies (GWAS).3,4 Genetic predisposition may modify the excess weight effect on gout risk. 

To investigate the potential role of genetic predisposition on the association between excess weight (i.e., BMI ≥ 25 kg/m2) and gout risk in two US prospective longitudinal cohorts over >26 years, stratified by sex.

We examined the association between excess weight and future risk of incident gout meeting the ACR survey criteria,5 according to genetic risk, in 18,512 women from the Nurses’ Health Study (NHS) over 32 years, and 10,917 men from Health Professionals Follow-Up Study (HPFS) over 26 years. We derived a genetic risk score (GRS) using 114 serum urate single nucleotide polymorphisms (SNPs) from the latest GWAS.3 We also calculated the population attributable risk (PAR) for excess weight according to GRS stratum.

We ascertained 530 incident gout cases in NHS and 983 in HPFS. While the relative risks (RRs) due to excess weight (overweight or obesity) appeared larger among women above the mean than below the mean, the RRs among men appeared similar according to genetic predisposition. The RRs among women for excess weight compared to normal were 1.66 (95% CI, 1.17 to 2.37) and 2.55 (1.95 to 3.34) below and above the mean GRS, respectively, whereas corresponding RRs among men were 1.68 (95% CI, 1.31 to 2.16) and 1.76 (1.47 to 2.10). Multiplicative interaction was borderline among women (P=0.06) and null among men (P=0.8); however, additive interaction on the absolute risk scale was significant, with the relative risk difference (RRD) between excess weight relative to normal being 0.69 and 2.38 respectively among women with GRS below and above mean, resulting in the relative excess risk due to interaction (RERI) of 1.69 (95% CI, 1.03 to 2.35) (P=5.4x10-7). For men, the corresponding RRDs were 0.70 and 1.46, with RERI = 0.76 (0.26, 1.25) (P = 2.6x10-3). Accordingly, excess weight accounted for a larger proportion of incident gout cases among women with GRS above the mean (PAR, 48.5% [95% CI, 38.8 to 55.9]) compared to those with GRS below the mean (PAR, 29.0% [95% CI, 10.5 to 42.1]) while the PARs among men were similar: 31.6% vs 29.7%, respectively. 

Conclusions: These large scale longitudinal prospective cohorts suggest maintaining healthy weight is an important gout prevention strategy, regardless of one’s underlying genetic risk. In genetically predisposed individuals, addressing excess weight may prevent a large proportion of gout cases, especially among women.

1. Safiri et al., PMID 32755051
2. Xia et al., PMID 31624843
3. Tin et al., PMID 31578528 
4. Tai et al., PMID: 32017447
5. Wallace et al., PMID: 856219